1965-scott-geneticsandthesocialbehaviorofthedog.pdf: “Genetics and the Social Behavior of the Dog [Dog Behavior: The Genetic Basis]”, John Paul Scott, John L. Fuller (1965):
Classic study of dog behavior, the authoritative information from 20 years of research at the Jackson Laboratory. The authors synthesize developmental problems and canine genetics, based on study of 470 dogs. Central to the book is the role heredity plays in the development of behavior. Giving puppies an environment designed on the principles of a well-run school, Scott and Fuller tested five breeds representing the major dog groups and carried out a Mendelian experiment with two of the most different breeds: The basenji and the cocker spaniel. They found that heredity affects almost every trait tested; that gender affects aggressiveness and the dominance order, but not trainability and problem-solving; that emotional traits profoundly influence performance; that, although breeds differ widely in emotional and motivational characteristics, none shows distinct superiority in problem solving; and that detailed statistical analyses indicate a highly complex pathway between primary gene action and its final effect on behavior. Includes important information on rearing methods, the origin and history of dog breeds, basic behavior patterns and the psychological and behavioral development of puppies. Their careful scientific work demonstrated the importance and existence of time limited phases in the early life of dogs within which certain experiences need to occur or the dogs may be forever deficient. Their work (with that of Eckhard Hess’s on ducks and geese) demonstrated that these critical or sensitive periods in early development could be scientifically studied in ways compatible with a scientific psychology. This book will always be especially valuable to dog breeders and trainers; its last chapters summarize in very clear terms the particular phases in early development and experiences the dog needs to be adequately socialized. The reader can refer back to earlier chapters to get more information on how the experiments were conducted and the distribution of results. It answers questions on proper age that puppies can be separated from their mothers, what experiences are important to provide at what age, etc. Originally published in 1965. [ISBN: 0-226-74335-7]
1976-loehlin-heredityenvironmentandpersonality.pdf: “Heredity, Environment, & Personality: A Study of 850 Sets of Twins”, John C. Loehlin, Robert C. Nichols (1976):
This volume reports on a study of 850 pairs of twins who were tested to determine the influence of heredity and environment on individual differences in personality, ability, and interests. It presents the background, research design, and procedures of the study, a complete tabulation of the test results, and the authors’ extensive analysis of their findings. Based on one of the largest studies of twin behavior ever conducted, the book challenges a number of traditional beliefs about genetic and environmental contributions to personality development.
The subjects were chosen from participants in the National Merit Scholarship Qualifying Test of 1962 and were mailed a battery of personality and interest questionnaires. In addition, parents of the twins were sent questionnaires asking about the twins’ early experiences. A similar sample of nontwin students who had taken the merit exam provided a comparison group. The questions investigated included how twins are similar to or different from non-twins, how identical twins are similar to or different from fraternal twins, how the personalities and interests of twins reflect genetic factors, how the personalities and interests of twins reflect early environmental factors, and what implications these questions have for the general issue of how heredity and environment influence the development of psychological characteristics. In attempting to answer these questions, the authors shed new light on the importance of both genes and environment and have formed the basis for new approaches in behavior genetic research.
1986-provine.pdf: “Geneticists and Race”, William B. Provine (1986):
During the twentieth century, geneticists have dramatically changed their assessments of the biological and social consequences of human race differences and race crossing.
In the first quarter of the century, most geneticists thought that human races differed hereditarily by important mental as well as physical differences and that wide race crosses were biologically and socially harmful. The period from 1925 to the outbreak of World War II saw no change in geneticists’ views on hereditary mental differences between human races, but a shift to agnosticism on the issue of wide race crosses. By the early 1950s, geneticists generally argued that wide race crosses were at worst biologically harmless, but still held to earlier beliefs about hereditary mental differences between races. The final period from 1951 to the present has witnessed the shift to agnosticism on the issue of hereditary mental differences between races. The changes in geneticists’ assessments of race differences and race crossing were caused by increased understanding of the complex relationship between genes and environment and by cultural changes.
1993-lykken.pdf: “Heritability of interests: a twin study”, David T. Lykken, Thomas J. Bouchard, M. K. Mcgue, A Tellegen (1993):
The authors administered inventories of vocational and recreational interests and talents to 924 pairs of twins who had been reared together and to 92 pairs separated in infancy and reared apart. Factor analysis of all 291 items yielded 39 identifiable factors and 11 superfactors. The data indicated that about 50% of interests variance (about two thirds of the stable variance) was associated with genetic variation. The authors show that heritability can be conservatively estimated from the within-pair correlations of adult monozygotic twins reared together. Evidence for nonadditive genetic effects on interests may explain why heritability estimates based on family studies are so much lower. The authors propose a model in which precursor traits of aptitude and personality, in part genetically determined, guide the development of interests through the mechanisms of gene-environment correlation and interaction.
1994-koopmans.pdf: “Smoking and Sports Participation”, Judith R. Koopmans, Lorenz J. P. van Doornen, Dorret I. Boomsma (1994-01-01):
It has long been recognized that both smoking and sports participation tend to cluster in families. In this chapter, we first describe the current status of smoking and sports participation as cardiovascular risk factors. After an outline of the principles of the quantitative genetic approaches to the analysis of individual differences in behaviour, we will review the literature on genetic and environmental determinants of smoking and sports participation. In the second half of this chapter, results from the Dutch Twin/
Family Study of Health-Related Behavior are presented.
1999-stoolmiller.pdf: “Implications of the restricted range of family environments for estimates of heritability and nonshared environment in behavior-genetic adoption studies”, Mike Stoolmiller (1999-07-01):
Group and individual-difference adoption designs lead to opposite conclusions concerning the importance of shared environment (SE) for the child outcomes of IQ and antisocial behavior. This paradox could be due to the range restriction (RR) of family environments (FE) that goes with adoption studies. Measures of FE from 2 of the most recent adoption studies indicate that RR is substantial, about 67%, which corresponds to the top half of a normal FE distribution. FE of 57% cuts effect sizes and R² statistics by factors of 3 and 2–2.5, respectively. Because selection into an option study is inherently a between-family process and assuming that comparable restriction of genetic (G) influences are absent, estimates of SE, G, and nonshared influences will be substantially biased, respectively, down, up, and up by RR. Corrections for RR applied to adoption studies indicate that SE could account for as much as 50% of the variance in IQ. [Keywords: restricted range of family environments, estimates of heritability & nonshared environment for child outcomes of IQ & antisocial behavior in behavior-genetic adoption studies]
2001-bouchard.pdf: “Individual differences in response to regular physical activity”, Claude Bouchard, Tuomo Rankinen (2001-06-01):
Purpose: The purpose of this review was to address the question of interindividual variation in responsiveness to regular exercise training and to define the contributions of age, sex, race, and pretraining phenotype level to this variability.
Methods: A literature review was conducted of the studies reporting interindividual variation in responsiveness to standardized and controlled exercise-training programs, and included an analysis of the contribution of age, sex, race, and initial phenotype values to the heterogeneity in VO2max, high-density lipoprotein (HDL)-C and submaximal exercise, heart rate (HR), and systolic blood pressure (SBP) training responses in subjects from the HERITAGE Family Study.
Results: Several studies have shown marked individual differences in responsiveness to exercise training. For example, VO2max responses to standardized training programs have ranged from almost no gain up to 100% increase in large groups of sedentary individuals. A similar pattern of heterogeneity has been observed for other phenotypes. Data from the HERITAGE Family Study show that age, sex, and race have little impact on interindividual differences in training responses. On the other hand, the initial level of a phenotype is a major determinant of training response for some traits, such as submaximal exercise heart rate and blood pressure (BP) but has only a minor effect on others (e.g., VO2max, HDL-C). The contribution of familial factors (shared environment and genetic factors) is supported by data on substantial familial aggregation of training response phenotypes.
Conclusions: There is strong evidence for considerable heterogeneity in the responsiveness to regular physical activity. Age, sex, and ethnic origin are not major determinants of human responses to regular physical activity, whereas the pretraining level of a phenotype has a considerable impact in some cases. Familial factors also contribute substantially to variability in training response.
2002-maia.pdf: “Genetic factors in physical activity levels: A Twin Study”, José A.R Maia, Martine Thomis, Gaston Beunen (2002-08-01):
Background: Substantial interindividual variation is observed in sports participation and physical activity levels in youth. This study aimed to (1) estimate the relative contribution of genes, along with shared and nonshared environmental factors, to variation in sports participation index (SPI) and leisure-time physical activity (LTPA); and (2) test differences in those factors in males and females.
Methods: The sample was comprised of 411 Portuguese twin pairs of different zygosity aged 12 to 25 years. The SPI and LTPA were assessed with the Baecke questionnaire. Quantitative genetic modeling was used to test alternative models for the presence of additive gene effects (a2), common or shared environment within the family (c2), and unique environmental factors (e2).
Results: The best-fitting models showed sex-specific effects for the two phenotypes. Variance components for SPI in males were a2 = 68.4%, c2 = 20%, and e2 = 11.6%; and in females, a2 = 39.8%, c2 = 28.4%, and e2 = 31.8%. For variation in LTPA, genetic factors in males explained 63%, common environment was not statistically-significant, and unique environment explained 37%. In females, contributing factors were a2 = 32%, c2 = 38%, and e2 = 30%.
Conclusions: Genetic effects explained a considerable amount of variation in SPI and LTPA, which were greater in males than in females. The relevance of shared environmental factors (family and peers) and nonshared environmental factors in SPI and LTPA is particularly evident in females. [Keywords: exercise, genetics, physical fitness, twins]
2006-maes.pdf: “Genetic and Cultural Transmission of Smoking Initiation: An Extended Twin Kinship Model”, Hermine H. Maes, Michael C. Neale, Kenneth S. Kendler, Nicholas G. Martin, Andrew C. Heath, Lindon J. Eaves (2006-06-30):
Background: Considerable evidence from twin and adoption studies indicates that genetic and shared environmental factors play a statistically-significant role in the initiation of smoking behavior. Although twin and adoption designs are powerful to detect genetic and environmental influences, they do not provide information on the processes of assortative mating and parent-offspring transmission and their contribution to the variability explained by genetic and/
or environmental factors.
Methods: We examined the role of genetic and environmental factors for smoking initiation using an extended kinship design. This design allows the simultaneous testing of additive and non-additive genetic, shared and individual-specific environmental factors, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission. A dichotomous lifetime smoking measure was obtained from twins and relatives in the Virginia 30,000 sample.
Results: Results demonstrate that both genetic and environmental factors play a statistically-significant role in the liability to smoking initiation. Major influences on individual differences appeared to be additive genetic and unique environmental effects, with smaller contributions from assortative mating, shared sibling environment, twin environment, cultural transmission and resulting genotype-environment covariance. The finding of negative cultural transmission without dominance led us to investigate more closely two possible mechanisms for the lower parent-offspring correlations compared to the sibling and DZ twin correlations in subsets of the data: (1) age × gene interaction, and (2) social homogamy. Neither mechanism provided a statistically-significantly better explanation of the data, although age regression was statistically-significant.
Conclusions: This study showed statistically-significant heritability, partly due to assortment, and statistically-significant effects of primarily non-parental shared environment on smoking initiation.
2006-nettle.pdf: “The evolution of personality variation in humans and other animals”, Daniel Nettle (2006-09-01):
A comprehensive evolutionary framework for understanding the maintenance of heritable behavioral variation in humans is yet to be developed. Some evolutionary psychologists have argued that heritable variation will not be found in important, fitness-relevant characteristics because of the winnowing effect of natural selection. This article propounds the opposite view. Heritable variation is ubiquitous in all species, and there are a number of frameworks for understanding its persistence. The author argues that each of the Big Five dimensions of human personality can be seen as the result of a trade-off between different fitness costs and benefits. As there is no unconditionally optimal value of these trade-offs, it is to be expected that genetic diversity will be retained in the population.
2007-liinamo.pdf: “Genetic variation in aggression–related traits in Golden Retriever dogs”, Anna-Elisa Liinamo, Lindavan den Berg, Peter A.J. Leegwater, Matthijs B.H. Schilder, Johan A.M. van Arendonk, Bernard A. van Oost (2007-04-01):
In this study, heritabilities of several measures of aggression were estimated in a group of 325 Golden Retrievers, using the Restricted Maximum Likelihood method. The studied measures were obtained either through owner opinions or by using the Canine Behavioural Assessment and Research Questionnaire (CBARQ). The aim of the study was to determine which of the aggression measures showed sufficient genetic variation to be useful as phenotypes for future molecular genetic studies on aggression in this population.
The most reliable heritability estimates seemed to be those for simple dog owner impressions of human-directed and dog-directed aggression, with heritability estimates of 0.77 (S.E. 0.09) and 0.81 (S.E. 0.09), respectively. In addition, several CBARQ-derived measures related to human-directed aggression showed clear genetic differences between the dogs. The correlation between the estimated breeding values for owner impressions on human-directed and dog-directed aggression was relatively low. The low correlation suggests that these two traits have a partially different genetic background. They will therefore have to be treated as separate traits in further genetic studies. [Keywords: dogs, aggressive behaviour, questionnaire, heritability, estimated breeding values]
2007-sacerdote.pdf: “How Large are the Effects from Changes in Family Environment? A Study of Korean American Adoptees”, Bruce Sacerdote (2007-02-01):
I analyze a new set of data on Korean American adoptees who were quasi-randomly assigned to adoptive families.
I find large effects on adoptees’ education, income, and health from assignment to parents with more education and from assignment to smaller families. Parental education and family size are statistically-significantly more correlated with adoptee outcomes than are parental income or neighborhood characteristics. Outcomes such as drinking, smoking, and the selectivity of college attended are more determined by nurture than is educational attainment.
Using the standard behavioral genetics variance decomposition, I find that shared family environment explains 14% of the variation in educational attainment, 35% of the variation in college selectivity, and 33% of the variation in drinking behavior.
2008-eaves-2.pdf: “Transmission of Attitudes Toward Abortion and Gay Rights: Effects of Genes, Social Learning and Mate Selection”, Lindon J. Eaves, Peter K. Hatemi (2008-03-29):
The biological and social transmission of attitudes toward abortion and gay rights are analyzed in a large sample of adult twins, siblings, and their parents. We present a linear model for family resemblance allowing for both genetic and cultural transmission of attitudes from parents to offspring, as well as phenotypic assortative mating (the tendency to marry like) and other environmental sources of twin and sibling resemblance that do not depend on the attitudes of their parents. The model gives a close fit to the patterns of similarity between relatives for the two items. Results are consistent with a substantial role of genetic liability in the transmission of both attitudes. Contrary to the dominant paradigm of the social and political sciences, the kinship data are consistent with a relatively minor non-genetic impact of parental attitudes on the development of adult attitudes in their children. By contrast, the choice of mate is a social action that has a marked impact on the polarization of social attitudes and on the long-term influence that parents exert upon the next generation. [Keywords: Abortion, Gay rights, Assortative mating, Political and social attitudes]
2010-aaltonen.pdf: “A longitudinal study on genetic and environmental influences on leisure time physical activity in the Finnish Twin Cohort”, Sari Aaltonen, Alfredo Ortega-Alonso, Urho M. Kujala, Jaakko Kaprio (2010):
The purpose of this study was to examine changes in the contribution of genetic and environmental influences to leisure time physical activity among male and female twins over a 6-year follow-up. At baseline the sample comprised 4,280 monozygotic and 9,276 dizygotic twin individuals, and at follow-up 4,383 monozygotic and 9,439 dizygotic twin individuals. Participants were aged 18–54 years at baseline. Genetic modeling results showed that genetic influences on leisure time physical activity declined from baseline (44%) to follow-up (34%). Most of the genetic influences identified at baseline were present at followup (rg= 0.72). Specific environmental influences increased from baseline (56%) to follow-up (66%) while at follow-up new environmental time-specific influences were observed (re= 0.23). The model with sex differences showed a higher estimate of genetic influences for men than women both at baseline (men 47% vs. women 42%) and at follow-up (men 38% vs. women 31%). The additive genetic correlation for this phenotype was greater for men (rg= 0.79) than women (rg= 0.64). The specific environmental influences were corresponding; at baseline men 53% and women 56% and at follow-up men 62 % and women 69%. The environmental correlations between the two time points were similar for men (re= 0.21) and for women (re= 0.24). In conclusion, in a sample of healthy twins most of the genetic influences on leisure time physical activity expressed at baseline were present at 6 years of follow-up. New specific environmental factors underlying follow-up leisure time physical activity were observed.
2010-hatemi.pdf: “Not by Twins Alone: Using the Extended Family Design to Investigate Genetic Influence on Political Beliefs”, Peter K. Hatemi, John R. Hibbing, Sarah E. Medland, Matthew C. Keller, John R. Alford, Kevin B. Smith, Nicholas G. Martin, Lindon J. Eaves (2020-07-01):
Variance components estimates of political and social attitudes suggest a substantial level of genetic influence, but the results have been challenged because they rely on data from twins only. In this analysis, we include responses from parents and nontwin full siblings of twins, account for measurement error by using a panel design, and estimate genetic and environmental variance by maximum-likelihood structural equation modeling. By doing so, we address the central concerns of critics, including that the twin-only design offers no verification of either the equal environments or random mating assumptions. Moving beyond the twin-only design leads to the conclusion that for most political and social attitudes, genetic influences account for an even greater proportion of individual differences than reported by studies using more limited data and more elementary estimation techniques. These findings make it increasingly difficult to deny that—however indirectly—genetics plays a role in the formation of political and social attitudes.
