23andMe SNP testing

Discussion of my genetic results. Nothing particularly actionable or notable.
psychology, statistics, biology, survey
6 Oct 201430 April 2016 in progress certainty: possible importance: 1

ordered: 10/07/2014 physically received from relative: 11/3 23andMe surveys done: 11/3, ~4 hours sent: 11/5 arrived at lab: 11/11 raw data available: 11/17 (made Promethease that day) ancestry reports finished: 11/20


Neanderthal: 2.4% (18th percentile) No surprises in the ancestry haplotypes - Dutch through father, and indeed, ‘R1b1b2a1a1 is most commonly found on the fringes of the North Sea.’ https://www.23andme.com/you/haplogroup/paternal/ ; quasi-English through my mother, so I1a1 and ‘Example Populations: Celtic Britons, Georgians, Azeris, Sindhi’ https://www.23andme.com/you/haplogroup/maternal/ 99.8% european, 36% British/Irish, 21.7% French/German, 29.5% ‘broadly northern European’, 1.2% Ashkenazi Jew. so the family summary that we’re British/Dutch seems to be… actually completely right. except for the Jewish bit 12:46:59 <@gwern> and 64 is log2(64) = 6, so that’s 1parents/2grandparents/3great-grandparents/4great-great-grandparents/5great-great-great-grandparents/6great-great-great-great-grandparents 12:47:08 <@gwern> I think? Ashkenazi 1.2% https://www.23andme.com/you/labs/ancestry_finder/?ngp=1&cln=1&ash=1 https://www.23andme.com/you/community/thread/19073/ https://www.23andme.com/you/ancestry/composition/ if it’s on my father’s side, that’s a bit more plausible; who knows what my Dutch/German ancestors were up to? not so much on the maternal side, they’ve been on this side of the pond for quite a while DNA matches: 3 2-3rd cousins, 430 4th cousins, 531 more distant

about Promethease: http://snpedia.com/index.php/Promethease http://www.technologyreview.com/featuredstory/531461/how-a-wiki-is-keeping-direct-to-consumer-genetics-alive/ https://en.wikipedia.org/wiki/SNPedia

Promethease: 11 minutes 32 seconds Total 998 seconds https://dl.dropboxusercontent.com/u/5317066/2014-11-17-promethease.zip

On risks: https://en.wikipedia.org/wiki/Genetic_Information_Nondiscrimination_Act http://ideas.4brad.com/without-knowing-it-were-all-gene-databases-already http://venturebeat.com/2013/11/26/warning-letter-to-23andme-could-be-a-landmark-case-for-health-care/ mastectomy? harmful info: http://www.wired.com/2010/06/ff_sergeys_search/all/1 > But, surprisingly, the concept of genetic information as toxic has persisted, possibly because it presumes that people aren’t equipped to learn about themselves. But research shows this presumption to be unfounded. In 2009, The New England Journal of Medicine published results of the Risk Evaluation and Education for Alzheimer’s Disease study, an 11-year project that sought to examine how people react to finding out that they have a genetic risk for Alzheimer’s. Like Parkinson’s, Alzheimer’s is a neurodegenerative condition centering on the brain. But unlike Parkinson’s, Alzheimer’s has no known treatment. So learning you have a genetic predisposition should be especially toxic. In the study, a team of researchers led by Robert Green, a neurologist and geneticist at Boston University, contacted adults who had a parent with Alzheimer’s and asked them to be tested for a variation in a gene known as ApoE. Depending on the variation, an ApoE mutation can increase a person’s risk for Alzheimer’s from three to 15 times the average. One hundred sixty-two adults agreed; 53 were told they had the mutation. The results were delivered to the participants with great care: A genetic counselor walked each individual through the data, and all the subjects had follow-up appointments with the counselor. Therapists were also on call. “People were predicting catastrophic reactions,” Green recalls. “Depression, suicide, quitting their jobs, abandoning their families. They were anticipating the worst.” But that isn’t what happened. People told that they were at dramatically higher risk for developing Alzheimer’s later in life seemed to process the information and integrate it into their lives, often choosing to lead more healthy lifestyles. “People are handling it,” Green says. “It doesn’t seem to be producing any clinically apparent distress.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191239/ “Using Alzheimer’s disease as a model for genetic risk disclosure: Implications for personal genomics” Roberts et al 2011; as I expected from the research on the stability of happiness; if actually becoming a paraplegic doesn’t turn out to bother people much, why would an abstract prediction of Alzheimer’s? no changes? http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007275.pub2/abstract http://www.nejm.org/doi/full/10.1056/NEJMoa1011893

