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Nat Commun. 2018 Jan 17;9(1):260. doi: 10.1038/s41467-017-02662-2.

Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.

Jiang X1,2, O'Reilly PF3, Aschard H1,4, Hsu YH5,6,7, Richards JB8, Dupuis J9,10, Ingelsson E11,12, Karasik D5, Pilz S13, Berry D14, Kestenbaum B15, Zheng J16, Luan J16, Sofianopoulou E17, Streeten EA18, Albanes D19, Lutsey PL20, Yao L20, Tang W20, Econs MJ21, Wallaschofski H22,23, Völzke H23,24, Zhou A25, Power C14, McCarthy MI26,27,28, Michos ED29,30, Boerwinkle E31, Weinstein SJ19, Freedman ND19, Huang WY32, Van Schoor NM33, van der Velde N34,35, Groot LCPGM36, Enneman A34, Cupples LA9,10, Booth SL37, Vasan RS10, Liu CT9, Zhou Y9, Ripatti S38, Ohlsson C39, Vandenput L39, Lorentzon M40, Eriksson JG41,42, Shea MK37, Houston DK43, Kritchevsky SB43, Liu Y44, Lohman KK45, Ferrucci L46, Peacock M21, Gieger C47, Beekman M48, Slagboom E48, Deelen J48,49, Heemst DV50, Kleber ME51, März W51,52,53, de Boer IH54, Wood AC55, Rotter JI56, Rich SS57,58, Robinson-Cohen C59, den Heijer M60, Jarvelin MR61,62,63,64, Cavadino A14,65, Joshi PK66, Wilson JF66,67, Hayward C67, Lind L12, Michaëlsson K68, Trompet S50,69, Zillikens MC60, Uitterlinden AG34,60, Rivadeneira F34,60, Broer L60, Zgaga L70, Campbell H66,71, Theodoratou E66,71, Farrington SM71, Timofeeva M71, Dunlop MG71, Valdes AM72,73, Tikkanen E74, Lehtimäki T75,76, Lyytikäinen LP75,76, Kähönen M77,78, Raitakari OT79,80, Mikkilä V81, Ikram MA34, Sattar N82, Jukema JW69,83, Wareham NJ16, Langenberg C16, Forouhi NG16, Gundersen TE84, Khaw KT17, Butterworth AS17, Danesh J17,85, Spector T72, Wang TJ86, Hyppönen E87,88, Kraft P1, Kiel DP89,90,91.