2011-conway.pdf: “The Biological Roots of Complex Thinking: Are Heritable Attitudes More Complex?”, Lucian Gideon Conway, Daniel P. Dodds, Kirsten Hands Towgood, Stacey McClure, James M. Olson (2011-02-01):
Are highly heritable attitudes more or less complex than less heritable attitudes? Over 2,000 participant responses on topics varying in heritability were coded for overall integrative complexity and its 2 subcomponents (dialectical complexity and elaborative complexity). Across different heritability sets drawn from 2 separate prior twin research programs, the present results yielded a consistent pattern: Heritability was always statistically-significantly positively correlated with integrative complexity. Further analyses of the subcomponents suggested that the manner in which complexity was expressed differed by topic type: For societal topics, heritable attitudes were more likely to be expressed in dialectically complex terms, whereas for personally involving topics, heritable attitudes were more likely to be expressed in elaboratively complex terms. Most of these relationships remained statistically-significant even when controlling for measurements of attitude strength. The authors discuss the genetic roots of complex versus simple attitudes, implications for understanding attitude development more broadly, and the contribution of these results to previous work on both heritability and complexity.
2011-demoor.pdf: “Exercise Participation in Adolescents and Their Parents: Evidence for Genetic and Generation Specific Environmental Effects”, M.H.M. de Moor, G. Willemsen, I. Rebollo Mesa, J.H. Stubbe, E.J.C. de Geus, D.I. Boomsma (2011):
Individual differences in adolescent exercise behavior are to a large extent explained by shared environmental factors. The aim of this study was to explore to what extent this shared environment represents effects of cultural transmission of parents to their offspring, generation specific environmental effects or assortative mating. Survey data on leisure-time exercise behavior were available from 3,525 adolescent twins and their siblings (13–18 years) and 3,138 parents from 1,736 families registered at the Netherlands Twin Registry. Data were also available from 5,471 adult twins, their siblings and spouses similar in age to the parents. Exercise participation (No/
Yes, using a cut-off criterion of 4 metabolic equivalents and 60 min weekly) was based on questions on type, frequency and duration of exercise. A model to analyze dichotomous data from twins, siblings and parents including differences in variance decomposition across sex and generation was developed. Data from adult twins and their spouses were used to investigate the causes of assortative mating (correlation between spouses = 0.41, due to phenotypic assortment). The heritability of exercise in the adult generation was estimated at 42%. The shared environment for exercise behavior in adolescents mainly represents generation specific shared environmental influences that seem somewhat more important in explaining familial clustering in girls than in boys (52 versus 41%). A small effect of vertical cultural transmission was found for boys only (3%). The remaining familial clustering for exercise behavior was explained by additive genetic factors (42% in boys and 36% in girls). Future studies on adolescent exercise behavior should focus on identification of the generation specific environmental factors.
2012-allentoft.pdf: “The half-life of DNA in bone: measuring decay kinetics in 158 dated fossils”, Morten E. Allentoft, Matthew Collins, David Harker, James Haile, Charlotte L. Oskam, Marie L. Hale, Paula F. Campos, Jose A. Samaniego, M. Thomas P. Gilbert, Eske Willerslev, Guojie Zhang, R. Paul Scofield, Richard N. Holdaway, Michael Bunce (2012-10-10):
Claims of extreme survival of DNA have emphasized the need for reliable models of DNA degradation through time. By analysing mitochondrial DNA (mtDNA) from 158 radiocarbon-dated bones of the extinct New Zealand moa, we confirm empirically a long-hypothesized exponential decay relationship. The average DNA half-life within this geographically constrained fossil assemblage was estimated to be 521 years for a 242 bp mtDNA sequence, corresponding to a per nucleotide fragmentation rate (
) of 5.50 × 10
per year. With an effective burial temperature of 13.1°C, the rate is almost 400 times slower than predicted from published kinetic data of
DNA depurination at pH 5. Although best described by an exponential model (
= 0.39), considerable sample-to-sample variance in DNA preservation could not be accounted for by geologic age. This variation likely derives from differences in taphonomy and bone diagenesis, which have confounded previous, less spatially constrained attempts to study DNA decay kinetics. Lastly, by calculating DNA fragmentation rates on Illumina HiSeq data, we show that nuclear DNA has degraded at least twice as fast as mtDNA. These results provide a baseline for predicting long-term DNA survival in bone.
2012-kirzinger.pdf: “Genetic and Environmental Influences on Media Use and Communication Behaviors”, Ashley E. Kirzinger, Christopher Weber, Martin Johnson (2014-04-01):
A great deal of scholarly work has explored the motivations behind media consumption and other various communication traits. However, little research has investigated the sources of these motivations and virtually no research considers their potential genetic underpinnings. Drawing on the field of behavior genetics, we use a classical twin design study to examine the genetic and environmental influences on nine communication behaviors. Our findings indicate a substantial portion of the total variance in media habits can be attributed to genes, as much as one-third of the variance in some instances. Mass communication scholars would benefit by paying closer attention to heritability when thinking about the causes as well as the consequences of media traits in contemporary society.
2012-lee.pdf: “Correlation and Causation in the Study of Personality”, James Jung-Hun Lee (2012-07-26):
Personality psychology aims to explain the causes and the consequences of variation in behavioural traits. Because of the observational nature of the pertinent data, this endeavour has provoked many controversies. In recent years, the computer scientist Judea Pearl has used a graphical approach to extend the innovations in causal inference developed by Ronald Fisher and Sewall Wright. Besides shedding much light on the philosophical notion of causality itself, this graphical framework now contains many powerful concepts of relevance to the controversies just mentioned. In this article, some of these concepts are applied to areas of personality research where questions of causation arise, including the analysis of observational data and the genetic sources of individual differences.
2012-miller.pdf: “The heritability and genetic correlates of mobile phone use: a twin study of consumer behavior”, Geoffrey F. Miller, Gu Zhu, Margaret J. Wright, Narelle K. Hansell, Nicholas G. Martin (2012):
There has been almost no overlap between behavior genetics and consumer behavior research, despite each field’s importance in understanding society. In particular, both have neglected to study genetic influences on consumer adoption and usage of new technologies—even technologies as important as the mobile phone, now used by 5.8 out of 7.0 billion people on earth. To start filling this gap, we analyzed self-reported mobile phone use, intelligence, and personality traits in two samples of Australian teenaged twins (mean ages 14.2 and 15.6 years), totaling 1,036 individuals. ACE modeling using Mx software showed substantial heritabilities for how often teens make voice calls (.60 and .34 in samples 1 and 2, respectively) and for how often they send text messages (.53 and. 50). Shared family environment—including neighborhood, social class, parental education, and parental income (i.e., the generosity of calling plans that parents can afford for their teens)—had much weaker effects. Multivariate modeling based on cross-twin, cross-trait correlations showed negative genetic correlations between talking/
texting frequency and intelligence (around –.17), and positive genetic correlations between talking/ texting frequency and extraversion (about .20 to .40). Our results have implications for assessing the risks of mobile phone use such as radiofrequency field (RF) exposure and driving accidents, for studying adoption and use of other emerging technologies, for understanding the genetic architecture of the cognitive and personality traits that predict consumer behavior, and for challenging the common assumption that consumer behavior is shaped entirely by culture, media, and family environment.
2012-segal.pdf: “Fullerton Virtual Twin Study: An Update”, Nancy L. Segal, Shirley A. McGuire, Jamie L. Graham, Joanne Hoven Stohs (2012):
Virtual twins (VTs) are same-age unrelated siblings reared together from early infancy. These unique sibling sets replicate twinship, but without the genetic link. The first VT pair was identified and studied at the University of Minnesota in 1990, launching the development of the Fullerton Virtual Twin Study at California State University, Fullerton (CSUF) in 1991. The registry currently includes 151 pairs, mostly children, with new pairs identified on a continuous basis. Research with VTs includes studies of general intelligence, body size, interpersonal trust, social coordination, social networks, and parenting. In some cases, VTs have been studied in conjunction with pairs of monozygotic twins, dizygotic twins, full siblings, and friends as part of TAPS (Twins, Adoptees, Peers and Siblings), a collaborative project conducted between CSUF and the University of San Francisco, 2002–2006. VTs will also serve as a comparison group for epigenetic analyses of young Chinese twins reared apart and together.
2012-vandongen.pdf: “The continuing value of twin studies in the omics era”, Jenny van Dongen, P. Eline Slagboom, Harmen H. M. Draisma, Nicholas G. Martin, Dorret I. Boomsma (2012-07-31):
The classical twin study has been a powerful heuristic in biomedical, psychiatric and behavioural research for decades. Twin registries worldwide have collected biological material and longitudinal phenotypic data on tens of thousands of twins, providing a valuable resource for studying complex phenotypes and their underlying biology. In this Review, we consider the continuing value of twin studies in the current era of molecular genetic studies. We conclude that classical twin methods combined with novel technologies represent a powerful approach towards identifying and understanding the molecular pathways that underlie complex traits.
In 1998, Robert Plomin and his Colorado Adoption Project (CAP) colleagues published the results of a longitudinal adoption study of personality. They found an average personality test score correlation of only 0.01 between birth-parents and their 240 adopted-away 16-year-old biological offspring, suggesting no genetic influences on personality. However, the researchers interpreted their results in the context of previous twin studies, produced an average 14% heritability estimate, and concluded that nonadditive genetic factors underlie personality traits. The author challenges these conclusions and notes that the near-zero correlation stands in contrast to other types of behavioral genetic methods, such as twin studies, that are more vulnerable to environmental confounds and other biases. The author shows that authoritative psychology texts frequently fail to mention this 1998 CAP study. When it is mentioned, the original researchers’ conclusions are usually accepted without critical analysis. The author also assesses the results in the context of the 20-year failure to discover the genes that behavioral geneticists believe underlie personality traits. He concludes that this 1998 investigation is a “lost study” in the sense that, although it is one of the most methodologically sound behavioral genetic studies ever performed, its results are largely unknown. [Keywords: adoption study, behavioral genetics, Colorado Adoption Project, genes for personality, heritability, personality, Plomin, twin study]
2014-burt.pdf: “Pulling Back The Curtain On Heritability Studies: Biosocial Criminology In The Postgenomic Era”, Callie H. Burt, Ronald L. Simons (2014-03-28):
Unfortunately, the nature-versus-nurture debate continues in criminology. Over the past 5 years, the number of heritability studies in criminology has surged. These studies invariably report sizeable heritability estimates (~50%) and minimal effects of the so-called shared environment for crime and related outcomes. Reports of such high heritabilities for such complex social behaviors are surprising, and findings indicating negligible shared environmental influences (usually interpreted to include parenting and community factors) seem implausible given extensive criminological research demonstrating their importance. Importantly, however, the models on which these estimates are based have fatal flaws for complex social behaviors such as crime. Moreover, the goal of heritability studies—partitioning the effects of nature and nurture—is misguided given the bidirectional, interactional relationship among genes, cells, organisms, and environments. This study provides a critique of heritability study methods and assumptions to illuminate the dubious foundations of heritability estimates and questions the rationale and utility of partitioning genetic and environmental effects. After critiquing the major models, we call for an end to heritability studies. We then present what we perceive to be a more useful biosocial research agenda that is consonant with and informed by recent advances in our understanding of gene function and developmental plasticity.
2014-groenblokhuis.pdf: “Attention-Deficit/Hyperactivity Disorder Polygenic Risk Scores Predict Attention Problems in a Population-Based Sample of Children”, Maria M. Groen-Blokhuis, Christel M. Middeldorp, Kees-Jan Kan, Abdel Abdellaoui, Catharina E.M. van Beijsterveldt, Erik A. Ehli, Gareth E. Davies, Paul A. Scheet, Xiangjun Xiao, James J. Hudziak, Jouke-Jan Hottenga, Ben M. Neale, Dorret I. Boomsma, Psychiatric Genomics Consortium ADHD Working Group (2014-10-01):
Objective: Clinically, attention-deficit/
hyperactivity disorder (ADHD) is characterized by hyperactivity, impulsivity, and inattention and is among the most common childhood disorders. These same traits that define ADHD are variable in the general population, and the clinical diagnosis may represent the extreme end of a continuous distribution of inattentive and hyperactive behaviors. This hypothesis can be tested by assessing the predictive value of polygenic risk scores derived from a discovery sample of ADHD patients in a target sample from the general population with continuous scores of inattention and hyperactivity. In addition, the genetic overlap between ADHD and continuous ADHD scores can be tested across rater and age.
Method: The Psychiatric Genomics Consortium has performed the largest genome-wide analysis (GWA) study of ADHD so far, including 5,621 clinical patients and 13,589 controls. The effects sizes of single nucleotide polymorphisms (SNPs) estimated in this meta-analysis were used to obtain individual polygenic risk scores in an independent population-based cohort of 2,437 children from the Netherlands Twin Register. The variance explained in Attention Problems (AP) scale scores by the polygenic risk scores was estimated by linear mixed modeling.
Results: The ADHD polygenic risk scores statistically-significantly predicted both parent and teacher ratings of AP in preschool-aged and school-aged children.
Conclusion: These results indicate genetic overlap between a diagnosis of ADHD and AP scale scores across raters and age groups and provides evidence for a dimensional model of ADHD. Future GWA studies on ADHD can likely benefit from the inclusion of population-based cohorts and the analysis of continuous scores. [Keywords: ADHD, attention problems, polygenic scores, genetics, dimensional models]
2014-li.pdf: “A Twin Study of Problematic Internet Use: Its Heritability and Genetic Association With Effortful Control”, Mengjiao Li, Jie Chen, Naishi Li, Xinying Li (2014-08):
Our goal was to estimate genetic and environmental sources of influence on adolescent problematic internet use, and whether these individual differences can be explained by effortful control, an important aspect of self-regulation. A sample of 825 pairs of Chinese adolescent twins and their parents provided reports of problematic internet use and effortful control. Univariate analysis revealed that genetic factors explained 58–66% of variance in problematic internet use, with the rest explained by non-shared environmental factors. Sex difference was found, suggesting boys’ problematic internet use was more influenced by genetic influences than girls’ problematic internet use. Bivariate analysis indicated that effortful control accounted for a modest portion of the genetic and non-shared environmental variance in problematic internet use among girls. In contrast, among boys, effortful control explained between 6% (parent report) and 20% (self-report) of variance in problematic internet use through overlapping genetic pathways. Adolescent problematic internet use is heritable, and poor effortful control can partly explain adolescent problematic internet use, with effects stronger for boys. Implications for future research are discussed.
2015-polderman.pdf: “Meta-analysis of the heritability of human traits based on fifty years of twin studies”, Tinca J. C. Polderman, Beben Benyamin, Christiaan A. de Leeuw, Patrick F. Sullivan, Arjen van Bochoven, Peter M. Visscher, Danielle Posthuma (2015-05-18):
Despite a century of research on complex traits in humans, the relative importance and specific nature of the influences of genes and environment on human traits remain controversial. We report a meta-analysis of twin correlations and reported variance components for 17,804 traits from 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits. Estimates of heritability cluster strongly within functional domains, and across all traits the reported heritability is 49%. For a majority (69%) of traits, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. The data are inconsistent with substantial influences from shared environment or non-additive genetic variation. This study provides the most comprehensive analysis of the causes of individual differences in human traits thus far and will guide future gene-mapping efforts. All the results can be visualized using the MaTCH webtool.
2015-yang.pdf: “Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index”, Jian Yang, Andrew Bakshi, Zhihong Zhu, Gibran Hemani, Anna A. E Vinkhuyzen, Sang Hong Lee, Matthew R. Robinson, John R. B. Perry, Ilja M. Nolte, Jana V. van VlietOstaptchouk, Harold Snieder, The LifeLines Cohort Study, Tonu Esko, Lili Milani, Reedik Mgi, Andres Metspalu, Anders Hamsten, Patrik K. E Magnusson, Nancy L. Pedersen, Erik Ingelsson, Nicole Soranzo, Matthew C. Keller, Naomi R. Wray, Michael E. Goddard, Peter M. Visscher (2015-08-31):
We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that ~97% and ~68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ~17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height-associated and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60–70% for height and 30–40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.
2015-zhou.pdf: “Genetic and Environmental Influences on Obesity–Related Phenotypes in Chinese Twins Reared Apart and Together”, Bin Zhou, Wenjing Gao, Jun Lv, Canqing Yu, Shengfeng Wang, Chunxiao Liao, Zengchang Pang, Liming Cong, Zhong Dong, Fan Wu, Hua Wang, Xianping Wu, Guohong Jiang, Xiaojie Wang, Binyou Wang, Weihua Cao, Liming Li (2015-03-12):
The relative importance of genetic and environmental influences on obesity-related phenotypes remains unclear, and few studies have targeted the Chinese population. Here, we used Chinese twins reared apart and together to explore genetic and environmental influences on body mass index (BMI), waist circumference (WC) and waist-height ratio (WHtR), further to differentiate phenotype heritability between different age groups and genders separately and to differentiate influences of rearing environment and correlated environment.
Phenotype heritability was calculated using the structural equation model in 11,401 twin pairs aged 25–85 years. BMI (0.70, 95% confidence interval (CI) 0.66–0.74) of the total population was highly heritable, while WC (0.53, 95% CI 0.50–0.57) and WHtR (0.48, 95% CI 0.45–0.51) were moderately heritable. Age and gender stratified analyses found higher heritability in the younger group and males than the older group and females.
The correlated environment had a greater influence on the phenotypes than the rearing environment, especially on WC and WHtR, indicating that more correlated environment actions should be taken to prevent the rising trend of abdominal obesity.