Experiences: http://too.blogspot.com/2008/09/lrrk2.html http://www.wired.com/2010/06/ff_sergeys_search/all/1 Brin http://philosophistry.com/archives/2011/02/dna-test-23andme-review.html https://news.ycombinator.com/item?id=2254648 http://willworkforjustice.blogspot.com/2011/01/23andme-results.html http://samsnyder.com/2010/12/16/new-23andme-results/ http://paulstamatiou.com/review-23andme-dna-testing-for-health-disease-ancestry https://news.ycombinator.com/item?id=1170074 http://techcrunch.com/2008/03/02/my-23andme-dna-results/ https://news.ycombinator.com/item?id=127734 http://manu.sporny.org/2011/public-domain-genome/ https://news.ycombinator.com/item?id=2211334 https://news.ycombinator.com/item?id=2211928 http://manu.sporny.org/2011/pd-genome-implications/ (2014 update: still happy https://twitter.com/manusporny/status/536569841323610112 ) http://www.vox.com/2014/9/9/5975653/with-genetic-testing-i-gave-my-parents-the-gift-of-divorce-23andme https://news.ycombinator.com/item?id=8292476 http://www.nytimes.com/2013/12/31/science/i-had-my-dna-picture-taken-with-varying-results.html?pagewanted=all&_r=0 http://ideas.4brad.com/odds-knowing-your-cousins-23andme-part-1 / http://ideas.4brad.com/privacy-risks-genetic-genealogy-23andme-part-2 http://www.jamesaltucher.com/2013/01/why-im-a-neanderthal-and-you-could-be-too/ http://www.unfinishedman.com/23andme-genetic-testing-for-terrible-diseases-sweet-perks-and-family/ http://jonsteinberg.tumblr.com/post/1298758017/how-23andme-saved-my-wife https://web.archive.org/web/20131208204809/http://blog.23andme.com/23andme-customer-stories/talking-about-breast-cancer/ https://news.ycombinator.com/item?id=6220891 https://www.quora.com/Has-anyone-who-has-done-genetic-mapping-by-23andMe-found-it-worth-it http://genomesunzipped.org/2011/06/3747.php http://nsaunders.wordpress.com/2010/05/14/23-and-me-yes-me-part-1/ http://nsaunders.wordpress.com/2010/05/23/23-and-me-%E2%80%93-yes-me-%E2%80%93-part-2/ http://nsaunders.wordpress.com/2010/06/22/23andme-yes-me-part-3/ http://dna-explained.com/2013/12/30/promethease-genetic-health-information-alternative/

Observed benefits: BRCA/breast cancer lactose intolerance Alzheimer’s risk APOE hematochromatosis reuniting with lost family members (http://www.fourstateshomepage.com/story/dna-helps-reunite-family/d/story/okB1oVl_ukq5It6zsrUWxA https://www.23andme.com/stories/ )

