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.

Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

“…The MetaboChip array includes approximately 200,000 single nucleotide polymorphisms (SNPs) selected for fine-mapping genome-wide association loci as previously described (13,14). Genotyping on the MetaboChip was performed according to the manufacturer's protocol (Illumina).…”

“…We created regional association plots using LocusZoom (44) to aid in assessing refinement. To plot the results of the African American PAGE study population, we used LD calculated within PAGE African Americans, because the LD patterns may vary from any pre-computed LD sources implemented in LocusZoom (13). To plot the results of the GLGC European descent population, we used LocusZoom-supplied 1KG Nov 2014 EUR LD.…”

“…Here we use SNPs on the MetaboChip array from over 54,000 participants of African American, Hispanic American, Asian, and American Indian descent. The MetaboChip array is a custom genotyping array designed for replication and fine-mapping of cardiometabolic traits; it includes 58 densely genotyped lipid regions previously reported in populations of European ancestry (13,14). In this multiethnic population, we aimed to: 1) identify novel signals previously undetected in any ancestry, 2) characterize signals specific to individual racial/ethnic populations, 3) find multiple signals (secondary and tertiary signals) within known lipid loci, and 4) refine the location of signals previously identified in European descent individuals.…”

Genetic meta-analysis of 15,901 African Americans identifies variation in EXOC3L1 is associated with HDL concentration

“…The number of variants discovered and the power to detect variants of lower allele frequency and effect size is directly proportional to the number of participants in the study, demonstrated by the success of gradually larger meta-analyses ( 1 ). Genetic variants generally appear to exert similar effects across ethnicities if tested in a suffi ciently powered cohort, but differences in allele frequency and regional linkage disequilibrium (LD) between ethnicities allows for the identifi cation of novel contributors to lipid metabolism (3)(4)(5). While efforts to identify additional variants associated with blood lipids in African-American populations have been successful ( 3,(6)(7)(8), the identifi cation of novel genetic loci in nonEuropean populations has been hampered by inadequate power due to limited sample size and genotyping platform designs made for optimal SNP coverage of European populations ( 3,9 ).…”

An ImmunoChip study of multiple sclerosis risk in African Americans

“…However, the utility of this platform in non-Europeans remains to be addressed. In addition, consistent with their longer evolutionary history, populations of African origin are known to have, on average, characteristically smaller blocks of linkage disequilibrium compared to populations with European ancestry (Tishkoff and Kidd, 2004), implying that the study of populations of African origin could help to narrow the regions of interest and assist in identifying causative variants (Buyske et al, 2012;Gong et al, 2013).…”