Genome-wide Association Study in 79,366 European-ancestry Individuals Informs the Genetic Architecture of 25-Hydroxyvitamin D Levels

Xia Jing, Paul F. O'Reilly, Hugues Aschard, Yi-Hsiang Hsu, J. Brent Richards, Josée Dupuis, Erik Ingelsson, David Karasik, Stefan Pilz, Diane J Berry, Bryan Kestenbaum, Jusheng Zheng, Jian'an Luan, Eleni Sofianopoulou, Elizabeth A Streeten, Demetrius Albanes, Pamela L. Lutsey, Lu Yao, Weihong Tang, Michael J. EconsHenri Wallaschofski, Henry Volzke, Ang Zhou, Chris Power, Mark I McCarthy, Erin D. Michos, Eric Boerwinkle, Stephanie J. Weinstein, Neal D Freedman, Wen-Yi Huang, Natasja M. van Schoor, Nathalie van der Velde, Lisette C P G M de Groot, Anke W Enneman, L. Adrienne Cupples, Sarah L. Booth, Ramachandran S. Vasan, Ching-Ti Liu, Yanhua Zhou, Samuli Ripatti, Claes Ohlsson, Liesbeth Vandenput, Mattias Lorentzon, Johan Eriksson, M Kyla Shea, Denise K Houston, Stephen B. Kritchevsky, Yongmei Liu, Kurt Lohman, Luigi Ferrucci, Munro Peacock, Christian Gieger, Marian Beekman, P Eline Slagboom, Joris Deelen, Diana van Heemst, Marcus E Kleber, Winfried Marz, Ian H de Boer, Alexis C Wood, Jerome I. Rotter, Stephen S. Rich, Cassianne Robinson-Cohen, Martin den Heijer, Marjo-Riitta Jarvelin, Alana Cavadino, Peter Joshi, James Wilson, Caroline Hayward, Lars Lind, Karl Michaëlsson, Stella Trompet, M Carola Zillikens, Andre G. Uitterlinden, Fernando Rivadeneira, Linda Broer, Lina Zgaga, Harry Campbell, Evropi Theodoratou, Susan Farrington, Maria Timofeeva, Malcolm Dunlop, Ana M. Valdes, Emmi Tikkanen, Terho Lehtimaki, Leo-Pekka Lyytikäinen, Mika Kahonen, Olli T. Raitakari, Vera Mikkila, M Arfan Ikram, Naveed Sattar, J. Wouter Jukema, Nicholas J. Wareham, Claudia Langenberg, Nita G. Forouhi, Thomas E Gundersen, Kay Tee Khaw, Adam S Butterworth, John Danesh, Timothy D. Spector, Thomas J. Wang, Elina Hypponen, Peter Kraft, Douglas P Kiel

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Vitamin D is an essential fat soluble vitamin and steroid pro-hormone that plays an important role in musculoskeletal health. Vitamin D deficiency has been linked to autoimmune1,2 and infectious disease3, cardiovascular disease4, cancer5 and neurodegenerative conditions6. Serum 25-hydroxyvitamin D, a primary circulating form of vitamin D and a measure that best reflects vitamin D stores, is influenced by many factors including sun exposure, age, body mass index7, dietary intake of certain foods such as fortified dairy products and oily fish, supplements, and genetic factors8. The concentration of 25-hydroxyvitamin D has been reported to be highly heritable, with heritability estimates of 50%-80% from classical twin studies9,10.
A genome-wide association study (GWAS) meta-analysis of serum 25-hydroxyvitamin D11 in 4,501 participants of European ancestry and replication in 2,221 samples identified variants in three loci (group component (GC), 7-dehydrochlesterol reductase (NADSYN1/DHCR7), and 25-hydroxylase (CYP2R1)). A larger GWAS conducted by the SUNLIGHT consortium in 16,125 European ancestry individuals, with a replication sample of 17,871, replicated these three loci and discovered one additional locus (CYP24A1)8. However, despite these loci being in or near genes encoding proteins involved in vitamin D synthesis, the associated variants collectively explain only a small fraction of the variance in 25-hydroxyvitamin D concentrations (~5%)8,11,12. Therefore, to extend our previous findings and better understand the genetic architecture underlying serum 25-hydroxyvitamin D, as well as test for interactions between dietary vitamin D intake and genetic factors, we conducted a large-scale GWAS meta-analysis on this important vitamin.
Our GWAS with 79,366 discovery samples and 40,562 replication samples replicate four previous loci and identify two new genetic loci for serum levels of 25-hydrovxyvitamin D. We further find evidence for a shared genetic basis between circulating 25-hydroxyvitamin D and autoimmune diseases. Our analyses suggest a relatively modest SNP-heritability rate of 25-hydroxyvitamin D when considering only common variants. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants. The novel genetic instruments identified by our results could be used in future Mendelian Randomization analyses of the association between vitamin D and complex traits
Original languageEnglish
JournalNature Communications
Early online date17 Jan 2018
Publication statusE-pub ahead of print - 17 Jan 2018


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