Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile. INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
Wang, TJ; Zhang, F; Richards, JB; Kestenbaum, B; van Meurs, JB; Berry, D; Kiel, DP; Streeten, EA; Ohlsson, C; Koller, DL; Peltonen, L; Cooper, JD; O'Reilly, PF; Houston, DK; Glazer, NL; Vandenput, L; Peacock, M; Shi, J; Rivadeneira, F; McCarthy, MI; Anneli, P; de Boer, IH; Mangino, M; Kato, B; Smyth, DJ; Booth, SL; Jacques, PF; Burke, GL; Goodarzi, M; Cheung, C-L; Wolf, M; Rice, K; Goltzman, D; Hidiroglou, N; Ladouceur, M; Wareham, NJ; Hocking, LJ; Hart, D; Arden, NK; Cooper, C; Malik, S; Fraser, WD; Hartikainen, A-L; Zhai, G; Macdonald, HM; Forouhi, NG; Loos, RJF; Reid, DM; Hakim, A; Dennison, E; Liu, Y; Power, C; Stevens, HE; Jaana, L; Vasan, RS; Soranzo, N; Bojunga, J; Psaty, BM; Lorentzon, M; Foroud, T; Harris, TB; Hofman, A; Jansson, J-O; Cauley, JA; Uitterlinden, AG; Gibson, Q; Järvelin, M-R; Karasik, D; Siscovick, DS; Econs, MJ; Kritchevsky, SB; Florez, JC; Todd, JA; Dupuis, J; Hyppönen, E; Spector, TD
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