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

Xia Jiang(Harvard University), Paul F. O’Reilly(King's College London), Hugues Aschard(Harvard University), Yi-Hsiang Hsu(Broad Institute), J. Brent Richards, Josée Dupuis(Boston University), Erik Ingelsson(Uppsala University), David Karasik(Hebrew SeniorLife), Stefan Pilz(Medical University of Graz), Diane J. Berry(University College London), Bryan Kestenbaum, Ju‐Sheng Zheng(University of Cambridge), Jian’an Luan(University of Cambridge), Eleni Sofianopoulou(University of Cambridge), Elizabeth A. Streeten(University of Maryland, Baltimore), Demetrius Albanes(National Cancer Institute), Pamela L. Lutsey(University of Minnesota), Lu Yao(University of Minnesota), Weihong Tang(University of Minnesota), Michael J. Econs(Indiana University – Purdue University Indianapolis), Henri Wallaschofski(Universitätsmedizin Greifswald), Henry Völzke(Universitätsmedizin Greifswald), Ang Zhou(University of South Australia), Chris Power(University College London), Mark I. McCarthy(Centre for Human Genetics), Erin D. Michos(Johns Hopkins University), Eric Boerwinkle(The University of Texas Health Science Center at Houston), Stephanie J. Weinstein(National Cancer Institute), Neal D. Freedman(National Cancer Institute), Wen‐Yi Huang(National Cancer Institute), Natasja M. van Schoor(Amsterdam UMC Location Vrije Universiteit Amsterdam), Nathalie van der Velde(Erasmus MC), C.P.G.M. de Groot(Wageningen University & Research), Anke W. Enneman(Erasmus MC), L. Adrienne Cupples(Boston University), Sarah L. Booth(Tufts University), Ramachandran S. Vasan(Framingham Heart Study), Ching‐Ti Liu(Boston University), Yanhua Zhou(Boston University), Samuli Ripatti(University of Helsinki), Claes Ohlsson(University of Gothenburg), Liesbeth Vandenput(University of Gothenburg), Mattias Lorentzon(Sahlgrenska University Hospital), Johan G. Eriksson(University of Helsinki), M. Kyla Shea(Tufts University), Denise K. Houston(Wake Forest University), Stephen B. Kritchevsky(Wake Forest University), Ching‐Ti Liu(Wake Forest University), Kurt K. Lohman(Wake Forest University), Luigi Ferrucci(National Institute on Aging), Munro Peacock(Indiana University – Purdue University Indianapolis), Christian Gieger(Helmholtz Zentrum München), Marian Beekman(Leiden University Medical Center), P. Eline Slagboom(Leiden University Medical Center), Joris Deelen(Leiden University Medical Center), Diana van Heemst(Leiden University Medical Center), Marcus E. Kleber(Heidelberg University), Winfried März(Medical University of Graz), Ian H. de Boer(University of Washington), Alexis C. Wood(Children's Nutrition Research Center at Baylor College of Medicine), Jerome I. Rotter(The Lundquist Institute), Stephen S. Rich(University of Virginia), Cassianne Robinson‐Cohen(Vanderbilt University Medical Center), Martin den Heijer(Erasmus MC), Marjo‐Riitta Järvelin(Oulu University Hospital), Alana Cavadino(Queen Mary University of London), Peter K. Joshi(University of Edinburgh), James F. Wilson(Western General Hospital), Caroline Hayward(Western General Hospital), Lars Lind(Uppsala University), Karl Michaëlsson(Uppsala University), Stella Trompet(Leiden University Medical Center), M. Carola Zillikens(Erasmus MC), André G. Uitterlinden(Erasmus MC), Fernando Rivadeneira(Erasmus MC), Linda Broer(Erasmus MC), Lina Zgaga(Trinity College Dublin), Harry Campbell(Western General Hospital), Evropi Τheodoratou(Western General Hospital), Susan M. Farrington(Western General Hospital), Maria Timofeeva(Western General Hospital), Malcolm G. Dunlop(Western General Hospital), Ana M. Valdes(King's College London), Emmi Tikkanen(University of Helsinki), Terho Lehtimäki(Tampere University), Leo‐Pekka Lyytikäinen(Tampere University), Mika Kähönen(Tampere University Hospital), Olli T. Raitakari(University of Turku), Vera Mikkilä(Research Council of Finland), M. Arfan Ikram(Erasmus MC), Naveed Sattar, J. Wouter Jukema(Leiden University Medical Center), Nicholas J. Wareham(University of Cambridge), Claudia Langenberg(University of Cambridge), Nita G. Forouhi(University of Cambridge), Thomas E. Gundersen(Vitas (Norway)), Kay‐Tee Khaw(University of Cambridge), Adam S. Butterworth(University of Cambridge), John Danesh(University of Cambridge), Timothy D. Spector(King's College London), Thomas J. Wang(Vanderbilt University), Elina Hyppönen(University of South Australia), Peter Kraft(Harvard University), Douglas P. Kiel(Broad Institute)
Nature Communications
January 11, 2018
10.1038/s41467-017-02662-2
Cited by 399Open Access
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Abstract

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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