Author information

1
Program in Genetic Epidemiology and Statistical Genetics. Department of Epidemiology, Harvard T.H.Chan School of Public Health, 677 Huntington Avenue, Boston, 02115, MA, USA.
2
Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Nobels vagen 13, Stockholm, 17177, Sweden.
3
Department of Social Genetic & Developmental Psychiatry, King's College London, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK.
4
Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, 75724, France.
5
Institute for Aging Research, Hebrew SeniorLife, 1200 Centre Street, Boston, MA, 02131, USA.
6
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02115, USA.
7
Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, 02142, USA.
8
Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, 3755 Côte Ste-Catherine Road, Suite H-413 Montréal, Québec, H3T 1E2, Canada.
9
Department of Biostatistics, Boston University School of Public Health, Crosstown Center. 801 Massachusetts Avenue 3rd Floor, Boston, MA, 02118, USA.
10
Framingham Heart Study, 73 Mt. Wayte Avenue, Framingham, MA, 01702, USA.
11
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine Stanford, Stanford, CA, 94305, USA.
12
Department of Medical Sciences, Uppsala University, 751 85, Uppsala, Sweden.
13
Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
14
Population, Policy and Practice, University College London, Great Ormond Street, Institute of Child Health, London, WC1E 6BT, UK.
15
Kidney Research Institute, Division of Nephrology, 325 Ninth Avenue, Seattle, WA, 98104, USA.
16
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
17
Department of Public Health & Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge, CB1 8RN, UK.
18
Genetics and Personalized Medicine Program, University of Maryland School of Medicine, Howard Hall Room 567, Baltimore, MD, 21201, USA.
19
Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 9609 Medical Center Drive, Bethesda, MD, 20892, USA.
20
Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, 1300S 2nd Street, Suite 300, Minneapolis, MN, 55454, USA.
21
Department of Medicine, Indiana University, Endocrinology, 1120W Michigan Street, Indianapolis, IN, 46202-5124, USA.
22
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17489, Greifswald, Germany.
23
DZHK (German Centre for Cardiovascular Research), Partner Site, Greifswald, 13316, Berlin, Germany.
24
Institut für Community Medicine, SHIP/Klinisch-Epidemiologische Forschung, Universitätsmedizin Greifswald, Walther-Rathenau-Str. 48, 17475, Greifswald, Germany.
25
Centre for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, 5001, SA, Australia.
26
Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ, UK.
27
Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.
28
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ, UK.
29
Division of Cardiology, Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.
30
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
31
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
32
Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 9609 Medical Center Drive, Bethesda, MD, 20892, USA.
33
Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, De Boelelaan 1089a, 1081 HV, Amsterdam, The Netherlands.
34
Erasmus MC Department of Epidemiology, Postbus 2040, 3000CA, Rotterdam, The Netherlands.
35
AMC, Internal Medicine, Geriatrics Department, PO Box 22700, 1100 DE, Amsterdam, The Netherlands.
36
Department of Human Nutrition, Wageningen University, PO-box 17, 6700 AA, Wageningen, The Netherlands.
37
Vitamin K Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA, 02111, USA.
38
Statistical and Translational Genetics, University of Helsinki, Tukholmankatu 8, Building, Biomedicum, Helsinki 2U, Finland.
39
Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Vita Stråket 11, Gothenburg, 41345, Sweden.
40
Department of Geriatric Medicine, University of Gothenburg and Sahlgrenska University Hospital, Mölndal, 43180, Sweden.
41
Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, University of Helsinki, P.O. Box 20, Tukholmankatu, 8 B 00014, Finland.
42
Folkhälsan Research Center, University of Helsinki, Helsinki, PO Box 2000014, Finland.
43
Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
44
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
45
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
46
Longitudinal Studies Section, Intramural Research Program of the National Institute on Aging, NIH, Baltimore, MD, 21225, USA.
47
German Research Center for Environmental Health, Molecular Epidemiology, AME, Ingolstädter Landstr 1, D-85764, Neuherberg, Germany.
48
Molecular Epidemiology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
49
Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931, Köln (Cologne), Germany.
50
Gerontology and Geriatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
51
Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer1, 68167, Mannheim, Germany.
52
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Graz, Austria.
53
SYNLAB Holding Deutschland GmbH, Gubener Straße 39, 86156, Augsburg, Germany.
54
Division of Nephrology and Kidney Research Institute, University of Washington, 325 ninth Avenue, Washington, DC, 98104, USA.
55
USDA/ARS Children's Nutrition Research Center, 1100 Bates Avenue, Houston, TX, 77071, USA.
56
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
57
Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908, USA.
58
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA.
59
Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, 1161 21st Ave S., Nashville, TN, 37232, USA.
60
Erasmus MC Department of Internal Medicine, Postbus 2040, 3000CA, Rotterdam, The Netherlands.
61
Epidemiology and Biostatistics School of Public Health, Imperial College London, 156 Norfolk Place, St. Mary's Campus, London, UK W2 1PG, UK.
62
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, 90014, Oulu, Finland.
63
Biocenter Oulu, University of Oulu, P.O. Box 5000, Aapistie 5A, FI-90014, Finland.
64
Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O. Box 20, FI-90220 Oulu, 90029 OYS, Finland.
65
Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
66
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK.
67
MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, the University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
68
Department of Surgical Sciences, Uppsala University, Dag Hammarskjöldsv 14 B, Uppsala Science Park, 751 85, Uppsala, Sweden.
69
Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, Netherlands.
70
Department of Public Health and Primary Care, Institute of Population Health, Trinity College Dublin, University of Dublin, Dublin 24, D02 PN40, Ireland.
71
Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
72
The Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Campus, Westminster Bridge Road, London, SE1 7EH, UK.
73
School of Medicine, University of Nottingham, City Hospital, Hucknall Rd, Nottingham, NG5 1PB, UK.
74
FIMM-Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, P.O. Box 20, FI-00014, Finland.
75
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland.
76
Department of Clinical Chemistry, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33014, Finland.
77
Department of Clinical Physiology, Tampere University Hospital, Tampere, 33521, Finland.
78
Department of Clinical Physiology, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33014, Finland.
79
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20521, Finland.
80
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20014, Finland.
81
Science Adviser at Academy of Finland, Hakaniemenranta 6, PO Box 131, FI-00531, Helsinki, Finland.
82
BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, University Avenue, Glasgow, G12 8QQ, UK.
83
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
84
Vitas AS, Gaustadaleen 21, N-0349, Oslo, Norway.
85
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
86
Division of Cardiovascular Medicine, Vanderbilt Heart and Vascular Institute, 2220 Pierce Avenue 383 Preston Research Building, Nashville, TN, 37232-6300, USA.
87
Population, Policy and Practice, University College London, Great Ormond Street, Institute of Child Health, London, WC1E 6BT, UK. elina.hypponen@unisa.edu.au.
88
Centre for Population Health Research, Sansom Institute for Health Research, University of South Australia, Adelaide, 5001, SA, Australia. elina.hypponen@unisa.edu.au.
89
Institute for Aging Research, Hebrew SeniorLife, 1200 Centre Street, Boston, MA, 02131, USA. kiel@hsl.harvard.edu.
90
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02115, USA. kiel@hsl.harvard.edu.
91
Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, 02142, USA. kiel@hsl.harvard.edu.

Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

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