2016-bagnall.pdf: “A Prospective Study of Sudden Cardiac Death among Children and Young Adults”, Richard D. Bagnall, Robert G. Weintraub, Jodie Ingles, Johan Duflou, Laura Yeates, Lien Lam, Andrew M. Davis, Tina Thompson, Vanessa Connell, Jennie Wallace, Charles Naylor, Jackie Crawford, Donald R. Love, Lavinia Hallam, Jodi White, Christopher Lawrence, Matthew Lynch, Natalie Morgan, Paul James, Desirée du Sart, Rajesh Puranik, Neil Langlois, Jitendra Vohra, Ingrid Winship, John Atherton, Julie McGaughran, Jonathan R. Skinner, Christopher Semsarian (2016-06-23):
Background: Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults.
Methods: We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation.
Results: A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred.
Conclusions: The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults.
2017-visscher.pdf: “10 Years of GWAS Discovery: Biology, Function, and Translation”, Peter M. Visscher, Naomi R. Wray, Qian Zhang, Pamela Sklar, Mark I. McCarthy, Matthew A. Brown, and Jian Yang (2017-07-06):
Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.
2018-bates.pdf: “The Nature of Nurture: Using a Virtual-Parent Design to Test Parenting Effects on Children's Educational Attainment in Genotyped Families”, Timothy C. Bates, Brion S. Maher, Sarah E. Medland, Kerrie McAloney, Margaret J. Wright, Narelle K. Hansell, Kenneth S. Kendler, Nicholas G. Martin, Nathan A. Gillespie (2018-03-13):
Research on environmental and genetic pathways to complex traits such as educational attainment (EA) is confounded by uncertainty over whether correlations reflect effects of transmitted parental genes, causal family environments, or some, possibly interactive, mixture of both. Thus, an aggregate of thousands of alleles associated with EA (a polygenic risk score; PRS) may tap parental behaviors and home environments promoting EA in the offspring. New methods for unpicking and determining these causal pathways are required. Here, we utilize the fact that parents pass, at random, 50% of their genome to a given offspring to create independent scores for the transmitted alleles (conventional EA PRS) and a parental score based on alleles not transmitted to the offspring (EA VP_PRS). The formal effect of non-transmitted alleles on offspring attainment was tested in 2,333 genotyped twins for whom high-quality measures of EA, assessed at age 17 years, were available, and whose parents were also genotyped. Four key findings were observed. First, the EA PRS and EA VP_PRS were empirically independent, validating the virtual-parent design. Second, in this family-based design, children’s own EA PRS statistically-significantly predicted their EA (β = 0.15), ruling out stratification confounds as a cause of the association of attainment with the EA PRS. Third, parental EA PRS predicted the SES environment parents provided to offspring (β = 0.20), and parental SES and offspring EA were statistically-significantly associated (β = 0.33). This would suggest that the EA PRS is at least as strongly linked to social competence as it is to EA, leading to higher attained SES in parents and, therefore, a higher experienced SES for children. In a full structural equation model taking account of family genetic relatedness across multiple siblings the non-transmitted allele effects were estimated at similar values; but, in this more complex model, confidence intervals included zero. A test using the forthcoming EA3 PRS may clarify this outcome. The virtual-parent method may be applied to clarify causality in other phenotypes where observational evidence suggests parenting may moderate expression of other outcomes, for instance in psychiatry.
2018-beaver.pdf: “On the Genetic and Genomic Basis of Aggression, Violence, and Antisocial Behavior”, Kevin M. Beaver, Eric J. Connolly, Joseph L. Nedelec, Joseph A. Schwartz (2018-04-01):
There is a great deal of interest in examining the genetic and environmental architecture to aggression, violence, and antisocial behaviors. This interest has resulted in hundreds of studies being published that estimate genetic and environmental effects on antisocial phenotypes. The results generated from these studies have been remarkably consistent and have contributed greatly to the knowledge base on the etiology of antisocial behavior. This chapter reviews the research on the genetic basis to antisocial phenotypes by presenting the results related to the heritability of antisocial phenotypes. It also discusses some of the molecular genetic association studies as well as genome-wide association studies that focus on the development of antisocial behaviors. In doing so, it also reviews findings related to gene-environment interactions. The chapter concludes by discussing some of the ways in which these findings could be used for intervention and prevention programs.
2018-contreras.pdf: “The Genomic Commons”, Jorge L. Contreras, Bartha M. Knoppers (2018-01-25):
Over its 30 or so years of existence, the genomic commons—the worldwide collection of publicly accessible repositories of human and nonhuman genomic data—has enjoyed remarkable, perhaps unprecedented, success. Thanks to the rapid public data release policies initiated by the Human Genome Project, free access to a vast array of scientific data is now the norm, not only in genomics, but in scientific disciplines of all descriptions. And far from being a monolithic creation of bureaucratic fiat, the genomic commons is an exemplar of polycentric, multistakeholder governance. But like all dynamic and rapidly evolving systems, the genomic commons is not without its challenges. Issues involving scientific priority, intellectual property, individual privacy, and informed consent, in an environment of data sets of exponentially expanding size and complexity, must be addressed in the near term. In this review, we describe the characteristics and unique history of the genomic commons, then address some of the trends, challenges, and opportunities that we envision for this valuable public resource in the years to come.
2018-das.pdf: “Genotype Imputation from Large Reference Panels”, Sayantan Das, Gonçalo R. Abecasis, Brian L. Browning (2018):
Genotype imputation has become a standard tool in genome-wide association studies because it enables researchers to inexpensively approximate whole-genome sequence data from genome-wide single-nucleotide polymorphism array data. Genotype imputation increases statistical power, facilitates fine mapping of causal variants, and plays a key role in meta-analyses of genome-wide association studies. Only variants that were previously observed in a reference panel of sequenced individuals can be imputed. However, the rapid increase in the number of deeply sequenced individuals will soon make it possible to assemble enormous reference panels that greatly increase the number of imputable variants. In this review, we present an overview of genotype imputation and describe the computational techniques that make it possible to impute genotypes from reference panels with millions of individuals.
2018-hannikainen.pdf: “Ideology Between the Lines”, Ivar R. Hannikainen (2018):
While philosophers emphasize the distinction between description and prescription, in practice people’s beliefs about contentious issues seem to reflect their normative commitments. Less is known about the way that people infer others’ ideology from their reports about matters of fact. In the context of scientific research on the heritability of intelligence, scientists’ normative views (Study 1a) and motives (Study 2) are inferred from the evidence they report—independently of their stated research objectives. Two preregistered replications (Studies 1b and 3) revealed that these effects generalize to other contentious domains of behavioral and social science research. Thus, laypeople view social scientific inquiry as (partly) a guided pursuit of evidence in favor of scientists’ personal ideology.
2018-kaplanis.pdf: “Quantitative analysis of population-scale family trees with millions of relatives”, Joanna Kaplanis, Assaf Gordon, Tal Shor, Omer Weissbrod, Dan Geiger, Mary Wahl, Michael Gershovits, Barak Markus, Mona Sheikh, Melissa Gymrek, Gaurav Bhatia, Daniel G. MacArthur, Alkes L. Price, Yaniv Erlich (2018-03-01):
Family trees have vast applications in multiple fields from genetics to anthropology and economics. However, the collection of extended family trees is tedious and usually relies on resources with limited geographical scope and complex data usage restrictions. Here, we collected 86 million profiles from publicly-available online data shared by genealogy enthusiasts. After extensive cleaning and validation, we obtained population-scale family trees, including a single pedigree of 13 million individuals. We leveraged the data to partition the genetic architecture of longevity by inspecting millions of relative pairs and to provide insights into the geographical dispersion of families. We also report a simple digital procedure to overlay other datasets with our resource in order to empower studies with population-scale genealogical data.
2018-martin-2.pdf: “Quantifying the contribution of recessive coding variation to developmental disorders”, Hilary C. Martin1, Wendy D. Jones, Rebecca McIntyre, Gabriela Sanchez-Andrade, Mark Sanderson, James D. Stephenson, Carla P. Jones, Juliet Handsaker, Giuseppe Gallone, Michaela Bruntraeger, Jeremy F. McRae, Elena Prigmore, Patrick Short, Mari Niemi, Joanna Kaplanis, Elizabeth J. Radford, Nadia Akawi, Meena Balasubramanian, John Dean, Rachel Horton, Alice Hulbert, Diana S. Johnson, Katie Johnson, Dhavendra Kumar, Sally Ann Lynch, Sarju G. Mehta, Jenny Morton, Michael J. Parker, Miranda Splitt, Peter D. Turnpenny, Pradeep C. Vasudevan, Michael Wright, Andrew Bassett, Sebastian S. Gerety, Caroline F. Wright, David R. FitzPatrick, Helen V. Firth, Matthew E. Hurles, Jeffrey C. Barrett (the Deciphering Developmental Disorders Study) (2018):
We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.
2018-miles.pdf: “Personality and Genetic Associations With Military Service”, Matthew R. Miles, Donald P. Haider-Markel (2018):
Existing literature connects military service to regional characteristics and family traditions, creating real distinctions between those who serve and those who do not. We engage this discussion by examining military service as a function of personality. In the second portion, we examine military service as predisposed by genetics. Our findings indicate there is a statistically-significant heritability component of serving in the military. We find a statistically-significant genetic correlation between personality traits associated with progressive political ambition and military service, suggesting that military service represents a different form of political participation to which individuals are genetically predisposed. We discuss the long-term implications of our findings for policy makers and recruiters.
2018-papageorge.pdf: “Genes, Education, and Labor Market Outcomes: Evidence from the Health and Retirement Study”, Nicholas W. Papageorge, Kevin Thom (2018-09):
Recent advances have led to the discovery of specific genetic variants that predict educational attainment. We study how these variants, summarized as a linear index—known as a polygenic score—are associated with human capital accumulation and labor market outcomes in the Health and Retirement Study (HRS). We present two main sets of results. First, we find evidence that the genetic factors measured by this score interact strongly with childhood socioeconomic status in determining educational outcomes. In particular, while the polygenic score predicts higher rates of college graduation on average, this relationship is substantially stronger for individuals who grew up in households with higher socioeconomic status relative to those who grew up in poorer households. Second, the polygenic score predicts labor earnings even after adjusting for completed education, with larger returns in more recent decades. These patterns suggest that the genetic traits that promote education might allow workers to better accommodate ongoing skill biased technological change. Consistent with this interpretation, we find a positive association between the polygenic score and non-routine analytic tasks that have benefited from the introduction of new technologies. Nonetheless, the college premium remains the dominant determinant of earnings differences at all levels of the polygenic score. Given the role of childhood SES in predicting college attainment, this raises concerns about wasted potential arising from limited household resources.
2018-pulit.pdf: “Meta-analysis of genome-wide association studies for body fat distribution in 694,649 individuals of European ancestry”, Sara L. Pulit, Charli Stoneman, Andrew P. Morris, Andrew R. Wood, Craig A. Glastonbury, Jessica Tyrrell, Loïc Yengo, Teresa Ferreira, Eirini Marouli, Yingjie Ji, Jian Yang, Samuel Jones, Robin Beaumont, Damien C. Croteau-Chonka, Thomas W. Winkler, GIANT Consortium, Andrew T. Hattersley, Ruth J. F Loos, Joel N. Hirschhorn, Peter M. Visscher, Timothy M. Frayling, Hanieh Yaghootkar, Cecilia M. Lindgren (2018-09-14):
More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.
2018-salvatore.pdf: “Genetics, the Rearing Environment, and the Intergenerational Transmission of Divorce: A Swedish National Adoption Study”, Jessica E. Salvatore, Sara Larsson Lönn, Jan Sundquist, Kristina Sundquist,, Kenneth S. Kendler (2018):
We used classical and extended adoption designs in Swedish registries to disentangle genetic and rearing-environment influences on the intergenerational transmission of divorce. In classical adoption analyses, adoptees (n = 19,715) resembled their biological parents, rather than their adoptive parents, in their history of divorce. In extended adoption analyses, offspring (n = 82,698) resembled their not-lived-with fathers and their lived-with mothers. There was stronger resemblance to lived-with mothers, providing indirect evidence of rearing-environment influences on the intergenerational transmission of divorce. The heritability of divorce assessed across generations was 0.13. We attempted to replicate our findings using within-generation data from adoptive and biological siblings (ns = 8,523–53,097). Adoptees resembled their biological, not adoptive, siblings in their history of divorce. Thus, there was consistent evidence that genetic factors contributed to the intergenerational transmission of divorce but weaker evidence for a rearing-environment effect of divorce. Within-generation data from siblings supported these conclusions.
2018-zapkowillmes.pdf: “Unravelling Quasi-Causal Environmental Effects via Phenotypic and Genetically Informed Multi-Rater Models: The Case of Differential Parenting and Authoritarianism”, Alexandra Zapko-Willmes, Rainer Riemann, Christian Kandler, René Mõttus (2018):
This study investigated the association between different experiences of parenting and individual right–wing authoritarianism (RWA) using twin family data comprising self– and informant reports. We applied a design that allowed us to examine whether the link between retrospective assessments of parenting and current RWA is effectively environmental or whether the association is attributable to genetic influences. We hypothesized that an authoritarian parenting style (low responsiveness and high demandingness) provided by the parents is associated with higher offspring’s RWA, and that this association is similar for both twin siblings as a function of their genetic relatedness and shared familial experiences—that is, genotype–environment correlation. A sample of 875 twins as well as 319 mothers and 268 fathers completed a questionnaire on twins’ parental environment and their own authoritarian attitudes. Additionally, 1322 well–informed peers assessed twins’ RWA. Applying structural equation modelling, we found twins’ experiences of parental responsiveness and demandingness to be positively associated with self–reported and peer–reported RWA. The correlation between responsiveness and RWA was similar for both twins due to their genetic similarity, whereas twin differences in demandingness were positively associated with twin differences in RWA, indicating quasi–causal environmental effects. Implications for the interdependence between parenting and RWA are discussed. Copyright © 2018 European Association of Personality Psychology
2019-acasusorivero.pdf: “Adaptive phenotypic plasticity for life-history and less fitness-related traits”, Cristina Acasuso-Rivero, Courtney J. Murren, Carl D. Schlichting, Ulrich K. Steiner (2019):
Organisms are faced with variable environments and one of the most common solutions to cope with such variability is phenotypic plasticity, a modification of the phenotype to the environment. These modifications are commonly modelled in evolutionary theories as adaptive, influencing ecological and evolutionary processes. If plasticity is adaptive, we would predict that the closer to fitness a trait is, the less plastic it would be. To test this hypothesis, we conducted a meta-analysis of 213 studies and measured the plasticity of each reported trait as a coefficient of variation. Traits were categorized as closer to fitness—life-history traits including reproduction and survival related traits, and farther from fitness—non-life-history traits including traits related to development, metabolism and physiology, morphology and behaviour. Our results showed, unexpectedly, that although traits differed in their amounts of plasticity, trait plasticity was not related to its proximity to fitness. These findings were independent of taxonomic groups or environmental types assessed. We caution against general expectations that plasticity is adaptive, as assumed by many models of its evolution. More studies are needed that test the adaptive nature of plasticity, and additional theoretical explorations on adaptive and non-adaptive plasticity are encouraged.
2019-ahmadzadeh.pdf: “Children of the Twins Early Development Study (CoTEDS): A Children-of-Twins Study”, Yasmin I. Ahmadzadeh, Thalia C. Eley, Robert Plomin, Philip S. Dale, Kathryn J. Lester, Bonamy R. Oliver, Andrew McMillan, Tom A. McAdams (2019-09-09):
The Children of the Twins Early Development Study (CoTEDS) is a new prospective children-of-twins study in the UK, designed to investigate intergenerational associations across child developmental stages. CoTEDS will enable research on genetic and environmental factors that underpin parent–child associations, with a focus on mental health and cognitive-related traits. Through CoTEDS, we will have a new lens to examine the roles that parents play in influencing child development, as well as the genetic and environmental factors that shape parenting behavior and experiences. Recruitment is ongoing from the sample of approximately 20,000 contactable adult twins who have been enrolled in the Twins Early Development Study (TEDS) since infancy. TEDS twins are invited to register all offspring to CoTEDS at birth, with 554 children registered as of May 2019. By recruiting the second generation of TEDS participants, CoTEDS will include information on adult twins and their offspring from infancy. Parent questionnaire-based data collection is now underway for 1- and 2-year-old CoTEDS infants, with further waves of data collection planned. Current data collection includes the following primary constructs: child mental health, temperament, language and cognitive development; parent mental health and social relationships; parenting behaviors and feelings; and other socioecological factors. Measurement tools have been selected with reference to existing genetically informative cohort studies to ensure overlap in phenotypes measured at corresponding stages of development. This built-in study overlap is intended to enable replication and triangulation of future analyses across samples and research designs. Here, we summarize study protocols and measurement procedures and describe future plans.
2019-belsky.pdf: “Phenotypic Annotation: Using Polygenic Scores to Translate Discoveries From Genome-Wide Association Studies From the Top Down”, Daniel W. Belsky, K. Paige Harden (2019):
Genome-wide association studies (GWASs) have identified specific genetic variants associated with complex human traits and behaviors, such as educational attainment, mental disorders, and personality. However, small effect sizes for individual variants, uncertainty regarding the biological function of discovered genotypes, and potential “outside-the-skin” environmental mechanisms leave a translational gulf between GWAS results and scientific understanding that will improve human health and well-being. We propose a set of social, behavioral, and brain-science research activities that map discovered genotypes to neural, developmental, and social mechanisms and call this research program phenotypic annotation. Phenotypic annotation involves (a) elaborating the nomological network surrounding discovered genotypes, (b) shifting focus from individual genes to whole genomes, and (c) testing how discovered genotypes affect life-span development. Phenotypic-annotation research is already advancing the understanding of GWAS discoveries for educational attainment and schizophrenia. We review examples and discuss methodological considerations for psychologists taking up the phenotypic-annotation approach.
