Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study

Abstract

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study of usual sleep duration was conducted using 18 population-based cohorts totaling 47,180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35-80 kb upstream from the thyroid-specific transcription factor PAX8 (lowest p=1.1 × 10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest p=9.3 × 10−4). The strongest combined association was at rs1823125 (p=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 minutes longer per night. The alleles associated with longer sleep duration were associated in previous genome-wide association studies with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

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

“…For sleep duration (n=111,975), the strongest association was observed at the PAX-8 locus (rs62158211T, β(se)=2.34(0.30) mins/allele, p =4.7×10 -14 , effect allele frequency (EAF) 0.213, Fig. 2a), confirming a previously reported association (r 2 =0.96, D'=1 to lead SNP rs1823125 in 1KG CEU) 12 . For insomnia symptoms (n=32,155 cases, 26,973 controls), significant associations were observed within MEIS1 (rs113851554T, OR [95%CI]=1.26[1.20-1.33], p =9.1×10 -19 , EAF 0.057, Fig.…”

“…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 .…”

Genetic Correlation Analysis Suggests Association between Increased Self-Reported Sleep Duration in Adults and Schizophrenia and Type 2 Diabetes

“…A recent genome-wide association study (GWAS) from the CHARGE consortium that included more than 47,000 participants from 18 population-based cohorts identified 2 genome-wide significant signals on chromosome 2 and chromosome 6, respectively. 13 The signal from chromosome 2, found between the PAX8 and CBWD2 genes, replicated in a cohort of 4,400 African Americans. Nominal associations for the associated variants were found with metabolic traits such as glycated hemoglobin and also with attention deficit hyperactivity disorder, thus highlighting potential shared etiology between sleep duration and metabolic and psychiatric disorders.…”

Genetic Pathways to Insomnia

“…There are far fewer GWAS of insomnia to date than other common psychiatric phenotypes (e.g., depression [63,64], schizophrenia [65]) and sleep phenotypes such as sleep duration (e.g., [66,67]), with only four studies examining potential genes involved in insomnia or related symptomatology. Brief descriptions of insomnia GWAS (and replications) are provided in Table 3.…”