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

Xia Jiang 1, 2 Paul O'Reilly 3 Hugues Aschard 1, 4 Yi-Hsiang Hsu 5, 6, 7 J. Brent Richards 8 Josée Dupuis 9, 10 Erik Ingelsson 11, 12 David Karasik 5 Stefan Pilz 13 Diane Berry 14 Bryan Kestenbaum 15 Jusheng Zheng 16 Jianan Luan 16 Eleni Sofianopoulou 16 Elizabeth Streeten 17 Demetrius Albanes 18 Pamela Lutsey 19 Lu Yao 19 Weihong Tang 19 Michael Econs 20 Henri Wallaschofski 21, 22 Henry Völzke 22, 21 Ang Zhou 23 Chris Power 14 Mark Mccarthy 24, 25 Erin Michos 26, 27 Eric Boerwinkle 28 Stephanie Weinstein 18 Neal Freedman 18 Wen-Yi Huang 18 Natasja van Schoor 29 Nathalie van der Velde 30, 31 Lisette de Groot 32 Anke Enneman 30 L. Adrienne Cupples 9, 10 Sarah Booth 33 Ramachandran Vasan 10 Ching-Ti Liu 9 Yanhua Zhou 9 Samuli Ripatti 34 Claes Ohlsson 35 Liesbeth Vandenput 35 Mattias Lorentzon 35, 36 Johan Eriksson 34 M. Kyla Shea 33 Denise Houston 37 Stephen Kritchevsky 37 Yongmei Liu 37 Kurt Lohman 37 Luigi Ferrucci 18 Munro Peacock 20 Christian Gieger 38 Marian Beekman 39 Eline Slagboom 39 Joris Deelen 39, 40 Diana Van Heemst 39 Marcus Kleber 41 Winfried März 41, 13 Ian de Boer 42 Alexis Wood 43 Jerome Rotter 44 Stephen Rich 45 Cassianne Robinson-Cohen 46 Martin den Heijer 30 Marjo-Riitta Jarvelin 47, 48, 49 Alana Cavadino 14, 50 Peter Joshi 51 James Wilson 51 Caroline Hayward 51 Lars Lind 12 Karl Michaëlsson 12 Stella Trompet 39 M. Carola Zillikens 30 Andre Uitterlinden 30 Fernando Rivadeneira 30 Linda Broer 30 Lina Zgaga 52 Harry Campbell 51 Evropi Theodoratou 51 Susan Farrington 51 Maria Timofeeva 51 Malcolm Dunlop 51 Ana Valdes 3, 53 Emmi Tikkanen 34 Terho Lehtimäki 54, 55 Leo-Pekka Lyytikäinen 54, 55 Mika Kähönen 56, 55 Olli Raitakari 57, 58 Vera Mikkilä 59 M. Arfan Ikram 30 Naveed Sattar 60 J. Wouter Jukema 39 Nicholas Wareham 16 Claudia Langenberg 16 Nita Forouhi 16 Thomas Gundersen 61 Kay-Tee Khaw 16 Adam Butterworth 16 John Danesh 16, 62 Timothy Spector 3 Thomas Wang 63 Elina Hyppönen 14, 23, * Peter Kraft 1, * Douglas Kiel 5, 6, 7, *
* Corresponding author
1 Harvard T.H. Chan School of Public Health
2 Karolinska Institutet [Stockholm]
3 King‘s College London
4 C3BI - Centre de Bioinformatique, Biostatistique et Biologie Intégrative
5 Hebrew SeniorLife [Boston]
6 BIDMC - Beth Israel Deaconess Medical Center [Boston]
7 Broad Institute [Cambridge]
8 McGill University = Université McGill [Montréal, Canada]
9 School of Public Health [Boston]
10 Framingham Heart Study
11 Stanford University
12 Uppsala University
13 Medical University Graz
14 UCL - University College of London [London]
15 KRI - Kidney Research Institute [Seattle]
16 CAM - University of Cambridge [UK]
17 University of Maryland School of Medicine
18 NIH - National Institutes of Health [Bethesda]
19 UMN - University of Minnesota [Twin Cities]
20 IUPUI - Indiana University - Purdue University Indianapolis
21 Universität Greifswald - University of Greifswald
22 DZHK - German Center for Cardiovascular Research
23 University of South Australia [Adelaide]
24 University of Oxford [Oxford]
25 Churchill Hospital Oxford Centre for Haematology
26 Johns Hopkins University School of Medicine [Baltimore]
27 Johns Hopkins Bloomberg School of Public Health [Baltimore]
28 UTHealth - The University of Texas Health Science Center at Houston
29 VU University Medical Center [Amsterdam]
30 Erasmus MC - Erasmus University Medical Center [Rotterdam]
31 AMC - Academic Medical Center - Academisch Medisch Centrum [Amsterdam]
32 WUR - Wageningen University and Research [Wageningen]
33 Tufts University [Medford]
34 University of Helsinki
35 GU - University of Gothenburg
36 Sahlgrenska University Hospital [Gothenburg]
37 Wake Forest School of Medicine [Winston-Salem]
38 German Research Center for Environmental Health - Helmholtz Center München (GmbH)
39 Leiden University Medical Center (LUMC)
40 Max planck Institute for Biology of Ageing [Cologne]
41 Universität Heidelberg [Heidelberg]
42 University of Washington [Seattle]
43 USDA - US Department of Agriculture [Beltsville]
44 Harbor UCLA Medical Center [Torrance, Ca.]
45 University of Virginia [Charlottesville]
46 Vanderbilt University Medical Center [Nashville]
47 Imperial College London
48 University of Oulu
49 Oulu University Hospital [Oulu]
50 QMUL - Queen Mary University of London
51 University of Edinburgh
52 Trinity College Dublin
53 UON - University of Nottingham, UK
54 Fimlab Laboratories [Tampere, Finland]
55 University of Tampere [Finland]
56 Tampere University Hospital
57 TYKS - Turku University Hospital
58 University of Turku
59 Academy of Finland
60 BHF GCRC - British Heart Foundation Glasgow Cardiovascular Research Centre
61 Vitas Ltd
62 The Wellcome Trust Sanger Institute [Cambridge]
63 Vanderbilt University [Nashville]
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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Xia Jiang, Paul O'Reilly, Hugues Aschard, Yi-Hsiang Hsu, J. Brent Richards, et al.. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.260. ⟨10.1038/s41467-017-02662-2⟩. ⟨pasteur-03278560⟩

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