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

Steven Buyske; Ying Wu; Cara L. Carty; Iona Cheng; Themistocles L. Assimes; Logan Dumitrescu; Lucia A. Hindorff; Sabrina Mitchell; Jose Luis Ambite; Eric Boerwinkle; Petra Buzkova; Chris S. Carlson; Barbara Cochran; David Duggan; Charles B. Eaton; Megan D. Fesinmeyer; Nora Franceschini; Jeffrey Haessler; Nancy Jenny; Hyun Min Kang; Charles Kooperberg; Yi Lin; Loic Le Marchand; Tara C. Matise; Jennifer G. Robinson; Carlos Rodriguez; Fredrick R. Schumacher; Benjamin F. Voight; Alicia Young; Teri A. Manolio; Karen L. Mohlke; Christopher A. Haiman; Ulrike Peters; Dana C. Crawford; Kari E. North

doi:10.1371/journal.pone.0035651

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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

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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

Steven Buyske, Ying Wu, Cara L. Carty, Iona Cheng, Themistocles L. Assimes, Logan Dumitrescu, Lucia A. Hindorff, Sabrina Mitchell, Jose Luis Ambite, Eric Boerwinkle, …

PloS one, Vol.7(4), pp.e35651-e35651

04/23/2012

DOI: 10.1371/journal.pone.0035651

PMCID: PMC3335090

PMID: 22539988

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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 = 3.5x10(-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 = 7.2x10(-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.

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Title: Subtitle: Evaluation of the Metabochip Genotyping Array in African Americans and Implications for Fine Mapping of GWAS-Identified Loci: The PAGE Study
Creators: Steven Buyske - Rutgers, The State University of New Jersey
Ying Wu - University of North Carolina at Chapel Hill
Cara L. Carty - Fred Hutch Cancer Center
Iona Cheng - University of Hawaiʻi at Mānoa
Themistocles L. Assimes - Stanford University
Logan Dumitrescu - Vanderbilt University
Lucia A. Hindorff - National Institutes of Health
Sabrina Mitchell - Vanderbilt University
Jose Luis Ambite - University of Southern California
Eric Boerwinkle - The University of Texas Health Science Center at Houston
Petra Buzkova - University of Washington
Chris S. Carlson - Fred Hutch Cancer Center
Barbara Cochran - Baylor College of Medicine
David Duggan - Translational Genomics Research Institute
Charles B. Eaton - Brown University
Megan D. Fesinmeyer - Fred Hutch Cancer Center
Nora Franceschini - University of North Carolina at Chapel Hill
Jeffrey Haessler - Fred Hutch Cancer Center
Nancy Jenny - University of Vermont
Hyun Min Kang - University of Michigan
Charles Kooperberg - Fred Hutch Cancer Center
Yi Lin - Fred Hutch Cancer Center
Loic Le Marchand - University of Hawaiʻi at Mānoa
Tara C. Matise - Rutgers, The State University of New Jersey
Jennifer G. Robinson - University of Iowa
Carlos Rodriguez - Wake Forest University
Fredrick R. Schumacher - University of Southern California
Benjamin F. Voight - Broad Institute
Alicia Young - Fred Hutch Cancer Center
Teri A. Manolio - National Institutes of Health
Karen L. Mohlke - University of North Carolina at Chapel Hill
Christopher A. Haiman - University of Southern California
Ulrike Peters - Fred Hutch Cancer Center
Dana C. Crawford - Vanderbilt University
Kari E. North - University of North Carolina at Chapel Hill
Resource Type: Journal article
Publication Details: PloS one, Vol.7(4), pp.e35651-e35651
DOI: 10.1371/journal.pone.0035651
PMID: 22539988
PMCID: PMC3335090
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library Science
Number of pages: 7
Grant note: T32GM080178 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) P01CA033619; R37CA054281; P30CA015704; U01CA136792; U01CA098758 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R37CA54281; R01 CA63; P01CA33619; U01CA136792; U01CA98758 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R41HL055018; R41HL055019; R01HL104199; R42HL055018 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) N01-HC-55015; N01-HC-55016; N01-HC-55018; N01-HC-55019; N01-HC-55020; N01-HC-55021; N01-HC-55022 / NHLBI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) National Heart, Lung, and Blood Institute (NHLBI) (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) U01HG004802; U01HG004803; U01HG004801; U01HG004790; U01HG004798 / NATIONAL HUMAN GENOME RESEARCH INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) National Institutes of Mental Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) N01HC055016; N01HC055015; N01HC055020; N01HC055019; N01HC055022; N01HC055018; N01HC055021 / DIVISION OF EPIDEMIOLOGY AND CLINICAL APPLICATIONS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Eye Institute (NEI) N01WH022110 / WOMEN'S HEALTH INITIATIVE - OFFICE OF THE DIRECTOR NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA U01HG004803; U01HG004798; U01HG004802; U01HG004790; U01HG004801 / National Human Genome Research Institute (NHGRI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) N01WH22110; 24152; 32100-2; 32105-6; 32108-9; 32111-13; 32115; 32118-32119; 32122; 42107-26; 42129-32; 44221 / U.S. Department of Health and Human Services
Language: English
Date published: 04/23/2012
Academic Unit: Epidemiology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984364425702771

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