Genome-wide association study (GWAS) of circulating vitamin D outcomes among individuals of African ancestry.
Level 3 - non-randomized controlled study
Cross-sectional genetic association analysis across cohort studies
PubMed 36811574 · doi:10.1016/j.ajcnut.2022.12.001
What was done
A genome-wide association study (GWAS) and fine-mapping analysis were performed to identify genetic variants linked to serum vitamin D binding protein (VDBP) and 25-hydroxyvitamin D concentrations in individuals of African ancestry. Data were drawn from 2,602 African American adults in the Southern Community Cohort Study (SCCS) and 6,934 African- or Caribbean-ancestry adults in the UK Biobank. Serum VDBP was measured via polyclonal ELISA (SCCS only), and serum 25-hydroxyvitamin D was measured via chemiluminescent immunoassay in both cohorts. Genotyping was performed on Illumina or Affymetrix platforms, followed by forward stepwise linear regression for fine-mapping of lead variants.
What was found
Four loci were significantly associated with VDBP levels in SCCS: rs7041 (beta = 0.61 μg/mL, SE = 0.05, P = 1.4 × 10^-48) and rs842998 (beta = 0.39 μg/mL, SE = 0.03, P = 4.0 × 10^-31) in GC, rs8427873 (beta = 0.31 μg/mL, SE = 0.04, P = 3.0 × 10^-14) near GC, and rs11731496 (beta = 0.21 μg/mL, SE = 0.03, P = 3.6 × 10^-11) between GC and NPFFR2. In conditional analyses, only rs7041 remained significant (P = 4.1 × 10^-21). For 25-hydroxyvitamin D, rs4588 in GC was the sole GWAS-identified variant (UK Biobank: beta = -0.11 μg/mL, SE = 0.01, P = 1.5 × 10^-13; SCCS: beta = -0.12 μg/mL, SE = 0.06, P = 2.8 × 10^-2).
Why it matters
This study demonstrates that the GC locus primarily regulates circulating VDBP and 25-hydroxyvitamin D concentrations in individuals of African ancestry, matching patterns established in European-ancestry populations.
Limits
VDBP concentrations were measured in only one cohort (SCCS, n = 2,602), preventing replication across cohorts for VDBP. Total sample size for 25-hydroxyvitamin D (n = 9,536) is relatively small for GWAS discovery, limiting power for rare or small-effect loci. Cross-sectional biochemical measurements do not provide longitudinal clinical outcomes.
Cited by
- supports Individuals of African heritage traditionally have lower measured levels of vitamin D.