Whole-genome use: http://www.nytimes.com/2010/03/11/health/research/11gene.html?ref=science Whole-genome cost (for 30x coverage): https://en.wikipedia.org/wiki/Personal_genomics#Cost_of_sequencing_an_individual.27s_genome out of date https://www.genebygene.com/pages/dnadtc# $7.4k http://www.autismspeaks.org/blog/2014/06/10/autism-research-intersection-genomic-discovery-and-big-data Robert Ring 10 June 2014 “Today, with technological innovations, we can sequence an entire genome of any individual for around $2,500 in two weeks.” https://www.kickstarter.com/projects/784741307/personal-genome-sequencing projected $3.5k per-genome, but failed to launch http://clinical.illumina.com/clinical/illumina_clinical_laboratory/how-to-order.html no listed price, need physician approval (but ~$5k in early 2013 http://www.theguardian.com/science/2013/jun/08/genome-sequenced and with very large upfront purchase, may be possible to do amortized genomes at a wholesale cost of $1k each http://www.nature.com/news/is-the-1-000-genome-for-real-1.14530 - consumer prices would be higher though ) https://www.scienceexchange.com/services/whole-genome-seq very sketchy labs offering whole-genomes at $2.5k-$3k Knome: ??? https://www.fullgenomes.com/news/ $2k, Full Genomes VeritasGenetics: announced ~30 September 2015 offering $1k genomes to PGP participants http://www.veritasgenetics.com/pgp/ http://www.nature.com/news/is-the-1-000-genome-for-real-1.14530 ; began offering to general public in March 2016 https://www.veritasgenetics.com/documents/VG-launches-999-whole-genome.pdf NIH CIDR: charges $2.3k for 30x whole genome using Illumina, as of 10 Dec 2015: http://www.cidr.jhmi.edu/services/pricing.pdf FullGenomes: $1650 30x whole genome, 29 February 2016 https://www.fullgenomes.com/purchases/5/

Orgs: PGP http://www.personalgenomes.org/ http://genomesunzipped.org/project http://www.snpedia.com/index.php/Genomes http://daver.info/ysub/

Research: http://blog.23andme.com/health-traits/autism-study-reveals-no-genetic-associations/

TODO: generate own ancestry graphs? http://www.genetics.ucla.edu/software/admixture/ http://pngu.mgh.harvard.edu/~purcell/plink/ and http://esquilax.stanford.edu/ and http://www.isogg.org/23andmetools.html and http://www.23andyou.com/3rdparty borrow ideas from http://diyhpl.us/wiki/genetic-modifications/ and https://old.reddit.com/r/Nootropics/search?q=23andme&restrict_sr=on SNPs: schizophrenia autism? alcohol/health caffeine consumption Rietveld modafinil

rs9536314   13  33628138    TT
["Life Extension Factor Klotho Enhances Cognition"](http://www.cell.com/cell-reports/fulltext/S2211-1247%2814%2900287-3), Dubal et al 2014 - benefits from (G;T)

http://www.nytimes.com/2015/03/08/opinion/sunday/the-feel-good-gene.html the mentioned SNP which doubled cannabis dependence rates: http://snpedia.com/index.php/Rs324420 / ttps://www.23andme.com/you/explorer/snp/?snp_name=rs324420 ; see also http://www.unz.com/gnxp/genetics-of-why-finns-are-less-anxious-than-italians/ - I’m CC, incidentally, so additional reason for me to avoid marijuana

“Showing that you care: The evolution of health altruism”, Hanson 2008: placebo genetics: COMT -> dopaminergic -> reward sensitivity -> social ties?

These same kinds of patients might actually do worse than others on certain kinds of active drug therapies. In two independent studies, healthy people who had the placebo-responding version of the COMT gene fared better on cognitive and memory tasks after taking an inert pill than they did after taking tolcapone, a drug that is used in Parkinson’s patients to inhibit the COMT9,10 enzyme and control disease symptoms. Those with the opposite COMT genotype, however, did better on tolcapone in both studies, suggesting that tolcapone and other drugs that act via dopamine signaling may interfere with the placebo response.

  1. Apud, J.A. et al. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology 32, 1011-1020 (2007).
  2. Farrell S.M., Tunbridge E.M., Braeutigam S., & Harrison P.J. COMT Val158Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition. Biological Psychiatry 71, 538–544 (2012).


The findings showed that among the IBS patients who had been in the waitlist treatment arm there was no difference in treatment responses between met/met, val/val and met/val genotypes as determined by the IBS-Symptom Severity Scale and Adequate Relief. Among those in the group that received a placebo administered in a businesslike manner, the met/met genotypes showed a small improvement over their val/val and met/val counterparts. But, says Hall, among the individuals who had received placebo treatment from the warm supportive health care providers, there was a striking difference: the “met/mets” demonstrated a six-fold greater improvement in their IBS symptoms relative to the “val/vals.”

