Genome-wide association study (GWAS) of circulating vitamin D outcomes among individuals of African ancestry

Abstract

Background: Vitamin D deficiency is more common among African-ancestry individuals and may be associated with adverse health outcomes. Vitamin D binding protein (VDBP) regulates concentrations of biologically active vitamin D.

Objective: We conducted genome-wide association study (GWAS) of VDBP and 25-hydroxyvitamin D among African-ancestry individuals.

Methods: Data were collected from 2,602 African American adults from the Southern Community Cohort Study (SCCS) and 6,934 African- or Caribbean-ancestry adults from the UK Biobank. Serum VDBP concentrations were available only in the SCCS and were measured by using the Polyclonal Human VDBP ELISA kit. Serum 25-hydroxyvitamin D concentrations for both study samples were measured by using Diasorin Liason, a chemiluminescent immunoassay. Participants were genotyped for single nucleotide polymorphisms (SNPs) with genome-wide coverage by using Illumina or Affymetrix platforms. Fine-mapping analysis was performed by using forward stepwise linear regression models including all variants with P value < 5 × 10^-8 and within 250 kbps of a lead SNP.

Results: We identified 4 loci notably associated with VDBP concentrations in the SCCS population: rs7041 (per allele β = 0.61 μg/mL, SE = 0.05, P = 1.4 × 10^-48) and rs842998 (per allele β = 0.39 μg/mL, SE = 0.03, P = 4.0 × 10^-31) in GC, rs8427873 (per allele β = 0.31 μg/mL, SE = 0.04, P = 3.0 × 10^-14) near GC and rs11731496 (per allele β = 0.21 μg/mL, SE = 0.03, P = 3.6 × 10^-11) in between GC and NPFFR2. In conditional analyses, which included the above-mentioned SNPs, only rs7041 remained notable (P = 4.1 × 10^-21). SNP rs4588 in GC was the only GWAS-identified SNP associated with 25-hydroxyvitamin D concentration. Among UK Biobank participants: per allele β = -0.11 μg/mL, SE = 0.01, P = 1.5 × 10^-13; in the SCCS: per allele β = -0.12 μg/mL, SE = 0.06, P = 2.8 × 10^-02). rs7041 and rs4588 are functional SNPs that influence the binding affinity of VDBP to 25-hydroxyvitamin D.

Conclusions: Our results were in line with previous studies conducted in European-ancestry populations, showing that GC, the gene that directly encodes for VDBP, would be important for VDBP and 25-hydroxyvitamin D concentrations. The current study extends our knowledge of the genetics of vitamin D in diverse populations.

Keywords: 25-hydroxyvitamin D; African-ancestry populations; GC gene; genome-wide association study; vitamin D binding protein.