2019-border.pdf: “No Support for Historical Candidate Gene or Candidate Gene–by–Interaction Hypotheses for Major Depression Across Multiple Large Samples”, Richard Border, Emma C. Johnson, Luke M. Evans, Andrew Smolen, Noah Berley, Patrick F. Sullivan, Matthew C. Keller (2019):
Objective: Interest in candidate gene and candidate gene-by-environment interaction hypotheses regarding major depressive disorder remains strong despite controversy surrounding the validity of previous findings. In response to this controversy, the present investigation empirically identified 18 candidate genes for depression that have been studied 10 or more times and examined evidence for their relevance to depression phenotypes.
Methods: Utilizing data from large population-based and case-control samples (_n_s ranging from 62,138 to 443,264 across subsamples), the authors conducted a series of preregistered analyses examining candidate gene polymorphism main effects, polymorphism-by-environment interactions, and gene-level effects across a number of operational definitions of depression (e.g., lifetime diagnosis, current severity, episode recurrence) and environmental moderators (e.g., sexual or physical abuse during childhood, socioeconomic adversity).
Results: No clear evidence was found for any candidate gene polymorphism associations with depression phenotypes or any polymorphism-by-environment moderator effects. As a set, depression candidate genes were no more associated with depression phenotypes than non-candidate genes. The authors demonstrate that phenotypic measurement error is unlikely to account for these null findings.
Conclusions: The study results do not support previous depression candidate gene findings, in which large genetic effects are frequently reported in samples orders of magnitude smaller than those examined here. Instead, the results suggest that early hypotheses about depression candidate genes were incorrect and that the large number of associations reported in the depression candidate gene literature are likely to be false positives.
2019-curtis.pdf: “Extreme morning chronotypes are often familial and not exceedingly rare: the estimated prevalence of advanced sleep phase, familial advanced sleep phase, and advanced sleep-wake phase disorder in a sleep clinic population”, Brian John Curtis, Liza H. Ashbrook, Terry Young, Laurel A. Finn, Ying-Hui Fu, Louis J. Ptáček, Christopher R. Jones (2019):
Study Objectives: Report the first prevalence estimates of advanced sleep phase (ASP), familial advanced sleep phase (FASP), and advanced sleep-wake phase disorder (ASWPD). This can guide clinicians on the utility of screening for extreme chronotypes both for clinical decision-making and to flag prospective participants in the study of the genetics and biology of FASP.
Methods: Data on morning or evening sleep schedule preference (chronotype) were collected from 2422 new patients presenting to a North American sleep center over 9.8 years. FASP was determined using a severity criterion that has previously identified dominant circadian mutations in humans. All patients were personally seen and evaluated by one of the authors (C.R.J.).
Results: Our results demonstrate an ASP prevalence of 0.33%, an FASP prevalence of 0.21%, and an ASWPD prevalence of at least 0.04%. Most cases of young-onset ASP were familial.
Conclusions: Among patients presenting to a sleep clinic, conservatively 1 out of every 300 patients will have ASP, 1 out of every 475 will have FASP, and 1 out of every 2500 will have ASWPD. This supports obtaining a routine circadian history and, for those with extreme chronotypes, obtaining a family history of circadian preference. This can optimize treatment for evening sleepiness and early morning awakening and lead to additional circadian gene discovery. We hope these findings will lead to improved treatment options for a wide range of sleep and medical disorders in the future. [Keywords: advanced sleep phase, advanced sleep-wake phase disorder, familial advanced sleep phase, circadian, prevalence]
2019-domingo.pdf: “The Causes and Consequences of Genetic Interactions (Epistasis)”, Júlia Domingo, Pablo Baeza-Centurion, Ben Lehner (2019):
The same mutation can have different effects in different individuals. One important reason for this is that the outcome of a mutation can depend on the genetic context in which it occurs. This dependency is known as epistasis. In recent years, there has been a concerted effort to quantify the extent of pairwise and higher-order genetic interactions between mutations through deep mutagenesis of proteins and RNAs. This research has revealed two major components of epistasis: nonspecific genetic interactions caused by nonlinearities in genotype-to-phenotype maps, and specific interactions between particular mutations. Here, we provide an overview of our current understanding of the mechanisms causing epistasis at the molecular level, the consequences of genetic interactions for evolution and genetic prediction, and the applications of epistasis for understanding biology and determining macromolecular structures.
2019-freeman.pdf: “Is Apostasy Heritable? A Behavior Genetics Study”, Jason A. Freeman (2019-04-16):
The present study explores whether genetic factors explain variation in the levels of apostasy — defined as a disengagement from religious belief, identity and/
or practice — in a US-based sample during the transition from adolescence to early adulthood. I posit that genetic factors at least partially explain the variance of three measures of apostasy: disengagement from religious institutions, cessation of prayer and religious disaffiliation. I argue that genetic factors associated with risk-taking behaviors, externalizing behaviors and/ or correlates of apostasy may all influence the likelihood of becoming an apostate during the transition from adolescence to early adulthood in the USA. Results reveal that genetic factors explain approximately 34% of the variance in cessation of prayer and 75% of the variance in religious disaffiliation. However, genetic factors do not influence disengagement from religious institutions. This study advances our knowledge of the etiology of apostasy and highlights the need to incorporate genetic data into social scientific research.
2019-herd.pdf: “Genes, Gender Inequality, and Educational Attainment”, Pamela Herd, Jeremy Freese, Kamil Sicinski, Benjamin W. Domingue, Kathleen Mullan Harris, Caiping Wei,, Robert M. Hauser (2019-11-22):
Women’s opportunities have been profoundly altered over the past century by reductions in the social and structural constraints that limit women’s educational attainment. Do social constraints manifest as a suppressing influence on genetic indicators of potential, and if so, did equalizing opportunity mean equalizing the role of genetics? We address this with three cohort studies: the Wisconsin Longitudinal Study (WLS; birth years 1939 to 1940), the Health and Retirement Study, and the National Longitudinal Study of Adolescent Health (Add Health; birth years 1975 to 1982). These studies include a “polygenic score” for educational attainment, providing a novel opportunity to explore this question. We find that within the WLS cohort, the relationship between genetics and educational outcomes is weaker for women than for men. However, as opportunities changed in the 1970s and 1980s, and many middle-aged women went back to school, the relationship between genetic factors and education strengthened for women as they aged. Furthermore, utilizing the HRS and Add Health, we find that as constraints limiting women’s educational attainment declined, gender differences in the relationship between genetics and educational outcomes weakened. We demonstrate that genetic influence must be understood through the lens of historical change, the life course, and social structures like gender.
2019-kandler-2.pdf: “The nature and nurture of HEXACO personality trait differences: An extended twin family study”, Christian Kandler, Julia Richter, Alexandra Zapko-Willmes (2019):
This study was designed to provide detailed estimates of genetic and environmental sources of variance in the HEXACO personality traits. For this purpose, we analyzed data from a German extended twin family study including 573 pairs of twins as well as 208 mothers, 119 fathers, 228 spouses, and 143 offspring of twins. All participants provided self-reports on the HEXACO-60. Extended twin family analyses using structural equation modeling (SEM) yielded that additive and nonadditive genetic influences accounted for about 50% of the variance in personality traits. The remaining variance was primarily due to individual-specific environmental sources and random measurement error. Spousal similarity in Openness was attributable to assortative mating, whereas spousal similarity in Honesty-Humility was attributable to environmental circumstances, partly due to a shared social background and spouse-specific effects. Our analyses yielded specifics for different personality traits. However, transmission of trait similarity from one generation to the next was primarily genetic.
2019-kandler.pdf: “The Study of Personality Architecture and Dynamics (SPeADy): A Longitudinal and Extended Twin Family Study”, Christian Kandler, Angelika Penner, Julia Richter, Alexandra Zapko-Willmes (2019-09-09):
The Study of Personality Architecture and Dynamics (SPeADy) is a German research project that aims to investigate the sources of interindividual differences in intraindividual personality development. The main focus lies in the dynamic interplay between more stable core characteristics and more environmentally malleable surface characteristics, as well as between personality and life experiences over time. SPeADy includes a twin family study encompassing data from 1962 individuals (age: 14–94) of 682 families, including 570 complete twin pairs (plus 1 triplet set), 327 parents, 236 spouses and 145 children of twins. Data collection started in 2016 and data from the first wave are currently obtainable as open source. Available data comprise a broad range of personality variables, such as personality trait constructs, motives, interests, values, moral foundations, religiosity and self-related concepts. For the currently ongoing second wave of data collection, we added retrospective reports on major life events. Special features of this genetically informative study are the extended twin family data and its longitudinal design. Three assessment waves in 2 years’ intervals are planned until 2022. In this article, we briefly describe the design and contents of the SPeADy twin family study as well as some recent findings, future plans and open science issues.
2019-khera.pdf: “Rare Genetic Variants Associated With Sudden Cardiac Death in Adults”, Amit V. Khera, Heather Mason-Suares, Deanna Brockman, Minxian Wang, Martin J. VanDenburgh, Ozlem Senol-Cosar, Candace Patterson, Christopher Newton-Cheh, Seyedeh M. Zekavat, Julie Pester, Daniel I. Chasman, Christopher Kabrhel, Majken K. Jensen, JoAnn E. Manson, J. Michael Gaziano, Kent D. Taylor, Nona Sotoodehnia, Wendy S. Post, Stephen S. Rich, Jerome I. Rotter, Eric S. Lander, Heidi L. Rehm, Kenney Ng, Anthony Philippakis, Matthew Lebo, Christine M. Albert, Sekar Kathiresan (2019-11-18):
Background: Sudden cardiac death occurs in ~220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection.
Objectives: This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population.
Methods: The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death.
Results: Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death—corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02).
Conclusions: Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ~1% of asymptomatic adults.
2019-lakhani.pdf: “Repurposing large health insurance claims data to estimate genetic and environmental contributions in 560 phenotypes”, Chirag M. Lakhani, Braden T. Tierney, Arjun K. Manrai, Jian Yang, Peter M. Visscher, Chirag J. Patel (2019-01-14):
We analysed a large health insurance dataset to assess the genetic and environmental contributions of 560 disease-related phenotypes in 56,396 twin pairs and 724,513 sibling pairs out of 44,859,462 individuals that live in the United States. We estimated the contribution of environmental risk factors (socioeconomic status (SES), air pollution and climate) in each phenotype. Mean heritability (h2 = 0.311) and shared environmental variance (c2 = 0.088) were higher than variance attributed to specific environmental factors such as zip-code-level SES (varSES = 0.002), daily air quality (var~AQI` = 0.0004), and average temperature (vartemp = 0.001) overall, as well as for individual phenotypes. We found statistically-significant heritability and shared environment for a number of comorbidities (h2 = 0.433, c2 = 0.241) and average monthly cost (h2 = 0.290, c2 = 0.302). All results are available using our Claims Analysis of Twin Correlation and Heritability (CaTCH) web application.
2019-lambert.pdf: “Towards Clinical Utility of Polygenic Risk Scores”, Samuel A. Lambert, Gad Abraham, Michael Inouye (2019):
Prediction of disease risk is an essential part of preventative medicine, often guiding clinical management. Risk prediction typically includes risk factors such as age, sex, family history of disease and lifestyle (e.g. smoking status); however, in recent years, there has been increasing interest to include genomic information into risk models. Polygenic risk scores (PRS) aggregate the effects of many genetic variants across the human genome into a single score and have recently been shown to have predictive value for multiple common diseases. In this review, we summarize the potential use cases for seven common diseases (breast cancer, prostate cancer, coronary artery disease, obesity, type 1 diabetes, type 2 diabetes and Alzheimer’s disease) where PRS has or could have clinical utility. PRS analysis for these diseases frequently revolved around (i) risk prediction performance of a PRS alone and in combination with other non-genetic risk factors, (ii) estimation of lifetime risk trajectories, (iii) the independent information of PRS and family history of disease or monogenic mutations and (iv) estimation of the value of adding a PRS to specific clinical risk prediction scenarios. We summarize open questions regarding PRS usability, ancestry bias and transferability, emphasizing the need for the next wave of studies to focus on the implementation and health-economic value of PRS testing. In conclusion, it is becoming clear that PRS have value in disease risk prediction and there are multiple areas where this may have clinical utility.
2019-lopezcortegano.pdf: “Inferring the Nature of Missing Heritability in Human Traits Using Data from the GWAS Catalog”, Eugenio López-Cortegano, Armando Caballero (2019-07-01):
Thousands of genes responsible for many diseases and other common traits in humans have been detected by Genome Wide Association Studies (GWAS) in the last decade. However, candidate causal variants found so far usually explain only a small fraction of the heritability estimated by family data. The most common explanation for this observation is that the missing heritability corresponds to variants, either rare or common, with very small effect, which pass undetected due to a lack of statistical power. We carried out a meta-analysis using data from the NHGRI-EBI GWAS Catalog in order to explore the observed distribution of locus effects for a set of 42 complex traits and to quantify their contribution to narrow-sense heritability. With the data at hand, we were able to predict the expected distribution of locus effects for 16 traits and diseases, their expected contribution to heritability, and the missing number of loci yet to be discovered to fully explain the familial heritability estimates. Our results indicate that, for 6 out of the 16 traits, the additive contribution of a great number of loci is unable to explain the familial (broad-sense) heritability, suggesting that the gap between GWAS and familial estimates of heritability may not ever be closed for these traits. In contrast, for the other 10 traits, the additive contribution of hundreds or thousands of loci yet to be found could potentially explain the familial heritability estimates, if this were the case. Computer simulations are used to illustrate the possible contribution from nonadditive genetic effects to the gap between GWAS and familial estimates of heritability.
2019-pavan.pdf: “The Genetics of Human Skin and Hair Pigmentation”, William J. Pavan, Richard A. Sturm (2019):
Human skin and hair color are visible traits that can vary dramatically within and across ethnic populations. The genetic makeup of these traits—including polymorphisms in the enzymes and signaling proteins involved in melanogenesis, and the vital role of ion transport mechanisms operating during the maturation and distribution of the melanosome—has provided new insights into the regulation of pigmentation. A large number of novel loci involved in the process have been recently discovered through four large-scale genome-wide association studies in Europeans, two large genetic studies of skin color in Africans, one study in Latin Americans, and functional testing in animal models. The responsible polymorphisms within these pigmentation genes appear at different population frequencies, can be used as ancestry-informative markers, and provide insight into the evolutionary selective forces that have acted to create this human diversity.
2019-segal.pdf: “Fullerton Virtual Twin Project: Overview and 2019 Update”, Nancy L. Segal, Francisca J. Niculae (2019):
Virtual twins (VTs) are defined as same-age unrelated siblings raised together from early infancy. This special class of adoptive siblings replays the rearing situation of twins, absent genetic relatedness. The first such pair was identified and studied in 1990 at the University of Minnesota, leading to the creation of the Fullerton Virtual Twin Study (FVTS) at California State University, Fullerton (CSUF) the following year. The registry currently includes 169 VT pairs, mostly children, with new pairs identified on a regular basis. These sibling sets provide a direct estimate of environmental influences on developmental traits and, as such, offer informative comparisons with ordinary monozygotic and dizygotic twins, full siblings and adoptive brothers and sisters. The sample characteristics, assessment battery and findings to date are summarized in this 2019 update.
2019-trimmer.pdf: “Genetic variation across the human olfactory receptor repertoire alters odor perception”, C. Trimmer, A. Keller, N. R. Murphy, L. L. Snyder, J. R. Willer, M. H. Nagai, N. Katsanis, L. B. Vosshall, H. Matsunami, J. D. Mainland (2019):
Humans use a family of more than 400 olfactory receptors (ORs) to detect odors, but there is currently no model that can predict olfactory perception from receptor activity patterns. Genetic variation in human ORs is abundant and alters receptor function, allowing us to examine the relationship between receptor function and perception. We sequenced the OR repertoire in 332 individuals and examined how genetic variation affected 276 olfactory phenotypes, including the perceived intensity and pleasantness of 68 odorants at two concentrations, detection thresholds of three odorants, and general olfactory acuity. Genetic variation in a single OR was frequently associated with changes in odorant perception, and we validated 10 cases in which in vitro OR function correlated with in vivo odorant perception using a functional assay. In 8 of these 10 cases, reduced receptor function was associated with reduced intensity perception. In addition, we used participant genotypes to quantify genetic ancestry and found that, in combination with single OR genotype, age, and gender, we can explain between 10% and 20% of the perceptual variation in 15 olfactory phenotypes, highlighting the importance of single OR genotype, ancestry, and demographic factors in the variation of olfactory perception.
2019-udler.pdf: “Genetic risk scores for diabetes diagnosis and precision medicine”, Miriam S. Udler, Mark I. McCarthy, Jose C. Florez, Anubha Mahajan (2019):
During the last decade, there have been substantial advances in the identification and characterization of DNA sequence variants associated with individual predisposition to type 1 and type 2 diabetes. As well as providing insights into the molecular, cellular, and physiological mechanisms involved in disease pathogenesis, these risk variants, when combined into a polygenic score, capture information on individual patterns of disease predisposition that have the potential to influence clinical management. In this review, we describe the various opportunities that polygenic scores provide: to predict diabetes risk, to support differential diagnosis, and to understand phenotypic and clinical heterogeneity. We also describe the challenges that will need to be overcome if this potential is to be fully realized.