“Genetic marker for placebo response identified in IBS patients”:

possible replications:

  1. “An Opposite-Direction Modulation of the COMT Val158Met Polymorphism on the Clinical Response to Intrathecal Morphine and Triptans” /docs/genetics/heritable/2013-cargnin.pdf
  2. , Wendt et al 2014

http://snpedia.com/index.php/Rs4680 rs4680 22 19951271 GG

conversion chart from http://www.snpedia.com/index.php/Orientation: A->T T->A C->G G->C

and val=G, so I’m Val/Val; supposed to be good for modafinil

“Genetic biomarkers of placebo response: what could it mean for future trial design?”, Hall & Kaptchuk 2013, essay:

Furthermore, a differential effect of drugs and placebo, based on COMT Val158Met genotype, was observed in a series of studies that examined treatment outcomes relative to placebo and the COMT inhibitor Tolcapone [19,20]. These studies found that, whereas Val/Val subjects had a marginal placebo response relative to their strong drug response, Met/Met subjects had the opposite outcomes with a robust placebo response that was abrogated by the drug. Further research is warranted to examine whether the worsening of outcomes for Met/Met subjects is generalizable to other drug treatments, the mechanism of action of which interacts with the dopa-mine-mediated placebo pathway. Likewise, as other placebo genetic biomarkers become available, evaluating them for potential drug–placebo interactions will be important.

  1. Apud JA, Mattay V, Chen J, et al. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology. 2007;32(5):1011–1020. [PubMed]
  2. Farrell SM, Tunbridge EM, Braeutigam S, Harrison PJ. COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition. Biol. Psychiatry. 2012;71(6):538–544. [PMC free article] [PubMed]

“Catechol-O-methyltransferase, dopamine, and sleep-wake regulation”, Dauvilliers et al 2014 /docs/modafinil/2014-dauvilliers.pdf

Sleep and sleep disorders are complex and highly variable phenotypes regulated by many genes and environment. The catechol-O-methyltransferase (COMT) gene is an interesting candidate, being one of the major mammalian enzymes involved in the catabolism of catecholamines. The activity of COMT enzyme is genetically polymorphic due to a guanine-to-adenine transition at codon 158, resulting in a valine (Val) to methionine (Met) substitution. Individuals homozygous for the Val allele show higher COMT activity, and lower dopaminergic signaling in prefrontal cortex (PFC) than subjects homozygous for the Met allele. Since COMT has a crucial role in metabolising dopamine, it was suggested that the common functional polymorphism in the COMT gene impacts on cognitive function related to PFC, sleepwake regulation, and potentially on sleep pathologies. The COMT Val158Met polymorphism may predict inter-individual differences in brain electroencephalography (EEG) alpha oscillations and recovery processes resulting from partial sleep loss in healthy individuals. The Val158Met polymorphism also exerts a sexual dimorphism and has a strong effect on objective daytime sleepiness in patients with narcolepsycataplexy. Since the COMT enzyme inactivates catecholamines, it was hypothesized that the response to stimulant drugs differs between COMT genotypes. Modafinil maintained executive functioning performance and vigilant attention throughout sleep deprivation in subjects with Val/Val genotype, but less in those with Met/Met genotype. Also, homozygous Met/Met patients with narcolepsy responded to lower doses of modafinil compared to Val/Val carriers. We review here the critical role of the common functional COMT gene polymorphism, COMT enzyme activity, and the prefrontal dopamine levels in the regulation of sleep and wakefulness in normal subjects, in narcolepsy and other sleep-related disorders, and its impact on the response to psychostimulants.

COMT Val158Met

Among the monoaminergic genes that may be involved in traitlike individual differences in sleep, the catechol-Omethyltransferase (COMT) gene is an interesting candidate, being one of the major enzymes of the metabolic degradation of catecholamines [4]. COMT catalyzes the transfer of a methyl group from S-adenosyl-methionine to a hydroxyl group on a catechol nucleus of major neurotransmitters such as dopamine, epinephrine, and norepinephrine [5]. …Segregation analysis from family studies demonstrated that the pattern of inheritance is consistent with the presence of autosomal co-dominant alleles. This polymorphism is mainly due to a 544 guanine-to-adenine transition at codon 158 of the COMT gene, resulting in a valine (Val) to methionine (Met) substitution (single nucleotide polymorphism (SNP) rs4680) …because the alleles are codominant, heterozygous individuals have an enzyme activity midway between homozygous individuals [9]. Other known, yet less studied, polymorphisms in the COMT gene (i.e., rs2097603 located in the COMT promoter region, rs737865 located in intron 1, and rs6267 in exon 3) were reported and may also modify the enzyme activity [10].

