Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates

Abstract

Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration ( p < 5 × 10 −8 ; 43 loci at p < 6 × 10 −9 ). Replication is observed for PAX8 , VRK2 , and FBXL12/UBL5/PIN1 loci in the CHARGE study ( n = 47,180; p < 6.3 × 10 −4 ), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis ( n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways.

Polygenic score for neuroticism is related to sleep difficulties

“…In particular, higher genetic propensity to experience negative emotions was related to higher sleeping difficulties because it fostered risk factors for such difficulties, such as phenotypical neuroticism, anxiety and depressive symptoms. This finding adds to existing research that has identified genetic correlations between neuroticism and sleep‐related outcomes by highlighting the potential pathways through which this relationship may operate. However, the mediators tested in the present study explained only part of the relationship between PGS for neuroticism and sleep quality, and other factors may operate in this association.…”

“…The relationship between neuroticism and sleep quality may be explained in part by shared genetic factors, with genetic variants having pleiotropic effects on neuroticism and sleep quality. The evidence for genetic correlations between neuroticism and markers of sleep is mixed, with studies reporting positive genetic correlations with measures of sleep duration and insomnia complaints but not with insomnia disorder . In addition, polygenic risk for disrupted rest‐activity rhythm (an indicator of disrupted circadian function) is related to higher neuroticism .…”

Fxr1 regulates sleep and synaptic homeostasis

“…Indeed, variants in the Fxr1 locus have been GWAS-associated to insomnia 16 and mental illness including schizophrenia and bipolar disorder 40,41 . Fxr1 is also differentially expressed in the brain of people with schizophrenia 42 , while a schizophrenia-associated SNP in Fxr1 has been linked to selfreported sleep duration 17 .…”

“…Fxr1 is an RNA binding protein expressed in the brain and in neurons where it is localized in the cell bodies and dendrites in association with mRNAs and ribosomes 15 . Variants of the FXR1 locus are GWAS-identified risk factors for insomnia 16 and a schizophrenia-associated FXR1 variant is linked to sleep duration 17 . Interestingly, Fxr1 protein degradation is also regulated by Glycogen synthase kinase 3 beta (Gsk3) 18,19 and its brain expression is increased in response to lithium, a pharmacological agent inhibiting Gsk3 that is used for sleep regulation and the treatment of psychiatric disorders characterized by sleep disturbances, such as bipolar disorder 20,21 .…”

Nightmares share strong genetic risk with sleep and psychiatric disorders

“…In primary meta-analysis of GWAS in 28,596 subjects, we identified a significant association with nightmares for a locus intronic to PTPRJ (rs11039471, p=3.7e-8) (Figure 1, Supplementary Figure 1-2, Supplementary Table 1). Previously, an independent signal at the same locus, not driven by the same lead variants, associated with total sleep duration, short sleep duration and glycemic traits 25,26 suggesting a broader pleiotropic role for the PTPRJ locus in regulating sleep and symptoms of disturbed sleep such as nightmares.…”