Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits

Abstract

Chronic sleep disturbances, associated with cardio-metabolic diseases, psychiatric disorders and all-cause mortality 1,2 , affect 25-30% of adults worldwide 3 . While environmental factors contribute importantly to self-reported habitual sleep duration and disruption, these traits are heritable 4-9 , and gene identification should improve our understanding of sleep function, mechanisms linking sleep to disease, and development of novel therapies. We report single and multi-trait genome-wide association analyses (GWAS) of self-reported sleep duration, insomnia symptoms including difficulty initiating and/or maintaining sleep, and excessive daytime sleepiness in the UK Biobank (n=112,586), with discovery of loci for insomnia symptoms (near MEIS1, TMEM132E, CYCL1, TGFBI in females and WDR27 in males), excessive daytime sleepiness (near AR/OPHN1) and a composite sleep trait (near INADL and HCRTR2), as well as replication of a locus for sleep duration (at PAX-8). Genetic correlation was observed between longer sleep duration and schizophrenia (r G =0.29, p=1.90x10 -13 ) and between increased excessive daytime sleepiness and increased adiposity traits (BMI r G =0.20, p=3.12x10 -09 ; waist circumference r G =0.20, p=2.12x10 -07 ).Rather than being 'secondary', evidence suggests disordered sleep may play an important role in the etiology and maintenance of physical and mental health 1,2 . Heritability has been estimated at ~40% for sleep duration 4,6-8 , 25-45% for insomnia 9 and 17% for excessive daytime sleepiness 9 , but few genetic factors are known. A Mendelian short sleep mutation in BHLHE41 (P385R) has been identified, and confirmed in mouse models 10 . GWAS for sleep duration have been reported 11-14 , but only an association at the PAX8 locus reached genome-wide significance and was confirmed across ethnic groups 12 . There are several reported loci for restless legs syndrome (RLS) and narcolepsy, but no known robust genetic loci for insomnia symptoms or excessive daytime sleepiness 15,16 .

Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes

“…The severity of daytime sleepiness increased with older age, female sex, higher body mass index (BMI), various behavioral, social and environmental factors, and chronic diseases (Supplementary Table 1). Self-reported daytime sleepiness was positively but weakly correlated with self-reported insomnia symptoms, morning chronotype, ICD-10, or self-report of physician diagnosed sleep apnea and self-reported shorter and longer sleep duration, consistent with earlier reports or known clinical correlates 18 (Spearman correlation <0.2; Supplementary Table 1 and Supplementary Fig. 1).…”

“…Experimental studies have shown that there is also individual vulnerability to EDS following sleep restriction 11,12 . The heritability of daytime sleepiness is estimated to be between 0.37 and 0.48 in twin studies [13][14][15] , 0.17 in family studies 16 , and between 0.084 and 0.17 in GWAS 17,18 , suggesting that genetic factors contribute to variation in sleepiness. Despite multiple candidate gene studies 19 and GWAS 17,20,21 , including one from the first genetic release of the UK Biobank 18 , few genome-wide significant genetic variants have been reported, likely reflecting the heterogeneous and multifactorial etiology of the phenotype and low statistical power.…”

Sleep Duration and Adiposity in Children and Adults: Observational and Mendelian Randomization Studies

“…We chose the genetic variants based on genome‐wide significance and functional effect to fulfill the first assumption that the genotype should be strongly associated with exposure. At least three large GWAS have identified that the paired box 8 ( PAX8 ) gene locus is robustly associated with sleep duration across ethnic groups . rs7556815 near PAX8 is biologically associated with sleep duration.…”

Co‐shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome

“…Recently, a “pleiotropic enriched” GWAS study found shared common risk variants of SCZ and cardiovascular risk factors and MetS traits (dyslipidemia, waist‐to‐hip ratio, systolic blood pressure, and increased BMI) (Andreassen et al, ). A recent GWAS study detected shared loci of sleep disturbance traits with SCZ and the adiposity traits BMI and waist circumference (Lane et al, ). In a systematic review of genetic variants associated with MetS in SCZ patients, several genes showed strong evidence for association, including the genes leptin ( LEP ), leptin receptor ( LEPR ), 5‐hydroxytriptamine receptor 2C ( HTR2C ), FTO , and MTHFR (Malan‐Muller et al, ), with the latter two being also MDD‐risk genes (Amare et al, ).…”