The dopamine (DA) system has an established role in regulating motor control, cognition, and the maintenance of behavioral arousal [12]. In contrast to the striatum, the prefrontal cortex expresses low levels of dopamine transporter protein in general and none within synapses [13,14]. Because the dopamine transporter is the most efficient mechanism for clearing released dopamine from extracellular space, the PFC is more dependent on secondary mechanisms, such as the COMT enzyme, for terminating the action of released dopamine. Although the COMT enzyme has a widespread distribution in non-dopaminergic neurons and glia cells, pharmacological studies showed that catabolic flux of synaptic dopamine through the COMT pathway is a characteristic of the PFC [15]. The COMT enzyme accounts for more than 60% of the dopamine degradation in the PFC, but for less than 15% in the striatum [15].

Genetically modified mice, in which the dopamine active transporter (DAT) gene was deleted, exhibited reduced NREM sleep and prolonged wakefulness when compared to wildtype mice [18]. Moreover, functional genetic variation of the gene encoding DAT in humans modified the rebound in slow wave sleep after sleep deprivation in healthy volunteers [19]. …One study, however, demonstrated that DAT knock-out mice were unresponsive to the wake-promoting action of catecholaminergic drugs (i.e., amphetamine and modafinil), a finding consistant with the involvement of a dopaminergic mechanism [18]. A positron emission tomography study recently measured the acute effects of modafinil on the availability of extracellular dopamine and dopamine transporter in the male human brain [48]. Main results indicated that modafinil blocked dopamine transporters and increased dopamine in the putamen, the caudate, and the nucleus accumbens. Furthermore, modafinil intake (200 mg) during sleep deprivation in healthy volunteers affected distinct EEG frequency bands in NREM sleep in a DAT-genotype-dependent manner [19]. Modafinil is an effective treatment for narcolepsy; however substantial number of patients display none or only partial response. As detailed above, the dopamine metabolism pathway and in particular the COMT enzyme are putative targets for the stimulant effects of modafinil. We hypothesized that functional polymorphism of the COMT gene may influence the clinical response to modafinil in narcolepsy. We included a population of 84 patients with narcolepsycataplexy (mean age at 48.21 ± 19.25 y) treated with modafinil for 7.49 ± 4.35 y and receiving a minimum daily dose of 100e600 mg (mean daily dose at 307 ± 109 mg) [49]. The effect of modafinil on EDS was established on the basis of clinical investigation made at each visit and scored as 2 for good response (striking improvement up to disappearance of EDS), 1 for moderate response (intermediate improvement) and 0 when no effect was observed. We also determined the daily dose at maximum efficacy in each patient. Seventy-seven patients were classified as responders to modafinil (i.e., 52 good and 25 moderate responders) and only 7 as non-responders. The COMT genotype distribution differed between gender according to the response to modafinil. In women, 30 out of 32 narcoleptics (96.8%) were good or moderate responders against 46 out of 52 men (88.5%). In addition, patients with Val/Val (HH) genotype responded less efficiently to modafinil than patients with Met/Met or Met/Val (LL or HL) genotypes. The optimal daily dose of modafinil differed between gender with nearly 100 mg per day less in women (daily dose at 262.50 ± 16.65 mg for women and 343.34 ± 17.50 mg for men). Finally, the distribution of COMT genotype interacted with the optimal daily dose, such that patients with Met/Met genotype had less daily dose than the others. To summarize, the response to modafinil-based treatment of EDS differs between gender and COMT genotypes, with narcolepsy patients with higher dopaminergic tone (Met/Met genotype, low COMT enzyme activity) responding to lower doses of modafinil compared to patients with Val/Val genotype. These results strengthen the involvement of the dopaminergic pathway in the mechanism of action of modafinil. Studies in healthy men also reported an impact of the V158M COMT polymorphism on the efficacy of modafinil in improving EDS after sleep deprivation [50]. A placebo-controlled, double-blind, randomized crossover study showed that modafinil attenuated the progression of sleepiness and EEG 5e8 Hz activity during sleep deprivation in both Val/Val and Met/Met allele carriers. However, the V158M COMT polymorphism modulated the effects of modafinil on the NREM sleep in the recovery period after prolonged wakefulness with increased power in 3.0e6.75 Hz and >16.75 Hz in subjects with Val/Val genotype. Further results showed that modafinil maintained baseline executive function performance and vigilance throughout sleep deprivation in subjects with Val/Val genotype in contrast to those with Met/Met genotype [51]. Although these results highlight the role of dopaminergic mechanisms in impaired waking functions after sleep loss, the significance of the genotype-dependent changes after modafinil in EEG activity in NREM sleep remains to be elucidated. Together with recent findings [19], the available data suggest that genetic variation in the dopamine transporter DAT (i.e., the 10-repeat allele homozygotes for the variant SNP-rs28363170 having 20% reduced DAT availability in the striatum compared to homozygous 9-repeat and heterozygous allele carriers) rather than in COMT modulates sleep homeostasis in healthy humans.

