title: Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Full funding sources listed at end of paper (see Acknowledgments).
authors.affiliation: Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. tjwang@partners.org
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mesh_terms: D002170:Canada; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D015331:Cohort Studies; D019587:Dietary Supplements; D005060:Europe; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007118:Immunoassay; D007391:International Cooperation; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D012621:Seasons; D014481:United States; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics; D014808:Vitamin D Deficiency / Q000097:blood / Q000235:genetics* / Q000517:prevention & control; D044465:White People / Q000235:genetics*
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D