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Jiang, Xia and O’Reilly, Paul F. and Aschard, Hugues and Hsu, Yi-Hsiang and Richards, J. Brent and Dupuis, Josée and Ingelsson, Erik and Karasik, David and Pilz, Stefan and Berry, Diane and Kestenbaum, Bryan and Zheng, Jusheng and Luan, Jianan and Sofianopoulou, Eleni and Streeten, Elizabeth A. and Albanes, Demetrius and Lutsey, Pamela L. and Yao, Lu and Tang, Weihong and Econs, Michael J. and Wallaschofski, Henri and Völzke, Henry and Zhou, Ang and Power, Chris and McCarthy, Mark I. and Michos, Erin D. and Boerwinkle, Eric and Weinstein, Stephanie J. and Freedman, Neal D. and Huang, Wen-Yi and Van Schoor, Natasja M. and van der Velde, Nathalie and Groot, Lisette C. P. G. M. de and Enneman, Anke and Cupples, L. Adrienne and Booth, Sarah L. and Vasan, Ramachandran S. and Liu, Ching-Ti and Zhou, Yanhua and Ripatti, Samuli and Ohlsson, Claes and Vandenput, Liesbeth and Lorentzon, Mattias and Eriksson, Johan G. and Shea, M. Kyla and Houston, Denise K. and Kritchevsky, Stephen B. and Liu, Yongmei and Lohman, Kurt K. and Ferrucci, Luigi and Peacock, Munro and Gieger, Christian and Beekman, Marian and Slagboom, Eline and Deelen, Joris and Heemst, Diana van and Kleber, Marcus E. and März, Winfried and de Boer, Ian H. and Wood, Alexis C. and Rotter, Jerome I. and Rich, Stephen S. and Robinson-Cohen, Cassianne and den Heijer, Martin and Jarvelin, Marjo-Riitta and Cavadino, Alana and Joshi, Peter K. and Wilson, James F. and Hayward, Caroline and Lind, Lars and Michaëlsson, Karl and Trompet, Stella and Zillikens, M. Carola and Uitterlinden, Andre G. and Rivadeneira, Fernando and Broer, Linda and Zgaga, Lina and Campbell, Harry and Theodoratou, Evropi and Farrington, Susan M. and Timofeeva, Maria and Dunlop, Malcolm G. and Valdes, Ana M. and Tikkanen, Emmi and Lehtimäki, Terho and Lyytikäinen, Leo-Pekka and Kähönen, Mika and Raitakari, Olli T. and Mikkilä, Vera and Ikram, M. Arfan and Sattar, Naveed and Jukema, J. Wouter and Wareham, Nicholas J. and Langenberg, Claudia and Forouhi, Nita G. and Gundersen, Thomas E. and Khaw, Kay-Tee and Butterworth, Adam S. and Danesh, John and Spector, Timothy and Wang, Thomas J. and Hyppönen, Elina and Kraft, Peter and Kiel, Douglas P. (2018) Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nature Communications, 9 (1). 260/1-260/11. ISSN 2041-1723

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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