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.

Fig. 1

Plots for genome-wide association analysis results for sleep duration and short/long sleep. a Manhattan plot of sleep duration (n = 446,118) and b Miami plot of short (cases n = 106,192/305,742) and long (cases n = 34,184/305,742) sleep. Plots show the −log₁₀P values (y-axis) for all genotyped and imputed single-nucleotide polymorphisms (SNPs) passing quality control in each genome-wide association study (GWAS), plotted by chromosome (x-axis). Blue peaks represent genome-wide significant loci. Horizontal red line denotes genome-wide significance (P = 5 × 10⁻⁸)

Fig. 2

Pathway-based and tissue expression enrichment analyses for sleep duration. a Pathway analysis is based on MAGMA gene sets. Top 10 of 10,891 pathways are shown, and significant pathways are indicated in orange (P < 4.59 × 10⁻⁶). For each significant pathway, respective sleep genes are indicated with a colored orange box. Sleep genes from significant pathways that overlap with remaining pathways are indicated in blue. b Pathway analysis is based on Pascal (gene-set enrichment analysis using 1077 pathways from KEGG, REACTOME, BIOCARTA databases). Top 10 pathways are shown, and significant pathways are indicated in orange (P < 4.64 × 10⁻⁵). c MAGMA tissue expression analysis using gene expression per tissue based on GTEx RNA-seq data for 53 specific tissue types. Significant tissues are shown in red (P < 9.43 × 10⁻⁴). All pathway and tissue expression analyses in this figure can be found in tabular form in Supplementary Tables 9, 10, 12

Fig. 3

Shared genetic architecture between sleep duration and behavioral and disease traits. Linkage disequilibrium (LD) score regression estimates of genetic correlation (r_g) were obtained by comparing genome-wide association estimates for sleep duration with summary statistics estimates from 224 publically available genome-wide association studies (GWASs). Blue indicates positive genetic correlation and red indicates negative genetic correlation; r_g values are displayed for significant correlations. Larger colored squares correspond to more significant P values, and asterisks indicate significant (P < 2.2 × 10⁻⁴) genetic correlations. All genetic correlations in this report can be found in tabular form in Supplementary Data 18

Fig. 4

Bidirectional causal relationship of sleep duration with schizophrenia using Mendelian randomization. Association between single-nucleotide polymorphisms (SNPs) associated with sleep duration and schizophrenia (a) or SNP associated with schizophrenia and sleep duration (c) and forest plots show the estimate of the effect of genetically increased sleep duration on schizophrenia (b) or increased risk of schizophrenia on sleep duration (d). Lines identify the slopes for three Mendelian randomization (MR) association tests (a, c). Forest plots show each SNP with the 95% confidence interval (gray line segment; error bars) of the estimate and the inverse variance weighted, MR-Egger, and weighted median MR results in red