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

H Wang,Andrew Loudon ,S D Kyle ,Michael N Weedon ,Ja Zwart ,Katri Kantojärvi ,Brian E Cade ,Bendik S Winsvold ,Jonas B Nielsen ,Hanna Ollila ,Max A Little ,Kristian Hveem ,Samuel E Jones ,Linn Beate Strand ,David Ray ,Kati Kristiansson ,Martin K Rutter ,Jaakko Kaprio ,Tiina Paunio ,Susan Redline ,Richard Emsley ,Sonja Sulkava ,Jessica Tyrrell ,Teemu Palviainen ,Hassan S Dashti ,Xiaofeng Zhu ,Cristen J Willer ,Frank A.j.l Scheer ,Shaun Purcell ,Deborah A Lawlor ,Krunal Patel ,Ben Brumpton ,S G Anderson ,Christer Hublin ,Yanwei Song ,Rebecca C Richmond ,Vincent T Van Hees ,Jacqueline M Lane ,Andrew R Wood ,Kai Spiegelhalder ,Tamar Sofer ,Jack Bowden ,David A Bechtold ,T M Frayling ,Richa Saxena

doi:10.1016/j.sleep.2019.11.1140

Abstract

Excessive daytime sleepiness (EDS) affects 10–20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing. A main symptom of chronic insufficient sleep is excessive daytime sleepiness. Here, Wang et al. report 42 genome-wide significant loci for self-reported daytime sleepiness in 452,071 individuals from the UK Biobank that cluster into two biological subtypes of either sleep propensity or sleep fragmentation.

Highlights

Excessive daytime sleepiness (EDS) affects 10–20% of the population and is associated with substantial functional deficits
No association was seen with single-nucleotide polymorphisms (SNPs) reported in smaller independent GWAS of EDS, hypersomnia, or narcolepsy (Supplementary Table 4)
Despite the modest SNP-heritability (h2 = 6.9%, consistent with previous reports17,18), we identified 42 genome-wide significant loci (P < 5 × 10−8) given boosted statistical power with 452,071 samples

Summary

Introduction

Excessive daytime sleepiness (EDS) affects 10–20% of the population and is associated with substantial functional deficits. We identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. Excessive daytime sleepiness (EDS) is a chief symptom of chronic insufficient sleep[1] as well as of several primary sleep disorders, such as sleep apnea, narcolepsy, and circadian rhythm disorders[2,3]. While EDS occurs in a variety of settings associated with insufficient sleep, there is large inter-individual variability in levels of EDS that is not fully explained by sleep duration, sleep quality, or chronic disease[11]. We extend our GWAS of self-reported daytime sleepiness to the full UK Biobank dataset[22] and identify multiple genetic variants grouping into different biological subtypes that associate with sleepiness. Bioinformatics analyses further highlight relevant biological processes and reveal shared genetic background with other diseases

Methods

Results

Conclusion