  1. Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM. “Dopaminergic role in stimulant-induced wakefulness”. J Neurosci 2001;21:1787e94.

  2. Holst SC, Bersagliere A, Bachmann V, Berger W, Achermann P, Landolt HP. “Dopaminergic role in regulating neurophysiological markers of sleep homeostasis in humans”. J Neurosci 2014;34:566e73.

  3. Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, Telang F, et al. “Effects modafinil on dopamine and dopamine transporters in the male human brain: clinical implications”. JAMA 2009;18(301):1148e54.

  4. Dauvilliers Y, Neidhart E, Billiard M, Tafti M. “Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil”. Pharmacogenomics J 2002;2:65e8.

  5. Bodenmann S, Landolt HP. “Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT”. Sleep 2010;33:1027e35.

  6. Bodenmann S, Xu S, Luhmann UF, Arand M, Berger W, Jung HH, et al. “Pharmacogenetics of modafinil after sleep loss: catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep”. Clin Pharmacol Ther 2009;85:296e304.

The loss of normal dopaminergic function in humans contributes to several sleep disorders such as restless legs syndrome and REM sleep behavior disorder [24]. In particular, it leads to Parkinson’s disease, a neurodegenerative condition associated with disturbed sleep and vigilance [24].

The COMT genotype might also modulate the interaction between prefrontal activity and midbrain dopaminergic function in humans. Individuals homozygous for the Val158 allele show higher COMT activity, have more COMT protein in post-mortem brain tissues, and lower dopaminergic signaling in PFC than subjects homozygous for the Met158 allele [11]. A neuroimaging study performed in healthy volunteers reported that carriers of the Val158 allele had significantly higher midbrain 6-[ 18 F]-fluoro-L-3,4-dihydroxyphenylalanine (F-DOPA) uptake rates compared to homozygous Met158 carriers, indicating decreased dopaminergic tone in Met carriers [27]. Moreover, the regional cerebral blood flow in the PFC was correlated with midbrain dopamine uptake during a working memory challenge test as a function of COMT genotype. The COMT genotype was associated with performance differences in executive cognitive functions, such that carriers of the variant Met158 showed better executive function (mainly in males), with best performance in Met/Met homozygotes [28]. These findings strongly suggest that genetically-determined variation in COMT activity has neurobiological effects specific to the PFC. As the COMT enzyme plays an important role in the breakdown of cortical catecholamines in the PFC, an impact of the Val158Met polymorphism on normal sleep-wake regulation was hypothesized. In male homozygous Val carriers, alpha-peak-frequency in wakefulness was 1.4 Hz slower than in homozygous Met carriers [29]. Moreover, the two genotypes showed a stable and frequency-specific inter-individual difference in brain alpha oscillations, mainly in the 11e13 Hz band. Val/Val allele carriers exhibited less EEG 11e13 Hz power than Met/Met homozygotes in wakefulness, NREM sleep, and REM sleep. This difference resisted to both, the effects of sleep deprivation (40 h prolonged wakefulness) and modafinil. It is currently not known whether the observed effects of the Val158Met polymorphism on the EEG alpha-activity have any bearing on COMT genotype-dependent differences in cognitive functions. Although it was previously suggested that individuals with faster alpha-peak frequency and higher upper alpha-band power may show better cognitive and memory performance [30], such associations need to be interpreted with caution (discussed in [29]). Another study reported that Met/Met subjects show a greater decline in slow-wave EEG energy during five consecutive days of partial sleep deprivation compared to the Val/Val and the Val/Met subjects, despite comparable baseline values [31]. No cognitive (i.e., executive function performance) differences were found between the different genotypes, with similar subjective and physiological sleepiness in response to chronic sleep loss. Some evidence suggests an inverted U-shaped relationship between dopaminergic tone in the PFC and distinct PFC-dependent brain functions [32]. Whether such a relationship may exist for sleep-wake physiology is currently unknown. A recent long-term actigraphy study revealed that Val/Val and Met/Met homozygotes habitually prolonged sleep on rest days compared to workdays, whereas Val/Met heterozygotes did not significantly extend their sleep length on weekends [33]. These data are consistent with an inverted U-shaped relationship between COMT genotypedependent differences in PFC dopamine and the accumulation of a sleep debt during the workdays. Controlled intervention studies in appropriate study samples are needed to formally test this hypothesis. Collectively, the available findings in healthy individuals suggest that the Val158Met polymorphism of the COMT gene predicts inter-individual differences in distinct aspects of sleep-wake physiology.