2019-xing.pdf: “Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation”, Lijuan Xing, Guangsen Shi, Yulia Mostovoy, Nicholas W. Gentry, Zenghua Fan, Thomas B. Mcmahon, Pui-Yan Kwok, Christopher R. Jones, Louis J. Ptacek, Ying-Hui Fu (2019-10-16):
Sleep is a crucial physiological process for our survival and cognitive performance, yet the factors controlling human sleep regulation remain poorly understood. Here, we identified a missense mutation in a G protein–coupled neuropeptide S receptor 1 (NPSR1) that is associated with a natural short sleep phenotype in humans. Mice carrying the homologous mutation exhibited less sleep time despite increased sleep pressure. These animals were also resistant to contextual memory deficits associated with sleep deprivation. In vivo, the mutant receptors showed increased sensitivity to neuropeptide S exogenous activation. These results suggest that the NPS/NPSR1 pathway might play a critical role in regulating human sleep duration and in the link between sleep homeostasis and memory consolidation.
2019-zhong.pdf: “A genome-wide association study of bitter and sweet beverage consumption”, Victor W. Zhong, Alan Kuang, Rebecca D. Danning, Peter Kraft, Rob M. van Dam, Daniel I. Chasman, Marilyn C. Cornelis (2019):
Except for drinking water, most beverages taste bitter or sweet. Taste perception and preferences are heritable and determinants of beverage choice and consumption. Consumption of several bitter-tasting and sweet-tasting beverages has been implicated in development of major chronic diseases. We performed a genome-wide association study (GWAS) of self-reported bitter and sweet beverage consumption among ~370,000 participants of European ancestry, using a two-staged analysis design. Bitter beverages included coffee, tea, grapefruit juice, red wine, liquor and beer. Sweet beverages included artificially and sugar sweetened beverages (SSBs) and non-grapefruit juices. Five loci associated with total bitter beverage consumption were replicated (in/
near GCKR, ABCG2, AHR, POR and CYP1A1/2). No locus was replicated for total sweet beverage consumption. Sub-phenotype analyses targeting the alcohol, caffeine and sweetener components of beverages yielded additional loci: (1) four loci for bitter alcoholic beverages (GCKR, KLB, ADH1B and AGBL2); (2) five loci for bitter non-alcoholic beverages (ANXA9, AHR, POR, CYP1A1/2 and CSDC2); (3) 10 loci for coffee; six novel loci (SEC16B, TMEM18, OR8U8, AKAP6, MC4R and SPECC1L-ADORA2A); (4) FTO for SSBs. Of these 17 replicated loci, 12 have been associated with total alcohol consumption, coffee consumption, plasma caffeine metabolites or BMI in previous GWAS; none was involved in known sweet and bitter taste transduction pathways. Our study suggests that genetic variants related to alcohol consumption, coffee consumption and obesity were primary genetic determinants of bitter and sweet beverage consumption. Whether genetic variants related to taste perception are associated with beverage consumption remains to be determined.
2020-anderson.pdf: “The role of the shared environment in college attainment: An adoption study”, Elise L. Anderson, Gretchen R. B. Saunders, Emily A. Willoughby, William G. Iacono, Matt McGue (2020-10-14):
Objective: College attainment is one of the few phenotypes to have substantial variance accounted for by environmental factors shared by reared-together relatives. The shared environment is implicated by the consistently strong parent-to-offspring transmission of college attainment. The mechanisms underlying this relationship remain unclear. We use genetically informative methods with a longitudinal, adoption sample to identify possible environmental mechanisms underlying parent-offspring college transmission.
Method: Data were drawn from the Sibling Interaction and Behavior Study (SIBS), which includes 409 adoptive and 208 nonadoptive families, consisting of two offspring followed from adolescence into young adulthood and their rearing parents. Four domains of environmental mechanisms were examined: (a) skill enhancement; (b) academic support; (c) material advantage; and (d) supportive family environment.
Results: Both shared environmental and genetic factors contributed to the parent-offspring transmission of college attainment. However, highly educated parents did not appear to be increasing their adopted offspring’s attainment through skill development. The environmental factors that were associated with increased odds of offspring college attainment were mother’s academic expectations and family income.
Conclusion: While complete mediation of the parent-offspring transmission of college attainment was not identified, the results shed light on some of the mechanisms associated with the common environment variance in the college attainment phenotype.
2020-armstrongcarter.pdf: “The Earliest Origins of Genetic Nurture: The Prenatal Environment Mediates the Association Between Maternal Genetics and Child Development”, Emma Armstrong-Carter, Sam Trejo, Liam J. B. Hill, Kirsty L. Crossley, Dan Mason, Benjamin W. Domingue (2020-06-02):
Observed genetic associations with educational attainment may be due to direct or indirect genetic influences. Recent work highlights genetic nurture, the potential effect of parents’ genetics on their child’s educational outcomes via rearing environments. To date, few mediating childhood environments have been tested. We used a large sample of genotyped mother-child dyads (n = 2,077) to investigate whether genetic nurture occurs via the prenatal environment. We found that mothers with more education-related genes are generally healthier and more financially stable during pregnancy. Further, measured prenatal conditions explain up to one third of the associations between maternal genetics and children’s academic and developmental outcomes at the ages of 4 to 7 years. By providing the first evidence of prenatal genetic nurture and showing that genetic nurture is detectable in early childhood, this study broadens our understanding of how parental genetics may influence children and illustrates the challenges of within-person interpretation of existing genetic associations.
2020-barclay.pdf: “The heritability of insomnia: A meta-analysis of twin studies”, Nicola L. Barclay, Desi Kocevska, Wichor M. Bramer, Eus J. W. Van Someren, Philip Gehrman (2020-11-21):
Twin studies of insomnia exhibit heterogeneity in estimates of heritability. This heterogeneity is likely because of sex differences, age of the sample, the reporter and the definition of insomnia. The aim of the present study was to systematically search the literature for twin studies investigating insomnia disorder and insomnia symptoms and to meta-analyse the estimates of heritability derived from these studies to generate an overall estimate of heritability. We further examined whether heritability was moderated by sex, age, reporter and insomnia symptom. A systematic literature search of five online databases was completed on 24 January 2020. Two authors independently screened 5644 abstracts, and 160 complete papers for the inclusion criteria of twin studies from the general population reporting heritability statistics on insomnia or insomnia symptoms, written in English, reporting data from independent studies. We ultimately included 12 papers in the meta-analysis. The meta-analysis focussed on twin intra-class correlations for monozygotic and dizygotic twins. Based on these intra-class correlations, the meta-analytic estimate of heritability was estimated at 40%. Moderator analyses showed stronger heritability in females than males; and for parent-reported insomnia symptoms compared with self-reported insomnia symptoms. There were no other statistically-significant moderator effects, although this is likely because of the small number of studies that were comparable across levels of the moderators. Our meta-analysis provides a robust estimate of the heritability of insomnia, which can inform future research aiming to uncover molecular genetic factors involved in insomnia vulnerability.
2020-baselmans.pdf: “Risk in Relatives, Heritability, SNP-Based Heritability, and Genetic Correlations in Psychiatric Disorders: A Review”, Bart M.L. Baselmans, Loïc Yengo, Wouter van Rheenen, Naomi R. Wray (2020-06-09):
The genetic contribution to psychiatric disorders is observed through the increased rates of disorders in the relatives of those diagnosed with disorders. These increased rates are observed to be nonspecific; for example, children of those with schizophrenia have increased rates of schizophrenia but also a broad range of other psychiatric diagnoses. While many factors contribute to risk, epidemiological evidence suggests that the genetic contribution carries the highest risk burden. The patterns of inheritance are consistent with a polygenic architecture of many contributing risk loci. The genetic studies of the past decade have provided empirical evidence identifying thousands of DNA variants associated with psychiatric disorders. Here, we describe how these latest results are consistent with observations from epidemiology. We provide an R tool (CHARRGe) to calculate genetic parameters from epidemiological parameters and vice versa. We discuss how the single nucleotide polymorphism-based estimates of heritability and genetic correlation relate to those estimated from family records. [Keywords: Family register data, Genetic correlation, GWAS, Heritability, Psychiatric genetics, Risk in relatives]
2020-berry.pdf: “Human postprandial responses to food and potential for precision nutrition”, Sarah E. Berry, Ana M. Valdes, David A. Drew, Francesco Asnicar, Mohsen Mazidi, Jonathan Wolf, Joan Capdevila, George Hadjigeorgiou, Richard Davies, Haya Al Khatib, Christopher Bonnett, Sajaysurya Ganesh, Elco Bakker, Deborah Hart, Massimo Mangino, Jordi Merino, Inbar Linenberg, Patrick Wyatt, Jose M. Ordovas, Christopher D. Gardner, Linda M. Delahanty, Andrew T. Chan, Nicola Segata, Paul W. Franks, Tim D. Spector (2020-06-11):
Metabolic responses to food influence risk of cardiometabolic disease, but large-scale high-resolution studies are lacking. We recruited n = 1,002 twins and unrelated healthy adults in the United Kingdom to the PREDICT 1 study and assessed postprandial metabolic responses in a clinical setting and at home. We observed large inter-individual variability (as measured by the population coefficient of variation (s.d./
mean, %)) in postprandial responses of blood triglyceride (103%), glucose (68%) and insulin (59%) following identical meals. Person-specific factors, such as gut microbiome, had a greater influence (7.1% of variance) than did meal macronutrients (3.6%) for postprandial lipemia, but not for postprandial glycemia (6.0% and 15.4%, respectively); genetic variants had a modest impact on predictions (9.5% for glucose, 0.8% for triglyceride, 0.2% for C-peptide). Findings were independently validated in a US cohort (n = 100 people). We developed a machine-learning model that predicted both triglyceride (r = 0.47) and glycemic (r = 0.77) responses to food intake. These findings may be informative for developing personalized diet strategies. The ClinicalTrials.gov registration identifier is NCT03479866.
…The heritability of postprandial responses in the UK cohort was examined using classical twin methods (variance components analyses) to establish the upper bound of what might be predicted by directly measured genetic variation. Two-thirds of the cohort was recruited from the TwinsUK registry16, of which 230 twin pairs (n = 460; 183 monozygotic and 47 dizygotic) were studied for heritability. Additive genetic factors explained 48% of the variance in glucoseiAUC0–2h, whereas 0% of the variance in triglyceride6h-rise and 9% of the variance in insulin2h-rise were explained in this way (Figure 3b). The estimated genetic variances in insulin1h-rise and C-peptide1h-rise were close to 0 (Supplementary Table 4).
2020-bianco.pdf: “Recent Common Origin, Reduced Population Size, and Marked Admixture Have Shaped European Roma Genomes”, Erica Bianco, Guillaume Laval, Neus Font-Porterias, Carla García-Fernández, Begoña Dobon, Rubén Sabido-Vera, Emilija Sukarova Stefanovska, Vaidutis Kučinskas, Halyna Makukh, Horolma Pamjav, Lluis Quintana-Murci, Mihai G Netea, Jaume Bertranpetit, Francesc Calafell, David Comas (2020-06-26):
The Roma Diaspora—traditionally known as Gypsies—remains among the least explored population migratory events in historical times. It involved the migration of Roma ancestors out-of-India through the plateaus of Western Asia ultimately reaching Europe. The demographic effects of the Diaspora—bottlenecks, endogamy, and gene flow—might have left marked molecular traces in the Roma genomes. Here, we analyze the whole-genome sequence of 46 Roma individuals pertaining to four migrant groups in six European countries. Our analyses revealed a strong, early founder effect followed by a drastic reduction of ∼44% in effective population size. The Roma common ancestors split from the Punjabi population, from Northwest India, some generations before the Diaspora started, <2,000 years ago. The initial bottleneck and subsequent endogamy are revealed by the occurrence of extensive runs of homozygosity and identity-by-descent segments in all Roma populations. Furthermore, we provide evidence of gene flow from Armenian and Anatolian groups in present-day Roma, although the primary contribution to Roma gene pool comes from non-Roma Europeans, which accounts for >50% of their genomes. The linguistic and historical differentiation of Roma in migrant groups is confirmed by the differential proportion, but not a differential source, of European admixture in the Roma groups, which shows a westward cline. In the present study, we found that despite the strong admixture Roma had in their diaspora, the signature of the initial bottleneck and the subsequent endogamy is still present in Roma genomes.
[Keywords: Roma Diaspora, Gypsies, complete genomes, demographic history, endogamy, admixture]
2020-dawes.pdf: “On the genetic basis of political orientation”, Christopher T. Daws, Aaron C. Weinschenk (2020-08-01):
- Twin studies show that political ideology is about 40% heritable.
- More sophisticated designs also find a substantial genetic influence on ideology.
- Recent studies have examined how genes connect to ideology, finding some evidence that psychological traits may link genes and ideology.
- Genome-wide association studies have started to emerge, but findings should be taken as very preliminary at this point.
- Future work will benefit from large samples that provide enough power to study genetic variants related to ideology.
Scholars have long been interested in the underpinnings of political ideology. Over the past fifteen years or so, political scientists, psychologists, sociologists, and economists have started to take seriously the idea that ideology might be influenced by genes. In this article, we review the literature on the genetics of ideology. We begin by describing twin studies and more sophisticated approaches that have now emerged, which consistently show that ideology is about 40% heritable. Next, we examine the state of research on genetic influences on ideology over the life cycle and mechanisms that could link genes and ideology. We conclude by discussing the preliminary genome-wide studies that have been conducted. Existing research has provided important insights into the link between biology and ideology, but additional research is needed in order to provide a more nuanced understanding of the role of biology in the formation of political ideology.
2020-decasien.pdf: “Greater variability in chimpanzee (Pan troglodytes) brain structure among males”, Alex R. DeCasien, Chet C. Sherwood, Steven J. Schapiro, James P. Higham (2020-04-22):
Across the animal kingdom, males tend to exhibit more behavioural and morphological variability than females, consistent with the ‘greater male variability hypothesis’. This may reflect multiple mechanisms operating at different levels, including selective mechanisms that produce and maintain variation, extended male development, and X chromosome effects. Interestingly, human neuroanatomy shows greater male variability, but this pattern has not been demonstrated in any other species. To address this issue, we investigated sex-specific neuroanatomical variability in chimpanzees by examining relative and absolute surface areas of 23 cortical sulci across 226 individuals (135F/
91M), using permutation tests of the male-to-female variance ratio of residuals from MCMC generalized linear mixed models controlling for relatedness. We used these models to estimate sulcal size heritability, simulations to assess the significance of heritability, and Pearson correlations to examine inter-sulcal correlations. Our results show that: (i) male brain structure is relatively more variable; (ii) sulcal surface areas are heritable and therefore potentially subject to selection; (iii) males exhibit lower heritability values, possibly reflecting longer development; and (iv) males exhibit stronger inter-sulcal correlations, providing indirect support for sex chromosome effects. These results provide evidence that greater male neuroanatomical variability extends beyond humans, and suggest both evolutionary and developmental explanations for this phenomenon.
2020-delasheras.pdf: “Does the Brain-Derived Neurotrophic Factor Val66Met Polymorphism Modulate the Effects of Physical Activity and Exercise on Cognition?”, Bernat de las Heras, Lynden Rodrigues, Jacopo Cristini, Maxana Weiss, Anna Prats-Puig, Marc Roig (2020-12-10):
The Val66Met is a polymorphism of the brain-derived neurotrophic factor (BDNF) gene that encodes a substitution of a valine (Val) to methionine (Met) amino acid. Carrying this polymorphism reduces the activity-dependent secretion of the BDNF protein, which can potentially affect brain plasticity and cognition. We reviewed the biology of Val66Met and surveyed 26 studies (11,417 participants) that examined the role of this polymorphism in moderating the cognitive response to physical activity (PA) and exercise. Nine observational studies confirmed a moderating effect of Val66Met on the cognitive response to PA but differences between Val and Met carriers were inconsistent and only significant in some cognitive domains. Only five interventional studies found a moderating effect of Val66Met on the cognitive response to exercise, which was also inconsistent in its direction. Two studies showed a superior cognitive response in Val carriers and three studies showed a better response in Met carriers. These results do not support a general and consistent effect of Val66Met in moderating the cognitive response to PA or exercise. Both Val and Met carriers can improve specific aspects of cognition by increasing PA and engaging in exercise. Causes for discrepancies among studies, effect moderators, and future directions are discussed.
2020-eaves.pdf: “Birmingham and Beyond”, Lindon Eaves (2020-04-07):
Nick Martin was a doctoral student of mine at the University of Birmingham in the mid 1970s. In this review, I discuss two of Nick’s earliest and most seminal contributions to the field of behavior genetics. First, Martin and Eaves’ (1977) extension of the model-fitting approach to multivariate data, which laid the theoretical groundwork for a generation of multivariate behavior genetic studies. Second, the Martin et al.’s (1978) manuscript on the power of the classical twin design, which showed that thousands of twin pairs would be required in order to reliably estimate components of variance, and has served as impetus for the formation of large-scale twin registries across the world. I discuss these contributions against the historical backdrop of a time when we and others were struggling with the challenge of figuring out how to incorporate gene-by-environment interaction, gene-environment correlation, mate selection and cultural transmission into more complex genetic models of human behavior.
