Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study

Abstract

The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.

Figure 1. Distribution of minor allele frequencies on the Metabochip, the Affymetrix 6.0, and the Illumina 1 M.

Intervals are open on the left and closed on the right. The Metabochip MAFs are calculated from PAGE African American samples, while the Affymetrix and Illumina GWAS array MAFs are drawn from the HapMap ASW (African ancestry in Southwest USA) population, a difference not expected to substantially impact the allele frequency distribution.

Figure 2. Distribution of minor allele frequencies on the Metabochip, the Affymetrix 6.0, and the Illumina 1 M.

Same comparison as in Figure 1, except that in this figure the minor allele frequencies on the Metabochip are determined from the Malmö, Sweden, sample while those on the Affymetrix 6.0 and Illumina 1 M GWAS arrays are determined from the HapMap CEU sample.

Figure 3. Regional association plots for LDL-C near the CELSR2/PSRC1/SORT1 locus.

The LDL-C association signal near the CELSR2/PSRC1/SORT1 locus is narrower in African Americans than Europeans. (A) Association results from European-ancestry samples colored by LD (r²) in CEU with rs12740374. (B) Association results in African Americans from PAGE colored by LD (r²) in the same sample with rs12740374; (C) The same association results as in (B) but colored by their correlation (r²) in the Malmö, Sweden, sample with rs12740374. Positions shown are based on hg18. Recombination rate shown is based jointly on the CEU, YRI and JPT+CHB HapMap samples .

Figure 4. Regional association plot for HDL-C results from PAGE in African Americans near the CETP locus.

SNPs are colored by their LD (r²) in the same sample with rs17231520.