  1. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, et al. “Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype”. Nat Neurosci 2005;8:594e6.
  2. Bruder GE, Keilp JG, Xu H, Shikhman M, Schori E, Gorman JM, et al. “Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations”. Biol Psychiat 2005;58:901e7.
  3. Bodenmann S, Rusterholz T, Dürr R, Stoll C, Bachmann V, Geissler E, et al. “The functional Val158Met polymorphism of COMT predicts inter-individual differences in brain alpha oscillations in young men”. J Neurosci 2009;29:10855e62.

Moreover, female narcoleptics with high COMT activity (Val158 or HH genotype) fell asleep twice faster than those with low COMT activity (Met158 or LL genotype) during the multiple sleep latency test (MSLT). The opposite was true for men. Independent of gender, COMT genotype significantly affected the presence or absence of sleep paralysis, sleep latency at night, and the number of sleep-onset REM periods during the MSLT. This study was the first genetic evidence for the critical involvement of the dopaminergic/noradrenergic system in human narcolepsy and confirmed previous findings in the canine model of the disease [39]. Thus, Val158Met polymorphism of COMT has a sexual dimorphism and a strong effect on EDS in patients with narcolepsy. However, recent genome-wide association studies in narcolepsy could not confirm this association when designed as caseecontrol studies without taking into account gender and endophenotype such as the severity of EDS [40e42]. Recently an European case-control GWAS performed in narcolepsy-cataplexy looked for genetic variants and clinical traits [43]. The sample was relatively small to obtain enough power to detect a genome-wide significant signal. Neither the top hits nor the alleles of the functional COMT gene polymorphism (rs4680) were associated with the severity of EDS assessed by MSLT [43].

“The people who need very little sleep” http://www.bbc.com/future/story/20150706-the-woman-who-barely-sleeps “A Gene That Makes You Need Less Sleep?” http://www.newyorker.com/science/maria-konnikova/a-gene-makes-you-need-less-sleep ; HN discussion: https://news.ycombinator.com/item?id=8215872

“Heritability of Performance Deficit Accumulation During Acute Sleep Deprivation in Twins” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413799/ Kuna et al 2012

“The Transcriptional Repressor DEC2 Regulates Sleep Length in Mammals” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884988/ He et al 2010

“A Novel BHLHE41 Variant is Associated with Short Sleep and Resistance to Sleep Deprivation in Humans” /docs/genetics/heritable/2014-pellegrino.pdf Pellegrino et al 2014

homozygous on all SNPs: rs4963955: TT; rs4963956: CC; rs1480037: CC