Original Article | Published:

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

Molecular Psychiatry volume 20, pages 12321239 (2015) | Download Citation

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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 (GWAS) 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- to 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 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS 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.

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Acknowledgements

The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC–55022, R01HL087641, R01HL59367 and R01HL086694; 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. The Cardiovascular Health Study was supported by NHLBI contracts HHSN268201200036C, N01-HC-85239, N01-HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). DNA handling and genotyping was supported in part by the National Center for Research Resources grant UL1RR033176, now at the National Center for Advancing Translational Sciences CTSI grant UL1TR000124; the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (contract no. N01‐HC‐25195) and its contract with Affymetrix, Inc for genotyping services (contract no. N02‐HL‐6‐4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA‐II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The Health, Aging and Body Composition Study supported by NIA contracts N01-AG-62101, N01-AG-62103 and N01-AG-62106 and NIA grants 1R01AG032098-01A1 and 1R01AG030474-01A1. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, NIA. The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). The Nurses Health Study and Health Professional Follow-Up Study GWAS were supported by grants from the National Institutes of Health [NCI (CA40356, CA087969, CA055075, CA98233), NIDDK (DK058845, DK070756), NHGRI (HG004399), NHLBI (HL35464)] with additional support from Merck/Rosetta Research Laboratories, North Wales, PA. The Invecchiare in CHIANTI study baseline (1998–2000) was supported as a ‘targeted project’ (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). 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 (NIAMS), the National Institute on Aging (NIA), the National Center for Research Resources (NCRR), 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 (NHLBI) 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 NIAMS provides funding for the MrOS ancillary study ‘GWAS in MrOS and SOF’ under the grant number RC2ARO58973. The Quebec Family Study was funded by multiple grants from the Medical Research Council of Canada and the Canadian Institutes for Health Research. This work was supported by a team grant from the Canadian Institutes for Health Research (FRN-CCT-83028). Funding for the Queensland Institute of Medical Research Twin Study was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498), the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (NIH grants AA07535, AA10249, AA11998, AA13320, AA13321, AA13326, AA14041, MH66206). A portion of the genotyping on which this study was based (Illumina 370K scans) was carried out at the Center for Inherited Disease Research, Baltimore (CIDR), through an access award to our late colleague Dr Richard Todd (Psychiatry, Washington University School of Medicine, St Louis). Statistical analyses were carried out on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). EMB is supported by NHMRC grant 613608. The generation and management of GWAS genotype data for the Rotterdam Study are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus MC and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Henning Tiemeier was supported by the VIDI grant of ZonMw (2009-017.106.370). Karin Hek was supported by a grant from BavoEuropoort. Netherlands Twin Registry funding was obtained from the Netherlands Organization for Scientific Research (NWO: MagW/ZonMW grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192), Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007), VU University’s Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA), European Science Foundation (ESF, EU/QLRT-2001-01254), the European Community’s Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413); European Science Council (ERC 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA), and the National Institutes of Health (NIH, R01D0042157-01A, Grand Opportunity grants 1RC2MH089951-01 and 1RC2 MH089995-01). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. The Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG and the Caché Campus program of the InterSystems GmbH. The Study of Osteoporotic Fractures is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, and R01 AG026720. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the ancillary study ‘GWAS in MrOS and SOF’ under the grant number RC2ARO58973. TwinsUK was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE project grant agreement (HEALTH-F4-2007-201413). The study also receives support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. Genotyping was performed by the Wellcome Trust Sanger Institute, support of the National Eye Institute via an NIH/CIDR genotyping project. This research was supported for the Wisconsin Sleep Cohort Study by the National Heart, Lung, and Blood Institute (R01HL62252) and National Center for Research Resources (1UL1RR025011) and by NS23724. The Young Finns Study has been financially supported by the Academy of Finland: grants 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (grant 9M048 for 9N035 for TeLeht), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation.

Author information

Affiliations

  1. VA Boston Healthcare System, Boston, MA, USA

    • D J Gottlieb
    •  & T-h Chen
  2. Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    • D J Gottlieb
    • , B Cade
    • , S R Patel
    •  & S Redline
  3. Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    • D J Gottlieb
    • , T-h Chen
    •  & G T O'Connor
  4. The NHLBI’s Framingham Heart Study, Framingham, MA, USA

    • D J Gottlieb
    •  & G T O'Connor
  5. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands

    • K Hek
    •  & H Tiemeier
  6. Epidemiological and Social Psychiatric Research Institute, Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands

    • K Hek
    • , A Hofman
    • , A I Luik
    • , A G Uitterlinden
    •  & H Tiemeier
  7. Department of Neurology, University of Washington, Seattle, WA, USA

    • N F Watson
  8. UW Medicine Sleep Center, University of Washington, Seattle, WA, USA

    • N F Watson
    •  & S A Gharib
  9. Icelandic Heart Association, Kópavogur, Iceland

    • G Eiriksdottir
    • , A V Smith
    •  & V Gudnason
  10. The University of Queensland, Queensland Brain Institute, St Lucia, QLD, Australia

    • E M Byrne
  11. Queensland Institute of Medical Research, Brisbane, QLD, Australia

    • E M Byrne
    • , G W Montgomery
    •  & N G Martin
  12. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA

