Common genetic determinants of vitamin D insufficiency: a genome-wide association study
By Thomas J. Wang, Feng Zhang, J. B. Richards, B. Kestenbaum, J. V. van Meurs, D. Berry, Douglas P. Kiel, E. Streeten, C. Ohlsson, Daniel L. Koller and 67 more. The Lancet, 2010
1,460 citations recorded by the source corpus.
Background Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role. Methods We performed a genome-wide association study of 25-OH D among ∼30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication cohorts (n=8,378). Association results were combined using z-score-weighted meta-analysis. Vitamin D insufficiency was defined as 25-OH D <75 nmol/L or <50 nmol/L. Findings Variants at three loci reached genome-wide significance in the discovery cohorts, and were confirmed in the replication cohorts: 4p12 (overall P=1.9 × 10-109 for rs2282679, in GC); 11q12 (P=2.1 × 10-27 for rs12785878, near DHCR7); 11p15 (P=3.3 × 10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (P=6.0 × 10-10 for rs6013897). A genotype score was constructed using the three confirmed variants. Those in the top quartile of genotype scores had 2- to 2.5-fold elevated odds of vitamin D insufficiency (P≤1 × 10-26). Interpretation Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1, CYP24A1), and vitamin D transport (GC) influence vitamin D status. Genetic variation at these loci identifies individuals of European descent who have substantially elevated risk of vitamin D insufficiency.
Subfields: Genetics, Orthopedics and Sports Medicine, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/1e0fee847545d9256b4decd6d056031670d5ca0d
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Citations in the corpus
- Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts (2013, methodology): “For the vitamin D SNPs, the effect allele was the 25(OH)D lowering allele as established by the SUNLIGHT Consortium [27].”
- Vitamin D for Health: A Global Perspective (2013, neutral): “239 DHCR7 is a novel gene for association with 25(OH)D levels, as identified in 2 recent GWASs.(240,241)CYP24A1, which encodes 25(OH)De24-hydroxylase, has been identified as a candidate gene for vitamin D insufficiency in one GWAS but not in the other.”
- Vitamin D and Immune Function (2013, background): “Consequently, without supplementation, vitamin D status strongly depends on endogenous vitamin D production which is also influenced by genetic determinants, latitude, season, skin pigmentation and lifestyle such as the use of sunscreen and clothing [7,15].”