2020-floyd.pdf: “Heritability of affectionate communication: A twins study”, Kory Floyd, Chance York, Colter D. Ray (2020-05-13):
Using a twin study design, we explored the extent to which affectionate communication is a heritable behavioral trait. Participants (n = 928) were 464 adult twin pairs (229 monozygotic, 235 dizygotic) who provided data on their affectionate communication behaviors. Through ACE modeling, we determined that approximately 45% of the variance in trait expressed affectionate communication is heritable, whereas 21% of the variance in trait received affection was heritable. A bivariate Cholesky decomposition model also revealed that almost 26% of the covariation in expressed and received affection is attributable to additive genetic factors. These estimates were driven primarily by females and those 50 years of age and older. The results suggest the utility of giving greater attention to genetic and biological influences on communicative behaviors by expanding the scope of communication theory beyond consideration of only environmental influences. [Keywords: affectionate communication, genetics, twin study, ACE model, heritability, affection exchange theory]
2020-halpernmanners.pdf: “The intergenerational transmission of early educational advantages: New results based on an adoption design”, Andrew Halpern-Manners, Helge Marahrens, Jenae M. Neiderhiser, Misaki N. Natsuaki, Daniel S. Shaw, David Reiss, Leslie D. Leve (2020-06-01):
Sociological research has traditionally emphasized the importance of post-birth factors (i.e., social, economic, and cultural capital) in the intergenerational transmission of educational advantages, to the neglect of potentially consequential pre-birth endowments (e.g., heritable traits) that are passed from parent to child. In this study, we leverage an experiment of nurture—children who were adopted at birth into nonrelative families—in an effort to simultaneously model the effects associated with both pathways. To do so, we fit a series of simple linear regression models that relate the academic achievement of adopted children to the educational attainments of their adoptive and biological parents, using U.S. data from a recent nationwide sample of birth and adoptive families (the Early Growth and Development Study). Because our dataset includes both “genetic” and “environmental” relatives, but not “genetic-and-environmental” relatives, the separate contributions of each pathway can be identified, as well as possible interactions between the two. Our results show that children’s early achievements are influenced not only by the attainments of their adoptive parents, but also the attainments of their birth parents—suggesting the presence of environmental and genetically mediated effects. Supplementary analyses provide little evidence of effect moderation, using both distal and proximate measures of the childhood environment to model gene-by-environment interactions. These findings are robust to a variety of parameterizations, withstand a series of auxiliary checks, and remain intact even after controlling for intrauterine exposures and other measurable variables that could compromise our design. The implications of our results for theory and research in the stratification literature, and for those interested in educational mobility, are discussed.
2020-harden.pdf: “Using genetics for social science”, K. Paige Harden, Philipp D. Koellinger (2020-05-11):
Social science genetics is concerned with understanding whether, how and why genetic differences between human beings are linked to differences in behaviours and socioeconomic outcomes. Our review discusses the goals, methods, challenges and implications of this research endeavour. We survey how the recent developments in genetics are beginning to provide social scientists with a powerful new toolbox they can use to better understand environmental effects, and we illustrate this with several substantive examples. Furthermore, we examine how medical research can benefit from genetic insights into social-scientific outcomes and vice versa. Finally, we discuss the ethical challenges of this work and clarify several common misunderstandings and misinterpretations of genetic research on individual differences.
2020-hatemi.pdf: “The Barbarians Are at the Gate!”, Peter Hatemi (2020-04):
Nicholas Martin’s contribution to science is well known. This article reviews one small part of his pioneering work that integrated political and social attitudes with behavior genetics. Nick Martin, in part, led to a paradigm shift in the social sciences, and in political science in particular. These fields were previously wed to behavioralist approaches and now routinely include genetic influences in both theoretical and empirical study. This article also celebrates a part of Nick’s contribution that many do not know. Nick Martin does not just build science, he builds scientists. There are many who would not be academics or scholars without Nick’s guidance, mentorship and friendship. This review was written to express the deepest appreciation for what he has done and continues to do for science and the scientist.
2020-ishigaki.pdf: “Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases”, Kazuyoshi Ishigaki, Masato Akiyama, Masahiro Kanai, Atsushi Takahashi, Eiryo Kawakami, Hiroki Sugishita, Saori Sakaue, Nana Matoba, Siew-Kee Low, Yukinori Okada, Chikashi Terao, Tiffany Amariuta, Steven Gazal, Yuta Kochi, Momoko Horikoshi, Ken Suzuki, Kaoru Ito, Satoshi Koyama, Kouichi Ozaki, Shumpei Niida, Yasushi Sakata, Yasuhiko Sakata, Takashi Kohno, Kouya Shiraishi, Yukihide Momozawa, Makoto Hirata, Koichi Matsuda, Masashi Ikeda, Nakao Iwata, Shiro Ikegawa, Ikuyo Kou, Toshihiro Tanaka, Hidewaki Nakagawa, Akari Suzuki, Tomomitsu Hirota, Mayumi Tamari, Kazuaki Chayama, Daiki Miki, Masaki Mori, Satoshi Nagayama, Yataro Daigo, Yoshio Miki, Toyomasa Katagiri, Osamu Ogawa, Wataru Obara, Hidemi Ito, Teruhiko Yoshida, Issei Imoto, Takashi Takahashi, Chizu Tanikawa, Takao Suzuki, Nobuaki Sinozaki, Shiro Minami, Hiroki Yamaguchi, Satoshi Asai, Yasuo Takahashi, Ken Yamaji, Kazuhisa Takahashi, Tomoaki Fujioka, Ryo Takata, Hideki Yanai, Akihide Masumoto, Yukihiro Koretsune, Hiromu Kutsumi, Masahiko Higashiyama, Shigeo Murayama, Naoko Minegishi, Kichiya Suzuki, Kozo Tanno, Atsushi Shimizu, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Hirokazu Uemura, Keitaro Tanaka, Mariko Naito, Makoto Sasaki, Kenji Wakai, Shoichiro Tsugane, Masayuki Yamamoto, Kazuhiko Yamamoto, Yoshinori Murakami, Yusuke Nakamura, Soumya Raychaudhuri, Johji Inazawa, Toshimasa Yamauchi, Takashi Kadowaki, Michiaki Kubo, Yoichiro Kamatani (2020-06-08):
The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (p < 9.58 × 10−9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 statistically-significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
2020-latvala.pdf: “Association of parental substance misuse with offspring substance misuse and criminality: a genetically informed register-based study”, Antti Latvala, Ralf Kuja-Halkola, Brian M. D'Onofrio, Nitya Jayaram-Lindström, Henrik Larsson, Paul Lichtenstein (2020-06-29):
Background: Genetically informed studies have provided mixed findings as to what extent parental substance misuse is associated with offspring substance misuse and antisocial behavior due to shared environmental and genetic factors.
Methods: We linked data from nationwide registries for a cohort of 2 476 198 offspring born in Sweden 1958–1995 and their parents. Substance misuse was defined as International Classification of Diseases diagnoses of alcohol/
drug use disorders or alcohol/ drug-related criminal convictions. Quantitative genetic offspring-of-siblings analyses in offspring of monozygotic and dizygotic twin, full-sibling, and half-sibling parents were conducted.
Results: Both maternal and paternal substance misuse were robustly associated with offspring substance misuse [maternal adjusted hazard ratio (aHR) = 1.83 (95% confidence interval (CI) 1.80–1.87); paternal aHR = 1.96 (1.94–1.98)] and criminal convictions [maternal aHR = 1.56 (1.54–1.58); paternal aHR = 1.66 (1.64–1.67)]. Additive genetic effects explained 42% (95% CI 25–56%) and 46% (36–55%) of the variance in maternal and paternal substance misuse, respectively, and between 36 and 44% of the variance in substance misuse and criminality in offspring. The associations between parental substance misuse and offspring outcomes were mostly due to additive genetic effects, which explained 54–85% of the parent-offspring covariance. However, both nuclear and extended family environmental factors also contributed to the associations, especially with offspring substance misuse.
Conclusions: Our findings from a large offspring-of-siblings study indicate that shared genetic influences mostly explain the associations between parental substance misuse and both offspring substance misuse and criminality, but we also found evidence for the contribution of environmental factors shared by members of nuclear and extended families.
2020-lu.pdf: “Individuals with common diseases but with a low polygenic risk score could be prioritized for rare variant screening”, Tianyuan Lu, Sirui Zhou, Haoyu Wu, Vincenzo Forgetta, Celia M. T. Greenwood, J. Brent Richards (2020-10-28):
Purpose: Identifying rare genetic causes of common diseases can improve diagnostic and treatment strategies, but incurs high costs. We tested whether individuals with common disease and low polygenic risk score (PRS) for that disease generated from less expensive genome-wide genotyping data are more likely to carry rare pathogenic variants.
Methods: We identified patients with one of five common complex diseases among 44,550 individuals who underwent exome sequencing in the UK Biobank. We derived PRS for these five diseases, and identified pathogenic rare variant heterozygotes. We tested whether individuals with disease and low PRS were more likely to carry rare pathogenic variants. Results: While rare pathogenic variants conferred, at most, 5.18-fold (95% confidence interval [CI]: 2.32–10.13) increased odds of disease, a standard deviation increase in PRS, at most, increased the odds of disease by 5.25-fold (95% CI: 5.06–5.45). Among diseased patients, a standard deviation decrease in the PRS was associated with, at most, 2.82-fold (95% CI: 1.14–7.46) increased odds of identifying rare variant heterozygotes.
Conclusion: Rare pathogenic variants were more prevalent among affected patients with a low PRS. Therefore, prioritizing individuals for sequencing who have disease but low PRS may increase the yield of sequencing studies to identify rare variant heterozygotes
2020-maes.pdf: “Nicholas (Nick) G. Martin and the Extended Twin Model”, Hermine H. Maes (2020-04-07):
The extended twin model is a unique design in the genetic epidemiology toolbox that allows to simultaneously estimate multiple causes of variation such as genetic and cultural transmission, genotype-environment covariance and assortative mating, among others. Nick Martin has played a key role in the conception of the model, the collection of substantially large data sets to test the model, the application of the model to a range of phenotypes, the publication of the results including cross-cultural comparisons, the evaluation of bias and power of the design and the further elaborations of the model, such as the children-of-twins design.
2020-mills.pdf: “Sociology, Genetics, and the Coming of Age of Sociogenomics”, Melinda C. Mills, Felix C. Tropf (2020-05-11):
Recent years have seen the birth of sociogenomics via the infusion of molecular genetic data. We chronicle the history of genetics, focusing particularly on post-2005 genome-wide association studies, the post-2015 big data era, and the emergence of polygenic scores. We argue that understanding polygenic scores, including their genetic correlations with each other, causation, and underlying biological architecture, is vital. We show how genetics can be introduced to understand a myriad of topics such as fertility, educational attainment, intergenerational social mobility, well-being, addiction, risky behavior, and longevity. Although models of gene-environment interaction and correlation mirror agency and structure models in sociology, genetics is yet to be fully discovered by this discipline. We conclude with a critical reflection on the lack of diversity, nonrepresentative samples, precision policy applications, ethics, and genetic determinism. We argue that sociogenomics can speak to long-standing sociological questions and that sociologists can offer innovative theoretical, measurement, and methodological innovations to genetic research.
2020-murray.pdf: “Could Polygenic Risk Scores Be Useful in Psychiatry? A Review”, Graham K. Murray, Tian Lin, Jehannine Austin, John J. McGrath, Ian B. Hickie, Naomi R. Wray (2020-10-14):
Importance: Polygenic risk scores (PRS) are predictors of the genetic susceptibility to diseases, calculated for individuals as weighted counts of thousands of risk variants in which the risk variants and their weights have been identified in genome-wide association studies. Polygenic risk scores show promise in aiding clinical decision-making in many areas of medical practice. This review evaluates the potential use of PRS in psychiatry.
Observations: On their own, PRS will never be able to establish or definitively predict a diagnosis of common complex conditions (eg, mental health disorders), because genetic factors only contribute part of the risk and PRS will only ever capture part of the genetic contribution. Combining PRS with other risk factors has potential to improve outcome prediction and aid clinical decision-making (eg, determining follow-up options for individuals seeking help who are at clinical risk of future illness). Prognostication of adverse physical health outcomes or response to treatment in clinical populations are of great interest for psychiatric practice, but data from larger samples are needed to develop and evaluate PRS.
Conclusions and Relevance: Polygenic risk scores will contribute to risk assessment in clinical psychiatry as it evolves to combine information from molecular, clinical, and lifestyle metrics. The genome-wide genotype data needed to calculate PRS are inexpensive to generate and could become available to psychiatrists as a by-product of practices in other medical specialties. The utility of PRS in clinical psychiatry, as well as ethical issues associated with their use, should be evaluated in the context of realistic expectations of what PRS can and cannot deliver. Clinical psychiatry has lagged behind other fields of health care in its use of new technologies and routine clinical data for research. Now is the time to catch up.
2020-richter.pdf: “Genomic analyses implicate noncoding de novo variants in congenital heart disease”, Felix Richter, Sarah U. Morton, Seong Won Kim, Alexander Kitaygorodsky, Lauren K. Wasson, Kathleen M. Chen, Jian Zhou, Hongjian Qi, Nihir Patel, Steven R. DePalma, Michael Parfenov, Jason Homsy, Joshua M. Gorham, Kathryn B. Manheimer, Matthew Velinder, Andrew Farrell, Gabor Marth, Eric E. Schadt, Jonathan R. Kaltman, Jane W. Newburger, Alessandro Giardini, Elizabeth Goldmuntz, Martina Brueckner, Richard Kim, George A. Porter, Daniel Bernstein, Wendy K. Chung, Deepak Srivastava, Martin Tristani-Firouzi, Olga G. Troyanskaya, Diane E. Dickel, Yufeng Shen, Jonathan G. Seidman, Christine E. Seidman, Bruce D. Gelb (2020-06-29):
A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; p = 8.7 × 10−4). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, p = 1 × 10−5). We observed statistically-significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1–5.0, p = 5.4 × 10−3). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1–1.2, p = 8.8 × 10−5). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.
2020-segal.pdf: “Twins Living Apart: Behavioral Insights/Twin Study Reviews: Managing Monochorionic-Diamniotic Twin Pregnancies; Paternity Testing in Multiple Pregnancies; Twin Research on Resilience; Trisomies in Twin Pregnancies/Human Interest: Reunited Brazilian Twins; Website for Twins with Disabled Co-Twins; Twins Separated in Secret of the Nile Series; Mengele: Unmasking the Angel of Death; Twins Helping Others”, Nancy L. Segal (2020-11-16):
A brief review of research findings regarding twins living apart is presented. This review is followed by a look into the lives of a pair of monozygotic male twins who have lived in different continents for many years, but who stay closely connected. The reasons behind their decision and its impact on their behavioral resemblance and social relationship quality are examined. The next section summarizes recent studies that address the management of monochorionic-diamniotic twin pregnancies, paternity testing in multiple pregnancies, trisomies in twin pregnancies and the roots of resilience. The final portion of this article presents human-interest stories involving reunited Brazilian twins, a new resource for twins with disabled co-twins, twins separated in the Secret of the Nile television series, a new book about Dr Josef Mengele and his horrific twin experiments conducted at the Auschwitz-Birkenau concentration camp, and a pair of twins dedicated to helping others.
2020-smeland.pdf: “The polygenic architecture of schizophrenia—rethinking pathogenesis and nosology”, Olav B. Smeland, Oleksandr Frei, Anders M. Dale, Ole A. Andreassen (2020-06-11):
Abstract: Schizophrenia is a severe psychiatric disorder with considerable morbidity and mortality. Although the past two decades have seen limited improvement in the treatment of schizophrenia, research into the genetic causes of this condition has made important advances that offer new insights into the aetiology of schizophrenia. This Review summarizes the evidence for a polygenic architecture of schizophrenia that involves a large number of risk alleles across the whole range of population frequencies. These genetic risk loci implicate biological processes related to neurodevelopment, neuronal excitability, synaptic function and the immune system in the pathogenesis of schizophrenia. Mathematical models also suggest a substantial overlap between schizophrenia and psychiatric, behavioural and cognitive traits, a situation that has implications for understanding its clinical epidemiology, psychiatric nosology and pathobiology. Looking ahead, further genetic discoveries are expected to lead to clinically relevant predictive approaches for identifying high-risk individuals, improved diagnostic accuracy, increased yield from drug development programmes and improved stratification strategies to address the heterogeneous disease course and treatment responses observed among affected patients.
- Schizophrenia is characterized by ‘positive’ psychotic symptoms (including hallucinations and delusions) and ‘negative’ symptoms (including blunted affect, apathy and social impairment); this disorder is associated with considerable morbidity and mortality.
- In the past decade, important advances have been made in our understanding of the genetics of schizophrenia.
- The polygenic architecture of schizophrenia is accounted for by thousands of common genetic variants with small effect sizes and a few rare variants with large effect sizes.
- These genetic risk variants implicate dysregulation of biological processes linked to neurodevelopment, neuronal excitability, synaptic function and the immune system in schizophrenia.
- Genetic risk factors associated with schizophrenia transcend diagnostic boundaries and form a continuum with normal psychosocial traits, which challenges current psychiatric nosology.
- Although increasingly larger sample sizes will accelerate the discovery of genetic variants, novel statistical methodologies could also improve the efficiency of analyses, render discoveries clinically relevant and facilitate precision medicine approaches.
