Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.
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.
Jiang, X; O'Reilly, PF; Aschard, H; Hsu, Y-H; Richards, JB; Dupuis, J; Ingelsson, E; Karasik, D; Pilz, S; Berry, D; Kestenbaum, B; Zheng, J; Luan, J; Sofianopoulou, E; Streeten, EA; Albanes, D; Lutsey, PL; Yao, L; Tang, W; Econs, MJ; Wallaschofski, H; Völzke, H; Zhou, A; Power, C; McCarthy, MI; Michos, ED; Boerwinkle, E; Weinstein, SJ; Freedman, ND; Huang, W-Y; Van Schoor, NM; van der Velde, N; Groot, LCPGMD; Enneman, A; Cupples, LA; Booth, SL; Vasan, RS; Liu, C-T; Zhou, Y; Ripatti, S; Ohlsson, C; Vandenput, L; Lorentzon, M; Eriksson, JG; Shea, MK; Houston, DK; Kritchevsky, SB; Liu, Y; Lohman, KK; Ferrucci, L; Peacock, M; Gieger, C; Beekman, M; Slagboom, E; Deelen, J; Heemst, DV; Kleber, ME; März, W; de Boer, IH; Wood, AC; Rotter, JI; Rich, SS; Robinson-Cohen, C; den Heijer, M; Jarvelin, M-R; Cavadino, A; Joshi, PK; Wilson, JF; Hayward, C; Lind, L; Michaëlsson, K; Trompet, S; Zillikens, MC; Uitterlinden, AG; Rivadeneira, F; Broer, L; Zgaga, L; Campbell, H; Theodoratou, E; Farrington, SM; Timofeeva, M; Dunlop, MG; Valdes, AM; Tikkanen, E; Lehtimäki, T; Lyytikäinen, L-P; Kähönen, M; Raitakari, OT; Mikkilä, V; Ikram, MA; Sattar, N; Jukema, JW; Wareham, NJ; Langenberg, C; Forouhi, NG; Gundersen, TE; Khaw, K-T; Butterworth, AS; Danesh, J; Spector, T; Wang, TJ; Hyppönen, E; Kraft, P; Kiel, DP
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