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

Xia Jiang (1, 2) , Paul F. 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 A. Streeten (17) , Demetrius Albanes (18) , Pamela L. Lutsey (19) , Lu Yao (19) , Weihong Tang (19) , Michael J. Econs (20) , Henri Wallaschofski (21, 22) , Henry Völzke (22, 21) , Ang Zhou (23) , Chris Power (14) , Mark I. Mccarthy (24, 25) , Erin D. Michos (26, 27) , Eric Boerwinkle (28) , Stephanie J. Weinstein (18) , Neal D. Freedman (18) , Wen-Yi Huang (18) , Natasja M. van Schoor (29) , Nathalie van Der Velde (30, 31) , Lisette C. P. G. M. de Groot (32) , Anke Enneman (30) , L. Adrienne Cupples (9, 10) , Sarah L. Booth (33) , Ramachandran S. Vasan (10) , Ching-Ti Liu (9) , Yanhua Zhou (9) , Samuli Ripatti (34) , Claes Ohlsson (35) , Liesbeth Vandenput (35) , Mattias Lorentzon (35, 36) , Johan G. Eriksson (34) , M. Kyla Shea (33) , Denise K. Houston (37) , Stephen B. Kritchevsky (37) , Yongmei Liu (37) , Kurt K. 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 E. Kleber (41) , Winfried März (41, 13) , Ian H. de Boer (42) , Alexis C. Wood (43) , Jerome I. Rotter (44) , Stephen S. Rich (45) , Cassianne Robinson-Cohen (46) , Martin den Heijer (30) , Marjo-Riitta Jarvelin (47, 48, 49) , Alana Cavadino (14, 50) , Peter K. Joshi (51) , James F. Wilson (51) , Caroline Hayward (51) , Lars Lind (12) , Karl Michaëlsson (12) , Stella Trompet (39) , M. Carola Zillikens (30) , Andre G. Uitterlinden (30) , Fernando Rivadeneira (30) , Linda Broer (30) , Lina Zgaga (52) , Harry Campbell (51) , Evropi Theodoratou (51) , Susan M. Farrington (51) , Maria Timofeeva (51) , Malcolm G. Dunlop (51) , Ana M. Valdes (3, 53) , Emmi Tikkanen (34) , Terho Lehtimäki (54, 55) , Leo-Pekka Lyytikäinen (54, 55) , Mika Kähönen (56, 55) , Olli T. Raitakari (57, 58) , Vera Mikkilä (59) , M. Arfan Ikram (30) , Naveed Sattar (60) , J. Wouter Jukema (39) , Nicholas J. Wareham (16) , Claudia Langenberg (16) , Nita G. Forouhi (16) , Thomas E. Gundersen (61) , Kay-Tee Khaw (16) , Adam S. Butterworth (16) , John Danesh (16, 62) , Timothy Spector (3) , Thomas J. Wang (63) , Elina Hyppönen (14, 23) , Peter Kraft (1) , Douglas P. Kiel (5, 6, 7)

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
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 Helsingin yliopisto = Helsingfors universitet = 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] = Heidelberg University
42 University of Washington [Seattle]
43 USDA - United States Department of Agriculture
44 Harbor UCLA Medical Center [Torrance, Ca.]
45 University of Virginia
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]

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.

Domains: Human genetics; Santé publique et épidémiologie; Methodology [stat.ME]; Applications [stat.AP]; Bioinformatics [q-bio.QM]

Xia Jiang, Paul F. 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, 2018, 9 (1), pp.260. ⟨10.1038/s41467-017-02662-2⟩. ⟨pasteur-03278560⟩