2020-surendran.pdf: “Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals”, Praveen Surendran, Elena V. Feofanova, Najim Lahrouchi, Ioanna Ntalla, Savita Karthikeyan, James Cook, Lingyan Chen, Borbala Mifsud, Chen Yao, Aldi T. Kraja, James H. Cartwright, Jacklyn N. Hellwege, Ayush Giri, Vinicius Tragante, Gudmar Thorleifsson, Dajiang J. Liu, Bram P. Prins, Isobel D. Stewart, Claudia P. Cabrera, James M. Eales, Artur Akbarov, Paul L. Auer, Lawrence F. Bielak, Joshua C. Bis, Vickie S. Braithwaite, Jennifer A. Brody, E. Warwick Daw, Helen R. Warren, Fotios Drenos, Sune Fallgaard Nielsen, Jessica D. Faul, Eric B. Fauman, Cristiano Fava, Teresa Ferreira, Christopher N. Foley, Nora Franceschini, He Gao, Olga Giannakopoulou, Franco Giulianini, Daniel F. Gudbjartsson, Xiuqing Guo, Sarah E. Harris, Aki S. Havulinna, Anna Helgadottir, Jennifer E. Huffman, Shih-Jen Hwang, Stavroula Kanoni, Jukka Kontto, Martin G. Larson, Ruifang Li-Gao, Jaana Lindström, Luca A. Lotta, Yingchang Lu, Jian’an Luan, Anubha Mahajan, Giovanni Malerba, Nicholas G. D. Masca, Hao Mei, Cristina Menni, Dennis O. Mook-Kanamori, David Mosen-Ansorena, Martina Müller-Nurasyid, Guillaume Paré, Dirk S. Paul, Markus Perola, Alaitz Poveda, Rainer Rauramaa, Melissa Richard, Tom G. Richardson, Nuno Sepúlveda, Xueling Sim, Albert V. Smith, Jennifer A. Smith, James R. Staley, Alena Stanáková, Patrick Sulem, Sébastien Thériault, Unnur Thorsteinsdottir, Stella Trompet, Tibor V. Varga, Digna R. Velez Edwards, Giovanni Veronesi, Stefan Weiss, Sara M. Willems, Jie Yao, Robin Young, Bing Yu, Weihua Zhang, Jing-Hua Zhao, Wei Zhao, Wei Zhao, Evangelos Evangelou, Stefanie Aeschbacher, Eralda Asllanaj, Stefan Blankenberg, Lori L. Bonnycastle, Jette Bork-Jensen, Ivan Brandslund, Peter S. Braund, Stephen Burgess, Kelly Cho, Cramer Christensen, John Connell, Renée de Mutsert, Anna F. Dominiczak, Marcus Dörr, Gudny Eiriksdottir, Aliki-Eleni Farmaki, J. Michael Gaziano, Niels Grarup, Megan L. Grove, Göran Hallmans, Torben Hansen, Christian T. Have, Gerardo Heiss, Marit E. Jørgensen, Pekka Jousilahti, Eero Kajantie, Mihir Kamat, AnneMari Käräjämäki, Fredrik Karpe, Heikki A. Koistinen, Csaba P. Kovesdy, Kari Kuulasmaa, Tiina Laatikainen, Lars Lannfelt, I-Te Lee, Wen-Jane Lee, LifeLines Cohort Study, Allan Linneberg, Lisa W. Martin, Marie Moitry, Girish Nadkarni, Matt J. Neville, Colin N. A. Palmer, George J. Papanicolaou, Oluf Pedersen, James Peters, Neil Poulter, Asif Rasheed, Katrine L. Rasmussen, N. William Rayner, Reedik Mägi, Frida Renström, Rainer Rettig, Jacques Rossouw, Pamela J. Schreiner, Peter S. Sever, Emil L. Sigurdsson, Tea Skaaby, Yan V. Sun, Johan Sundstrom, Gudmundur Thorgeirsson, Tõnu Esko, Elisabetta Trabetti, Philip S. Tsao, Tiinamaija Tuomi, Stephen T. Turner, Ioanna Tzoulaki, Ilonca Vaartjes, Anne-Claire Vergnaud, Cristen J. Willer, Peter W. F. Wilson, Daniel R. Witte, Ekaterina Yonova-Doing, He Zhang, Naheed Aliya, Peter Almgren, Philippe Amouyel, Folkert W. Asselbergs, Michael R. Barnes, Alexandra I. Blakemore, Michael Boehnke, Michiel L. Bots, Erwin P. Bottinger, Julie E. Buring, John C. Chambers, Yii-Der Ida Chen, Rajiv Chowdhury, David Conen, Adolfo Correa, George Davey Smith, Rudolf A. de Boer, Ian J. Deary, George Dedoussis, Panos Deloukas, Emanuele Di Angelantonio, Paul Elliott, EPIC-CVD, EPIC-InterAct, Stephan B. Felix, Jean Ferrières, Ian Ford, Myriam Fornage, Paul W. Franks, Stephen Franks, Philippe Frossard, Giovanni Gambaro, Tom R. Gaunt, Leif Groop, Vilmundur Gudnason, Tamara B. Harris, Caroline Hayward, Branwen J. Hennig, Karl-Heinz Herzig, Erik Ingelsson, Jaakko Tuomilehto, Marjo-Riitta Järvelin, J. Wouter Jukema, Sharon L. R. Kardia, Frank Kee, Jaspal S. Kooner, Charles Kooperberg, Lenore J. Launer, Lars Lind, Ruth J. F. Loos, Abdulla al Shafi. Majumder, Markku Laakso, Mark I. McCarthy, Olle Melander, Karen L. Mohlke, Alison D. Murray, Børge Grønne Nordestgaard, Marju Orho-Melander, Chris J. Packard, Sandosh Padmanabhan, Walter Palmas, Ozren Polasek, David J. Porteous, Andrew M. Prentice, Michael A. Province, Caroline L. Relton, Kenneth Rice, Paul M. Ridker, Olov Rolandsson, Frits R. Rosendaal, Jerome I. Rotter, Igor Rudan, Veikko Salomaa, Nilesh J. Samani, Naveed Sattar, Wayne H.-H. Sheu, Blair H. Smith, Nicole Soranzo, Timothy D. Spector, John M. Starr, Sylvain Sebert, Kent D. Taylor, Timo A. Lakka, Nicholas J. Timpson, Martin D. Tobin, Understanding Society Scientific Group, Pim van der Harst, Peter van der Meer, Vasan S. Ramachandran, Niek Verweij, Jarmo Virtamo, Uwe Völker, David R. Weir, Eleftheria Zeggini, Fadi J. Charchar, Million Veteran Program, Nicholas J. Wareham, Claudia Langenberg, Maciej Tomaszewski, Adam S. Butterworth, Mark J. Caulfield, John Danesh, Todd L. Edwards, Hilma Holm, Adriana M. Hung, Cecilia M. Lindgren, Chunyu Liu, Alisa K. Manning, Andrew P. Morris, Alanna C. Morrison, Christopher J. O’Donnell, Bruce M. Psaty, Danish Saleheen, Kari Stefansson, Eric Boerwinkle, Daniel I. Chasman, Daniel Levy, Christopher Newton-Cheh, Patricia B. Munroe, Joanna M. M. Howson (2020-11-23):
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (p <5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
2020-taylor.pdf: “Etiology of Autism Spectrum Disorders and Autistic Traits Over Time”, Mark J. Taylor, Mina A. Rosenqvist, Henrik Larsson, Christopher Gillberg, Brian M. D’Onofrio, Paul Lichtenstein, Sebastian Lundström (2020-05-06):
Question: Has association between genetic factors and autism spectrum disorders (ASDs) changed over time?
Findings: In this study, data were available from 2 twin cohorts, one born between 1982 and 2008 (n = 22 678 pairs) and the other between 1992 and 2008 (n = 15 279 pairs). Genetic factors were associated with ASD and autistic traits and the relative importance of these factors was consistent over time, whereas environmental factors played a smaller role.
Meaning: Environmental factors associated with ASD have not increased in importance over time and are unlikely to explain the apparent increase in the prevalence of ASD.
Abstract: Importance: The frequency with which autism spectrum disorders (ASDs) are diagnosed has shown a marked increase in recent years. One suggestion is that this is partly because of secular changes in the environment, yet to our knowledge this hypothesis lacks evidence.
Objective: To assess whether the relative importance of genetic and environmental associations with ASD and autistic traits has changed over a 16-year and 26-year period.
Design, Setting, and Participants: A twin design was used to assess whether the heritability of ASD and autistic traits has changed over time. Data from 2 nationwide Swedish twin cohorts was used: the Swedish Twin Registry (STR; participants born between January 1982 and December 2008) and the Child and Adolescent Twin Study in Sweden (CATSS; participants born between January 1992 and December 2008). Autism spectrum disorder diagnoses were identified for twins in the STR, with follow-up to 2013. Questionnaires assigned screening diagnoses of ASD to CATSS participants and assessed autistic traits. Analyses were performed from September 1, 2018, to March 31, 2019.
Exposures: Each sample was divided into several birth cohorts covering 1982 to 1991 (for the STR only), 1992–1995, 1996–1999, 2000–2003, and 2004–2008.
Outcomes: We assessed whether the genetic and environment variance underlying autistic traits changed across birth cohorts and examined whether the relative contribution of genetics and environment to liability for autism changed across birth cohorts.
Results: Data were available for 22 678 twin pairs (5922 female same-sex pairs [26.1%], 5563 male same-sex pairs [24.5%], and 11193 opposite-sex pairs [49.4%]) in the STR and 15 280 pairs (4880 female same-sex pairs [31.9%], 5092 male same-sex pairs [33.3%], and 5308 opposite-sex pairs [34.7%]) in CATSS. The heritability of ASD diagnoses in the STR ranged from 0.88 (95% CI, 0.74–0.96) to 0.97 (95% CI, 0.89–0.99). The heritability of screening diagnoses in CATSS varied from 0.75 (95% CI, 0.58–0.87) to 0.93 (95% CI, 0.84–0.98). Autistic traits showed a modest variance increase over time that was associated with increases in genetic and environmental variance, with the total variance increasing from 0.95 (95% CI, 0.92–0.98) to 1.17 (95% CI, 1.13–1.21) over time.
Conclusions and Relevance: Weak evidence was found for changes in the genetic and environmental factors underlying ASD and autistic traits over time. Genetic factors played a consistently larger role than environmental factors. Environmental factors are thus unlikely to explain the increase in the prevalence of ASD.
2020-tubbs.pdf: “The Genes We Inherit and Those We Don’t: Maternal Genetic Nurture and Child BMI Trajectories”, Justin D. Tubbs, Robert M. Porsch, Stacey S. Cherny, Pak C. Sham (2020-07-17):
Recently, methods have been introduced using polygenic scores (PGS) to estimate the effects of genetic nurture, the environmentally-mediated effects of parental genotypes on the phenotype of their child above and beyond the effects of the alleles which are transmitted to the child. We introduce a simplified model for estimating genetic nurture effects and show, through simulation and analytical derivation, that our method provides unbiased estimates and offers an increase in power to detect genetic nurture of up to 1⁄3 greater than that of previous methods. Subsequently, we apply this method to data from the Avon Longitudinal Study of Parents and Children to estimate the effects of maternal genetic nurture on childhood body mass index (BMI) trajectories. Through mixed modeling, we observe a statistically-significant age-dependent effect of maternal PGS on child BMI, such that the influence of maternal genetic nurture appears to increase throughout development. [Keywords: Genetic nurture, BMI, Polygenic score, Cultural transmission, ALSPAC]
Professor Nicholas (Nick) Martin spearheaded initial investigations into the genetic basis of political attitudes and behaviors, demonstrating that behaviors that are perceived as socially constructed could have a biological basis. As he showed, the typical mode of inheritance for political attitudes consists of approximately equal proportions of variance from additive genetic, shared environmental and unique environmental sources. This differs from other psychological variables, such as personality traits, which tend to be characterized by genetic and unique environmental sources of variation. By treating political attitudes as a model phenotype, Nick Martin was able to leverage the unique pattern of observed intergenerational transmission for political attitudes to reexamine the quintessential assumptions of the classical twin model. Specifically, by creatively leveraging the nuances of the genetic architecture of political attitudes, he was able to demonstrate the robustness of the equal environments assumption and suggest corrections to account for assortative mating. These advances have had a substantial impact on both the fields of political science, as well as behavioral and quantitative genetics.
2020-vink.pdf: “Causes of Variation in Food Preference in the Netherlands”, Jacqueline M. Vink, Kirsten J. M. van Hooijdonk, Gonneke Willemsen, Edith J. M. Feskens, Dorret I. Boomsma (2020-09-04):
Our current society is characterized by an increased availability of industrially processed foods with high salt, fat and sugar content. How is it that some people prefer these unhealthy foods while others prefer more healthy foods? It is suggested that both genetic and environmental factors play a role. The aim of this study was to (1) identify food preference clusters in the largest twin-family study into food preference to date and (2) determine the relative contribution of genetic and environmental factors to individual differences in food preference in the Netherlands. Principal component analysis was performed to identify the preference clusters by using data on food liking/
disliking from 16,541 adult multiples and their family members. To estimate the heritability of food preference, the data of 7833 twins were used in structural equation models. We identified seven food preference clusters (Meat, Fish, Fruits, Vegetables, Savory snacks, Sweet snacks and Spices) and one cluster with Drinks. Broad-sense heritability (additive [A] + dominant [D] genetic factors) for these clusters varied between 0.36 and 0.60. Dominant genetic effects were found for the clusters Fruit, Fish (males only) and Spices. Quantitative sex differences were found for Meat, Fish and Savory snacks and Drinks. To conclude, our study convincingly showed that genetic factors play a substantial role in food preference. A next important step is to identify these genes because genetic vulnerability for food preference is expected to be linked to actual food consumption and different diet-related disorders.
2020-visscher.pdf: “Musings on Visscher et al. (2006)”, Peter M. Visscher (2020-05-19):
The classical twin design relies on a number of strong number of assumptions in order to yield unbiased estimates of heritability. This includes the equal environments assumption—that monozygotic and dizygotic twins experience similar degrees of environmental similarity—an assumption that is likely to be violated in practice for many traits of interest. An alternative method of estimating heritability that does not suffer from many of these limitations is to model trait similarity between sibling pairs as a function of their empirical genome-wide identity by descent sharing, estimated from genetic markers. In this review, I recount the story behind Nick Martin’s and my development of this method, our first attempts at applying it in a human population and more recent studies using the original and related methods to estimate trait heritability. [Keywords: Linkage; identity by descent; heritability; height; equal environments assumption]
2020-voichek.pdf: “Identifying genetic variants underlying phenotypic variation in plants without complete genomes”, Yoav Voichek, Detlef Weigel (2020-04-13):
Structural variants and presence/
absence polymorphisms are common in plant genomes, yet they are routinely overlooked in genome-wide association studies (GWAS). Here, we expand the type of genetic variants detected in GWAS to include major deletions, insertions and rearrangements. We first use raw sequencing data directly to derive short sequences, k-mers, that mark a broad range of polymorphisms independently of a reference genome. We then link k-mers associated with phenotypes to specific genomic regions. Using this approach, we reanalyzed 2,000 traits in Arabidopsis thaliana, tomato and maize populations. Associations identified with k-mers recapitulate those found with SNPs, but with stronger statistical support. Importantly, we discovered new associations with structural variants and with regions missing from reference genomes. Our results demonstrate the power of performing GWAS before linking sequence reads to specific genomic regions, which allows the detection of a wider range of genetic variants responsible for phenotypic variation.
2020-vujkovic.pdf: “Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis”, Marijana Vujkovic, Jacob M. Keaton, Julie A. Lynch, Donald R. Miller, Jin Zhou, Catherine Tcheandjieu, Jennifer E. Huffman, Themistocles L. Assimes, Kimberly Lorenz, Xiang Zhu, Austin T. Hilliard, Renae L. Judy, Jie Huang, Kyung M. Lee, Derek Klarin, Saiju Pyarajan, John Danesh, Olle Melander, Asif Rasheed, Nadeem H. Mallick, Shahid Hameed, Irshad H. Qureshi, Muhammad Naeem Afzal, Uzma Malik, Anjum Jalal, Shahid Abbas, Xin Sheng, Long Gao, Klaus H. Kaestner, Katalin Susztak, Yan V. Sun, Scott L. DuVall, Kelly Cho, Jennifer S. Lee, J. Michael Gaziano, Lawrence S. Phillips, James B. Meigs, Peter D. Reaven, Peter W. Wilson, Todd L. Edwards, Daniel J. Rader, Scott M. Damrauer, Christopher J. Oamp#x02019;Donnell, Philip S. Tsao, Mark A. Atkinson, Al C. Powers, Ali Naji, Klaus H. Kaestner, Goncalo R. Abecasis, Aris Baras, Michael N. Cantor, Giovanni Coppola, Aris N. Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander E. Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew L. Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William J. Salerno, Jeffrey C. Staples, Ashish Yadav, Marcus B. Jones, Lyndon J. Mitnaul, Samuel M. Aguayo, Sunil K. Ahuja, Zuhair K. Ballas, Sujata Bhushan, Edward J. Boyko, David M. Cohen, John Concato, Joseph I. Constans, Louis J. Dellitalia, Joseph M. Fayad, Ronald S. Fernando, Hermes J. Florez, Melinda A. Gaddy, Saib S. Gappy, Gretchen Gibson, Michael Godschalk, Jennifer A. Greco, Samir Gupta, Salvador Gutierrez, Kimberly D. Hammer, Mark B. Hamner, John B. Harley, Adriana M. Hung, Mostaqul Huq, Robin A. Hurley, Pran R. Iruvanti, Douglas J. Ivins, Frank J. Jacono, Darshana N. Jhala, Laurence S. Kaminsky, Scott Kinlay, Jon B. Klein, Suthat Liangpunsakul, Jack H. Lichy, Stephen M. Mastorides, Roy O. Mathew, Kristin M. Mattocks, Rachel McArdle, Paul N. Meyer, Laurence J. Meyer, Jonathan P. Moorman, Timothy R. Morgan, Maureen Murdoch, Xuan-Mai T. Nguyen, Olaoluwa O. Okusaga, Kris-Ann K. Oursler, Nora R. Ratcliffe, Michael I. Rauchman, R. Brooks Robey, George W. Ross, Richard J. Servatius, Satish C. Sharma, Scott E. Sherman, Elif Sonel, Peruvemba Sriram, Todd Stapley, Robert T. Striker, Neeraj Tandon, Gerardo Villareal, Agnes S. Wallbom, John M. Wells, Jeffrey C. Whittle, Mary A. Whooley, Junzhe Xu, Shing-Shing Yeh, Michaela Aslan, Jessica V. Brewer, Mary T. Brophy, Todd Connor, Dean P. Argyres, Nhan V. Do, Elizabeth R. Hauser, Donald E. Humphries, Luis E. Selva, Shahpoor Shayan, Brady Stephens, Stacey B. Whitbourne, Hongyu Zhao, Jennifer Moser, Jean C. Beckham, Jim L. Breeling, J. P. Casas Romero, Grant D. Huang, Rachel B. Ramoni, Saiju Pyarajan, Yan V. Sun, Kelly Cho, Peter W. Wilson, Christopher J. Oamp#x02019;Donnell, Philip S. Tsao, Kyong-Mi Chang, J. Michael Gaziano, Sumitra Muralidhar, Kyong-Mi Chang, Benjamin F. Voight, Danish Saleheen (2020-06-15):
We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.
