Evaluation of the Metabochip Genotyping Array in African Americans and Implications for Fine Mapping of GWAS-Identified Loci: The PAGE Study

• Published in: PloS one Vol. 7; no. 4; p. e35651
• Main Authors: Buyske, Steven, Wu, Ying, Carty, Cara L., Cheng, Iona, Assimes, Themistocles L., Dumitrescu, Logan, Hindorff, Lucia A., Mitchell, Sabrina, Ambite, Jose Luis, Boerwinkle, Eric, Buzkova, Petra, Carlson, Chris S., Cochran, Barbara, Duggan, David, Eaton, Charles B., Fesinmeyer, Megan D., Franceschini, Nora, Haessler, Jeffrey, Jenny, Nancy, Kang, Hyun Min, Kooperberg, Charles, Lin, Yi, Le Marchand, Loic, Matise, Tara C., Robinson, Jennifer G., Rodriguez, Carlos, Schumacher, Fredrick R., Voight, Benjamin F., Young, Alicia, Manolio, Teri A., Mohlke, Karen L., Haiman, Christopher A., Peters, Ulrike, Crawford, Dana C., North, Kari E.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.04.2012; Public Library of Science (PLoS)
• Subjects: African Americans; Algorithms; Analysis; Anthropometry; Arrays; Bioinformatics; Biology; Biophysics; Black or African American - genetics; Cancer; Cardiovascular Diseases - ethnology; Cardiovascular Diseases - genetics; Cholesterol Ester Transfer Proteins - genetics; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Chromosomes, Human - genetics; Cohort Studies; Epidemiology; Frequency variation; Gene Frequency; Gene mapping; Genes; Genetics; Genome-Wide Association Study; Genomes; Genomics; Genotype; Genotyping; Haplotypes; Health sciences; High density lipoprotein; Humans; Loci; Low density lipoprotein; Low density lipoproteins; Mapping; Medical research; Medicine; Metabolic Diseases - ethnology; Metabolic Diseases - genetics; Metabolism; Minority & ethnic groups; Physiology; Polymorphism, Single Nucleotide; Population; Principal components analysis; Public health; Quality control; Quantitative Trait Loci; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Type 2 diabetes; Womens health; North Carolina; Los Angeles California; United States > US; Tennessee; Texas; Hawaii; California; Maryland; Nashville Tennessee; New Jersey
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035651

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.