    • M Cornelis
    • , M K Jensen
    • , E B Rimm
    •  & F Hu
  13. Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • M Cornelis
    • , G C Curhan
    • , E B Rimm
    •  & F Hu
  14. Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, CA, USA

    • S C Warby
    •  & E Mignot
  15. Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy

    • S Bandinelli
  16. Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK

    • L Cherkas
    • , L Quaye
    • , T D Spector
    •  & M Mangino
  17. California Pacific Medical Center Research Institute, San Francisco, CA, USA

    • D S Evans
    • , G J Tranah
    •  & K L Stone
  18. Department of Psychiatry and Psychotherapy, HELIOS-Hospital Stralsund, University Medicine Greifswald, Greifswald, Germany

    • H J Grabe
  19. Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland

    • J Lahti
    •  & K Räikkönen
  20. Folkhalsan Research Centre, Helsinki, Finland

    • J Lahti
    •  & J G Eriksson
  21. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    • M Li
    • , L Kao
    •  & N M Punjabi
  22. Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland

    • T Lehtimäki
  23. Department of Statistics, University of Auckland, Auckland, New Zealand

    • T Lumley
  24. Department of Medicine, University of Washington, Seattle, WA, USA

    • K D Marciante
    • , B M Psaty
    •  & S A Gharib
  25. Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA

    • K D Marciante
    •  & B M Psaty
  26. Department of Kinesiology, Laval University, Quebec, Canada

    • L Pérusse
  27. Institute of Nutrition and Functional Foods, Laval University, Quebec, Canada

    • L Pérusse
    •  & M-C Vohl
  28. Department of Epidemiology and Health Services, University of Washington, Seattle, WA, USA

    • B M Psaty
  29. Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA

    • B M Psaty
  30. Department of Internal Medicine, University of California Davis, Sacramento, CA, USA

    • J Robbins
  31. Department of Biological Psychology, Netherlands Twin Register, VU University, Amsterdam, The Netherlands

    • J M Vink
    • , J-J Hottenga
    • , G Willemsen
    •  & D I Boomsma
  32. Precision Medicine, Cambridge, MA, USA

    • J B Wilk
  33. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA

    • J M Stafford
    •  & Y Liu
  34. Texas Biomedical Research Institute, San Antonio, TX, USA

    • C Bellis
    •  & J Blangero
  35. Department of Prosthodontics, Gerodontology and Dental Materials, Center of Oral Health, University Medicine Greifswald, Greifswald, Germany

    • R Biffar
  36. Pennington Biomedical Research Center, Baton Rouge, LA, USA

    • C Bouchard
  37. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    • G C Curhan
    • , D J Hunter
    • , P Kraft
    • , E B Rimm
    •  & F Hu
  38. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland

    • J G Eriksson
  39. Helsinki University Central Hospital, Helsinki, Finland

    • J G Eriksson
  40. National Institute for Health and Welfare, Helsinki, Finland

    • J G Eriksson
  41. Vasa Central Hospital, Vasa, Finland

    • J G Eriksson
  42. Department of Internal Medicine B—Cardiology, Pulmonary Medicine, Infectious Diseases and Intensive Care Medicine, University Medicine Greifswald, Greifswald, Germany

    • R Ewert
  43. Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA

    • L Ferrucci
    •  & T Tanaka
  44. Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA

    • T Fülöp
  45. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • P R Gehrman
  46. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA

    • R Goodloe
  47. Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD, USA

    • T B Harris
  48. Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA

    • A C Heath
  49. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA

    • D Hernandez
  50. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, USA

    • D J Hunter
    •  & P Kraft
  51. NHLBI Cardiovascular Epidemiology and Human Genomics Branch, The Framingham Heart Study, Framingham, MA, USA

    • A D Johnson
    •  & X Zhang
  52. Department of Clinical Physiology, Tampere University Hospital and School of Medicine University of Tampere, Tampere, Finland

    • M Kähönen
  53. Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

    • E K Larkin
  54. Department of Health Studies, University of Chicago, Chicago, IL, USA

    • D S Lauderdale
  55. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands

    • M Medici
    •  & A G Uitterlinden
  56. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    • A Palotie
    •  & E Widen
  57. Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • A Palotie
  58. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

    • A Palotie
  59. Division of Genetics and Cell Biology, San Raffaele Research Institute, Milano, Italy

    • G Pistis
  60. Universita' degli Studi di Trieste, Trieste, Italy

    • G Pistis
  61. Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

    • G Pistis
    •  & E Porcu
  62. Dipartimento di Scienze Biomediche, Universita' di Sassari, Sassari, Italy

    • G Pistis
    •  & E Porcu
  63. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, and Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland

    • O Raitakari
  64. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA

    • J I Rotter
  65. University of Iceland, Reykjavik, Iceland

    • A V Smith
    •  & V Gudnason
  66. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany

    • A Teumer
  67. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany

    • A Teumer
    •  & H Völzke
  68. Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging, Leiden, The Netherlands

    • A G Uitterlinden
  69. Department of Food Science and Nutrition, Laval University, Quebec, Canada

    • M-C Vohl
  70. Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

    • T Young
  71. Department of Medicine, Turku University Hospital and University of Turku, Turku, Finland

    • J Viikari
  72. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • N M Punjabi
  73. Department of Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, The Netherlands

    • H Tiemeier

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to D J Gottlieb.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/mp.2014.133

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Further reading