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

Xia Jiang, Paul F. O'Reilly, Hugues Aschard, Yi Hsiang Hsu, J.B. Richards, Josée Dupuis, Erik Ingelsson, David Karasik, Stefan Pilz, Diane Berry, Bryan Kestenbaum, Jusheng Zheng, Jianan Luan, Eleni Sofianopoulou, Elizabeth A. Streeten, Demetrius Albanes, Pamela L. Lutsey, Lu Yao, Weihong Tang, Michael J. EconsHenri Wallaschofski, Henry Völzke, 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 Enneman, L.A. Cupples, Sarah L. Booth, Ramachandran S. Vasan, Ching Ti Liu, Yanhua Zhou, Samuli Ripatti, Claes Ohlsson, Liesbeth Vandenput, Mattias Lorentzon, Johan G. Eriksson, M.K. Shea, Denise K. Houston, Stephen B. Kritchevsky, Yongmei Liu, Kurt K. Lohman, Luigi Ferrucci, Munro Peacock, Christian Gieger, Marian Beekman, Eline Slagboom, Joris Deelen, Joris Deelen, Diana van Heemst, Marcus E. Kleber, Winfried März, Ian H. De Boer, Alexis C. Wood, Jerome I. Rotter, Stephen S. Rich, Cassianne Robinson-Cohen, Martin Den Heijer, Marjo Riitta Jarvelin, Marjo Riitta Jarvelin, Alana Cavadino, Alana Cavadino, Peter K. Joshi, James F. Wilson, Caroline Hayward, Lars Lind, Karl Michaëlsson, Stella Trompet, M.C. Zillikens, Andre G. Uitterlinden, Fernando Rivadeneira

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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.
Original languageEnglish
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 17 Jan 2018

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    Jiang, X., O'Reilly, P. F., Aschard, H., Hsu, Y. H., Richards, J. B., Dupuis, J., Ingelsson, E., Karasik, D., Pilz, S., Berry, D., Kestenbaum, B., Zheng, J., Luan, J., Sofianopoulou, E., Streeten, E. A., Albanes, D., Lutsey, P. L., Yao, L., Tang, W., ... Rivadeneira, F. (2018). Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nature Communications, 9(1). https://doi.org/10.1038/s41467-017-02662-2