2020-xia.pdf: “Evidence of horizontal indirect genetic effects in humans”, Charley Xia, Oriol Canela-Xandri, Konrad Rawlik, Albert Tenesa (2020-12-14):
Indirect genetic effects, the effects of the genotype of one individual on the phenotype of other individuals, are environmental factors associated with human disease and complex trait variation that could help to expand our understanding of the environment linked to complex traits. Here, we study indirect genetic effects in 80,889 human couples of European ancestry for 105 complex traits. Using a linear mixed model approach, we estimate partner indirect heritability and find evidence of partner heritability on ~50% of the analysed traits. Follow-up analysis suggests that in at least ~25% of these traits, the partner heritability is consistent with the existence of indirect genetic effects including a wide variety of traits such as dietary traits, mental health and disease. This shows that the environment linked to complex traits is partially explained by the genotype of other individuals and motivates the need to find new ways of studying the environment.
2020-xu.pdf: “Analysis of genetic and environmental correlation between leisure activities and cognitive function in aging Chinese twins”, Chunsheng Xu, Chu Wang, Xiaocao Tian, Yili Wu, Dongfeng Zhang, Zengchang Pang, Shuxia Li, Qihua Ta (2020-12-09):
Objective: Leisure activity has been shown to be beneficial to mental health and cognitive aging. The biological basis of the correlation is, however, poorly understood. This study aimed at exploring the genetic and environmental impacts on correlation between leisure activities and cognitive function in the Chinese middle-aged and old-aged twins.
Methods: Cognition measured using a screening test (Montreal Cognitive Assessment, MoCA) and leisure activities including intellectual and social activity were investigated on 379 complete twin pairs of middle-aged and old-aged twins. Univariate and bivariate twin models were fitted to estimate the genetic and environmental components in their variance and covariance.
Results: Moderate heritability was estimated for leisure activities and cognition (0.44–0.53) but insignificant for social activity. Common environmental factors accounted for about 0.36 of the total variance to social activity with no statistically-significant contribution to leisure activity, intellectual activity and cognition. Unique environmental factors displayed moderate contributions (0.47–0.64) to leisure activities and cognition. Bivariate analysis showed highly and positively genetic correlations between leisure activities and cognition (rg = 0.80–0.96). Besides, intellectual activity and cognition presented low but statistically-significant unique environmental correlation (rE = 0.12).
Conclusions: Genetic factor had the moderate contribution to leisure activities and cognition. Cognitive function was highly genetically related to leisure activities. Intellectual activity and cognitive function may share some unique environmental basis. [Keywords: Classical twin method, genetic correlation, cognitive function, intellectual activity, social activity, leisure activities]
2020-yang.pdf: “The SNP-Based Heritability—A Commentary on Yang et al. (2010)”, Jiang Yang (2020-04-07):
I write this commentary as a part of a special issue published in this journal to celebrate Nick Martin’s contribution to the field of human genetics. In this commentary, I briefly describe the background of the Yang et al. (2010) study and show some of the unpublished details of this study, its contribution to tackling the missing heritability problem and Nick’s contribution to the work.
2020-yeung.pdf: “Amyloid, tau and risk of Alzheimer’s disease: a Mendelian randomization study”, Chris Ho Ching Yeung, Kathleen Wen Din Lau, Shiu Lun Au Yeung, C. Mary Schooling (2020-09-14):
This study was carried out to assess the effect of amyloid and tau on Alzheimer’s disease using two-sample Mendelian randomization design. Genetic associations with plasma amyloid species (amyloid precursor protein, amyloid-like protein 2, serum amyloid P-component, amyloid beta peptide), cerebrospinal fluid (CSF) amyloid beta, total tau, and phosphorylated tau181 were extracted from the largest genome-wide association study (GWAS) available. Genetic associations with Alzheimer’s disease were obtained from a GWAS of proxy-cases based on family history of Alzheimer’s disease with 314,278 participants from the UK Biobank and a GWAS with clinically diagnosed Alzheimer’s disease from the International Genomics of Alzheimer’s Project (IGAP) with 21,982 cases and 41,944 controls. Estimates were obtained using inverse variance weighting with sensitivity analyses including MR-Egger, weighted median and MR-PRESSO. Presence of bias due to selective survival and competing risk was also considered. Plasma amyloid species, CSF total tau and phosphorylated tau181 were not associated with Alzheimer’s disease. For CSF Aβ42, no association was found using the proxy-cases but an inverse association was found after removing outliers with MR-PRESSO using IGAP. Higher genetically predicted (p <1 × 10−5) plasma amyloid species, CSF total tau and phosphorylated tau181 (based on sample sizes ~ 3300) were not associated with Alzheimer’s disease using family history or clinically diagnosed cases while effects of CSF Aβ42 were inconsistent between the family history and IGAP GWAS.
2020-york.pdf: “Exploring Genetic Contributions to News Use Motives and Frequency of News Consumption: A Study of Identical and Fraternal Twins”, Chance York, Paul Haridakis (2020-05-27):
Prior research conducted within the Uses and Gratifications paradigm has considered the contribution of numerous background social and psychological characteristics to motives for media use and media consumption patterns. In this study, we explore the extent to which far more fundamental characteristics—genes—explain, in part, motives to use news media and frequency of news use. Utilizing original data collected on identical and fraternal twins (n = 334), we find that latent genetic traits explain a nontrivial amount of variance in two unique news use motives, surveillance and entertainment, as well as frequency of consumption across multiple news sources. Genetic traits were particularly influential in explaining the frequency of using sources commonly characterized as ideological, such as Fox News and CNN.
2021-andreola.pdf: “The heritability of reading and reading-related neurocognitive components: A multi-level meta-analysis”, Chiara Andreola, Sara Mascheretti, Raffaella Belotti, Anna Ogliari, Cecilia Marino, Marco Battaglia, Simona Scaini (2021-02):
- Heritability estimates vary widely across reading-related neurocognitive skills.
- Age-specific and school-grade-specific genetic influences have been reported.
- Previous meta-analyses focused on some reading skills without controlling for moderators.
- Reading-related skills show moderate-to-substantial meta-heritability estimates.
- School grade levels moderated the heritability of some reading-related skills.
Reading ability is a complex task requiring the integration of multiple cognitive and perceptual systems supporting language, visual and orthographic processes, working memory, attention, motor movements, and higher-level comprehension and cognition. Estimates of genetic and environmental influences for some of these reading-related neurocognitive components vary across reports.
By using a multi-level meta-analysis approach, we synthesized the results of behavioral genetic research on reading-related neurocognitive components (i.e. general reading, letter-word knowledge, phonological decoding, reading comprehension, spelling, phonological awareness, rapid automatized naming, and language) of 49 twin studies spanning 4.1–18.5 years of age, with a total sample size of more than 38,000 individuals.
Except for language for which shared environment seems to play a more important role, the causal architecture across most of the reading-related neurocognitive components can be represented by the following equation a2 > e2 > c2. Moderators analysis revealed that sex and spoken language did not affect the heritability of any reading-related skills; school grade levels moderated the heritability of general reading, reading comprehension and phonological awareness. [Keywords: meta-analysis, reading-related skills, twin study, heritability, genetics]
2021-fagereng.pdf: “Why Do Wealthy Parents Have Wealthy Children?”, Andreas Fagereng, Magne Mogstad, Marte Rønning (2021-02-05):
We show that family background matters statistically-significantly for children’s accumulation of wealth and investor behavior as adults, even when removing the genetic connection between children and the parents raising them. The analysis is made possible by linking Korean-born children who were adopted at infancy by Norwegian parents to a population panel data set with detailed information on wealth and socioeconomic characteristics. The mechanism by which these Korean-Norwegian adoptees were assigned to adoptive families is known and effectively random. This mechanism allows us to estimate the causal effects from an adoptee being raised in one type of family versus another.
…The linear rank correlations are 0.24 and 0.16 for the samples of non-adoptees and adoptees, respectively. This means that, on average, a 10 percentile increase in parent net wealth is associated with a 2.4 percentile increase in a biological child’s net wealth and a 1.6 percentile increase in an adoptee’s net wealth…On average, the adoptees accrue an extra US$2,250 of wealth if they are assigned to an adoptive family with US$10,000 of additional wealth. The magnitude of this estimate suggests that adoptees raised by parents with a wealth level that is 10% above the mean of the parent generation can expect to obtain a wealth level that is almost 3.7% above the mean of the child generation.
…We find that the indirect effects arising from changes in the observed mediator variables explain about 37% of the average causal effect from assignment to wealthier parents on children’s accumulation of wealth. Direct transfers of wealth are the most important mediator variable, accounting for almost 90% of the indirect effect.
…Columns 1 and 2 in panel A of Table 5 suggest that both family environment and genetics are important in explaining the variation in children’s wealth accumulation. Shared environment accounts for about 16% (10%) of the variation in net (financial) wealth accumulation. Relative to shared environment, the genetic factors explain a larger portion (twice as much or more) of the variation in wealth accumulation (both net and financial wealth). These findings are consistent with the results in Table 3, showing statistically-significant but less wealth transmission from parents to adoptees as compared with non-adoptees.
As shown in column 3 in panel A of Table 5, shared environment is also important for explaining the variation in financial risk-taking, as measured by the risky share. By comparison, genetic factors explain little of the variation in this measure of financial risk-taking. In column 4 of Table 5, we report results for education as measured by years of schooling. These results are close to the American study of Korean adoptees by Sacerdote (2007), who finds that 9% of the variation in years of schooling can be explained by shared environment, while 60% is attributable to genes.
2021-hwang.pdf: “The Augmented Classical Twin Design: Incorporating Genome-Wide Identity by Descent Sharing Into Twin Studies in Order to Model Violations of the Equal Environments Assumption”, Liang-Dar Hwang, Brittany L. Mitchell, Sarah E. Medland, Nicholas G. Martin, Michael C. Neale, David M. Evans (2021-02-13):
The Classical Twin Method (CTM) compares the similarity of monozygotic (MZ) twins with that of dizygotic (DZ) twins to make inferences about the relative importance of genes and environment in the etiology of individual differences. The design has been applied to thousands of traits across the biomedical, behavioral and social sciences and is arguably the most widely used natural experiment known to science.
The fundamental assumption of the CTM is that trait relevant environmental covariation within MZ pairs is the same as that found within DZ pairs, so that zygosity differences in within-pair variance must be due to genetic factors uncontaminated by the environment. This equal environments assumption (EEA) has been, and still is hotly contested, and has been mentioned as a possible contributing factor to the missing heritability conundrum.
In this manuscript, we introduce a new model for testing the EEA, which we call the Augmented Classical Twin Design which uses identity by descent (IBD) sharing between DZ twin pairs to estimate separate environmental variance components for MZ and DZ twin pairs, and provides a test of whether these are equal. We show through simulation that given large samples of DZ twin pairs, the model provides unbiased estimates of variance components and valid tests of the EEA under strong assumptions (e.g. no epistatic variance, IBD sharing in DZ twins estimated accurately etc.) which may not hold in reality. Sample sizes in excess of 50,000 DZ twin pairs with genome-wide genetic data are likely to be required in order to detect substantial violations of the EEA with moderate power.
Consequently, we recommend that the Augmented Classical Twin Design only be applied to datasets with very large numbers of DZ twin pairs (> 50 000 DZ twin pairs), and given the strong assumptions relating to the absence of epistatic variance, appropriate caution be exercised regarding interpretation of the results.
2021-jonsson.pdf: “Differences between germline genomes of monozygotic twins”, Hakon Jonsson, Erna Magnusdottir, Hannes P. Eggertsson, Olafur A. Stefansson, Gudny A. Arnadottir, Ogmundur Eiriksson, Florian Zink, Einar A. Helgason, Ingileif Jonsdottir, Arnaldur Gylfason, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Doruk Beyter, Thora Steingrimsdottir, Gudmundur L. Norddahl, Olafur Th. Magnusson, Gisli Masson, Bjarni V. Halldorsson, Unnur Thorsteinsdottir, Agnar Helgason, Patrick Sulem, Daniel F. Gudbjartsson, Kari Stefansson (2021-01-07):
Despite the important role that monozygotic twins have played in genetics research, little is known about their genomic differences. Here we show that monozygotic twins differ on average by 5.2 early developmental mutations and that approximately 15% of monozygotic twins have a substantial number of these early developmental mutations specific to one of them. Using the parents and offspring of twins, we identified pre-twinning mutations. We observed instances where a twin was formed from a single cell lineage in the pre-twinning cell mass and instances where a twin was formed from several cell lineages. CpG>TpG mutations increased in frequency with embryonic development, coinciding with an increase in DNA methylation. Our results indicate that allocations of cells during development shapes genomic differences between monozygotic twins.
2021-mompeo.pdf: “Genetic and Environmental Influences of Dietary Indices in a UK Female Twin Cohort”, Olatz Mompeo, Rachel Gibson, Paraskevi Christofidou, Tim D. Spector, Cristina Menni, Massimo Mangino (2021-01-18):
A healthy diet is associated with the improvement or maintenance of health parameters, and several indices have been proposed to assess diet quality comprehensively. Twin studies have found that some specific foods, nutrients and food patterns have a heritable component; however, the heritability of overall dietary intake has not yet been estimated. Here, we compute heritability estimates of the nine most common dietary indices utilized in nutritional epidemiology. We analyzed 2590 female twins from TwinsUK (653 monozygotic [MZ] and 642 dizygotic [DZ] pairs) who completed a 131-item food frequency questionnaire (FFQ). Heritability estimates were computed using structural equation models (SEM) adjusting for body mass index (BMI), smoking status, Index of Multiple Deprivation (IMD), physical activity, menopausal status, energy and alcohol intake. The AE model was the best-fitting model for most of the analyzed dietary scores (seven out of nine), with heritability estimates ranging from 10.1% (95% CI [.02, .18]) for the Dietary Reference Values (DRV) to 42.7% (95% CI [.36, .49]) for the Alternative Healthy Eating Index (A-HEI). The ACE model was the best-fitting model for the Healthy Diet Indicator (HDI) and Healthy Eating Index 2010 (HEI-2010) with heritability estimates of 5.4% (95% CI [−.17, .28]) and 25.4% (95% CI [.05, .46]), respectively. Here, we find that all analyzed dietary indices have a heritable component, suggesting that there is a genetic predisposition regulating what you eat. Future studies should explore genes underlying dietary indices to further understand the genetic disposition toward diet-related health parameters.
2021-rodin.pdf: “The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing”, Rachel E. Rodin, Yanmei Dou, Minseok Kwon, Maxwell A. Sherman, Alissa M. D’Gama, Ryan N. Doan, Lariza M. Rento, Kelly M. Girskis, Craig L. Bohrson, Sonia N. Kim, Ajay Nadig, Lovelace J. Luquette, Doga C. Gulhan, Brain Somatic Mosaicism Network, Peter J. Park, Christopher A. Walsh (2021-01-11):
We characterize the landscape of somatic mutations—mutations occurring after fertilization—in the human brain using ultra-deep (~250×) whole-genome sequencing of prefrontal cortex from 59 donors with autism spectrum disorder (ASD) and 15 control donors. We observe a mean of 26 somatic single-nucleotide variants per brain present in ≥4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces ~3.4 mutations, followed by 2–3 mutations in subsequent generations. This suggests that a typical individual possesses ~80 somatic single-nucleotide variants present in ≥2% of cells—comparable to the number of de novo germline mutations per generation—with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. ASD brains show an excess of somatic mutations in neural enhancer sequences compared with controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.
2021-sherman.pdf: “Large mosaic copy number variations confer autism risk”, Maxwell A. Sherman, Rachel E. Rodin, Giulio Genovese, Caroline Dias, Alison R. Barton, Ronen E. Mukamel, Bonnie Berger, Peter J. Park, Christopher A. Walsh, Po-Ru Loh (2021-01-11):
Although germline de novo copy number variants (CNVs) are known causes of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. In this study, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 probands with ASD and 5,500 unaffected siblings. We detected 46 mCNVs in probands and 19 mCNVs in siblings, affecting 2.8–73.8% of cells. Probands carried a statistically-significant burden of large (>4-Mb) mCNVs, which were detected in 25 probands but only one sibling (odds ratio = 11.4, 95% confidence interval = 1.5–84.2, p = 7.4 × 10−4). Event size positively correlated with severity of ASD symptoms (p = 0.016). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD (eg, 16p11.2). We further experimentally validated two mCNVs in postmortem brain tissue from 59 additional probands. These results indicate that mCNVs contribute a previously unexplained component of ASD risk.