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.

FIGURE 1

Manhattan plot displaying the associations between genomic loci and vitamin D binding protein in the African-ancestry population from the Southern Community Cohort Study. Chromosomal position is displayed on the x-axis and –log₁₀P value is displayed on the y-axis. Notable SNPs located on chromosome 4 are located in or near gene GC. Horizontal gray-dashed line represents the thresholds of P value = 5 × 10⁻⁸ for genome-wide significance. The results are displayed for participants of the Southern Community Cohort Study with African ancestry (N = 2602).

FIGURE 2

Regional Association Plots for the GWAS-significant SNPs associated with vitamin D binding protein in the African-ancestry population of the Southern Community Cohort Study. SNPs are displayed by chromosome position, where chromosomal position is displayed on the x-axis and –log₁₀P value is displayed on the y-axis. Gene annotations from the UCSC genome browser are displayed below. Panel A shows the index SNP, rs7041 as represented in red, all other SNPs are colored in reference to the linkage disequilibrium (LD) (r² value) structure with rs7041. Index SNPs rs842998 and rs842873 are displayed in green. Panel B shows the index SNP, rs11731496 as represented in red, all other SNPs are colored in reference to LD (r² value) with rs11731496.

FIGURE 3

Manhattan Plot displaying the associations between genomic loci and 25-hydroxyvitamin D in African/Caribbean populations from the UK Biobank. Chromosomal position is displayed on the x-axis and –log₁₀P value is displayed on the y-axis. Notable SNP located on chromosome 4 is located in gene GC. Horizontal gray-dashed line represents the thresholds of P value = 5 × 10⁻⁸ for genome-wide significance. The results are displayed for participants of the UK Biobank with African or Caribbean ancestry (N = 6934).

FIGURE 4

Regional Association Plots for the GWAS-significant SNP associated with 25-hydroxyvitamin D in the African/Caribbean populations from the UK Biobank. SNPs are displayed by chromosome position, where chromosomal position is displayed on the x-axis and –log₁₀P value is displayed on the y-axis. Gene annotations from the UCSC genome browser are displayed below. The index SNP, rs4588 is represented by a red diamond, all other SNPs are colored in reference to the linkage disequilibrium (r² value) with the SNP.

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