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

TitleEvaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.
Publication TypeJournal Article
Year of Publication2012
AuthorsBuyske S, Wu Y, Carty CL, Cheng I, Assimes TL, Dumitrescu L, Hindorff LA, Mitchell S, Ambite JLuis, Boerwinkle E, Bůžková P, Carlson CS, Cochran B, Duggan D, Eaton CB, Fesinmeyer MD, Franceschini N, Haessler J, Jenny N, Kang HMin, Kooperberg C, Lin Y, Le Marchand L, Matise TC, Robinson JG, Rodriguez C, Schumacher FR, Voight BF, Young A, Manolio TA, Mohlke KL, Haiman CA, Peters U, Crawford DC
Secondary AuthorsNorth KE
JournalPLoS One
Volume7
Issue4
Paginatione35651
Date Published2012
ISSN1932-6203
KeywordsAfrican Americans, Cardiovascular Diseases, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Cholesterol, LDL, Chromosomes, Human, Cohort Studies, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Metabolic Diseases, Polymorphism, Single Nucleotide, Quantitative Trait Loci
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.

DOI10.1371/journal.pone.0035651
Alternate JournalPLoS One
PubMed ID22539988
PubMed Central IDPMC3335090
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
32105-6 / / PHS HHS / United States
U01CA98758 / CA / NCI NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
T32 GM080178 / GM / NIGMS NIH HHS / United States
U01 HG004790 / HG / NHGRI NIH HHS / United States
R01 HL104199 / HL / NHLBI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
U01 HG004802 / HG / NHGRI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
42107-26 / / PHS HHS / United States
32115 / / PHS HHS / United States
U01CA136792 / CA / NCI NIH HHS / United States
U01HG004803 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
U01HG004802 / HG / NHGRI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
32100-2 / / PHS HHS / United States
24152 / / PHS HHS / United States
42129-32 / / PHS HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
U01 HG004803 / HG / NHGRI NIH HHS / United States
32118-32119 / / PHS HHS / United States
P01 CA033619 / CA / NCI NIH HHS / United States
U01HG004798 / HG / NHGRI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
32108-9 / / PHS HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
U01HG004801 / HG / NHGRI NIH HHS / United States
R37CA54281 / CA / NCI NIH HHS / United States
U01 CA098758 / CA / NCI NIH HHS / United States
U01HG004790 / HG / NHGRI NIH HHS / United States
U01 HG004798 / HG / NHGRI NIH HHS / United States
32122 / / PHS HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
44221 / / PHS HHS / United States
U01 CA136792 / CA / NCI NIH HHS / United States
32111-13 / / PHS HHS / United States
R37 CA054281 / CA / NCI NIH HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States
P01CA33619 / CA / NCI NIH HHS / United States
U01 HG004801 / HG / NHGRI NIH HHS / United States