Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ~50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2)was significantly associated with sleep duration (P = 9.8 × 10-7). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.
Bibliographical noteFunding Information:
B.E.C. is supported by National Institutes of Health grants (T32-HL007901-16, R01-HL113338-02). R.S. is supported by NIH R21 HL121728. Centralized CARe resources for the following eight cohorts were supported through a National Institutes of Health grant to the Broad Institute (N01-HC-65226). Atherosclerotic Risk in Communities (ARIC): The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C, R01HL087641, R01HL59367 and R01HL086694); a National Human Genome Research Institute contract (U01HG004402); and National Institutes of Health contract (HHSN268200625226C). Infrastructure was partly supported by Grant Number (UL1RR025005), a component of the National Institutes of Health and NIH Roadmap for Medical Research. Cardiovascular Health Study (CHS): This research was supported by contracts (HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086) and grant (HL080295) from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by (AG023629) from the National Institute on Aging. Cleveland Family Study (CFS): National Institutes of Health grants to Case Western Reserve University (RO1 HL46380-01-16, M01-RR-00080). Coronary Artery Risk in Young Adults (CARDIA): The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201300025C, HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C) and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging and an intra-agency agreement between the National Institute on Aging and the National Heart, Lung, and Blood Institute (AG0005). Framingham Heart Study (FHS): National Institutes of Health grants to Boston University (N01-HC-25195, R01-HL-092577, R01-HL-076784, R01-AG-028321). Jackson Heart Study (JHS): JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Multi-Ethnic Study of Atherosclerosis (MESA): MESA is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with MESA investigators. Support for MESA is provided by contracts (N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and CTSA UL1-RR-024156). Funding for CARe genotyping was provided by the National Heart, Lung, and Blood Institute contract (N01-HC-65226). Sleep Heart Health Study (SHHS): National Institutes of Health grants to Johns Hopkins University (U01HL064360), CaseWestern University (U01 HL063463), University of California, Davis (U01 HL053916), University of Arizona (U01 HL053938), University of Minnesota (relocated in 2006 to University of Arizona) (U01 HL053934), University of Pittsburgh (U01 HL077813), Boston University (U01 HL053941), MedStar Research Institute (U01 HL063429), Johns Hopkins University (U01 HL053937). Korean Genome and Epidemiology Study (KoGES): This studywas provided with biospecimens and data from the Korean Genome Analysis Project (4845-301), the Korean Genome and Epidemiology Study (2001-347-6111-221, 2002-347-6111-221) and Korea Biobank Project (4851-307, KBP-2013-25) that were supported by the Korea Center for Disease Control and Prevention, Republic of Korea. Religious Orders Study (ROS): The Religious Orders Study is supported by grants from the National Institute on Aging: P30AG10161, R01AG15819, R01AG24871, R01AG26147, R01AG26916, P01AG09466, P01AG14449; K08AG00849, K23AG23675, the Illinois Department of Public Health, the ElsieHeller Brain Bank EndowmentFund, and the Robert C. Borwell Chair of Neurological Sciences. Rush Memory and Aging Project (MAP): The Rush Memory and Aging Project is supported by the National Institutes of Health grants R01AG017917, P30AG010161, R01AG015819, R01AG024480, R01NS078009, R01AG036836 and R01AG030146. Osteoporotic Fractures in Men (MrOS) Study: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, the National Center for Research Resources, and NIH Roadmap for Medical Research under the following grant numbers: (U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810 and UL1 RR024140). The National Heart, Lung, and Blood Institute provides funding for the MrOS Sleep ancillary study 'Outcomes of Sleep Disorders in Older Men' under the following grant numbers: (R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838 and R01 HL070839). The National Institute of Arthritis and Musculoskeletal and Skin Diseases provides funding for the MrOS ancillary study 'GWAS in MrOS and SOF' under the grant number (RC2ARO58973). Study of Osteoporotic Fractures (SOF): The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging provides support under the following grant numbers: (R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574 and R01 AG027576). The SOF Sleep Study is supported by National Institutes of Health funding. The National Institute on Aging provides support under the following grant numbers: (R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576 and R01 AG026720).
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ASJC Scopus subject areas
- Molecular Biology