Common Genetic Determinants of Vitamin D Insufficiency: A Genome-Wide Association Study

Environmental disorders associated with vitamin D deficiency include musculoskeletal disorders (childhood rickets, osteomalacia, and fractures), and may include extraskeletal disorders (diabetes, cardiovascular disease, risk of falls, and cancer). There is high interindividual variability in the occurrence of both musculoskeletal and extraskeletal disorders. Previous twin and family studies suggested that genetic factors play a significant role in this variability. Little data exist on the possible effects of common genetic variation on vitamin D status; the available studies have been small and only small numbers of variants were examined. The SUNLIGHT consortium (study of underlying genetic determinants of vitamin D and highly related traits) was a multicenter genome-wide association study designed to identify common genetic variants that affect vitamin D concentrations and increase the risk of vitamin D insufficiency. Concentrations of vitamin D were determined in 33,996 individuals of European descent from 15 epidemiologic cohorts. Of these cohorts, 5 were designated as discovery cohorts (n = 16,125), 5 as in-silico replication cohorts (n = 9367), and 5 as de novo replication cohorts (n = 8504). Genome-wide analyses were conducted in all cohorts. Methods used to measure 25-hydroxyvitamin D concentrations varied between cohorts and included radioimmunoassay, chemiluminescent assay, enzyme-linked immunosorbent assay, or mass spectrometry. Concentrations lower than 75 nmol/L or 50 nmol/L were the defined threshold for vitamin D insufficiency. Combined effect estimates from the logistic regression analysis across cohorts were calculated by meta-analysis using a weighted Z-score-based approach. A genotype score was constructed by taking a weighted average of the confirmed variants. Genome-wide significance for association with 25-hydroxyvitamin D concentration was reached in variants at 3 loci in discovery cohorts, and was confirmed in replication cohorts: the first locus was 4p12 within or near the GC gene (overall P = 1.9 × 10−109 for rs2282679); the second was 11q12 near DHCR7 (P = 2.1 × 10−27 for rs12785878; and the third was11p15 near CYP2R1 (P = 3.3 × 10−20 for rs10741657). The first locus encoded an enzyme involved in cholesterol synthesis, the second encoded an enzyme implicated in 25-hydroxylation of vitamin D in the liver, and the third was involved in synthesis of a liver protein involved in transport of vitamin D and its metabolites. Genome-wide significance in the pooled sample was reached for variants at a fourth locus, 20q13, near CYP24A1 (P = 6.0 × 10−10 for rs6013897). A high genotype score in the highest quartile for the 3 confirmed variants in comparison with a score in the lowest quartile was associated with a substantial increase in the risk of vitamin D insufficiency (25-hydroxyvitamin D concentrations <75 nmol/L or <50 nmol/L; the odds ratio for <75 nmol/L was 2.47, with a 95% confidence interval of 2.20–2.78 (P = 2.3 × 10−48) and the odds ratio for <50 nmol/L was 1.92, with a 95% confidence interval of 1.70–2.16 (P = 1.0 × 10−26). These findings identify genetic variants at 3 confirmed loci involved in regulation of circulating 25-hydroxyvitamin D concentrations that substantially increase the risk of vitamin D insufficiency.