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 KangCharles Kooperberg, Yi Lin, Loic 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

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere35651
JournalPloS one
Volume7
Issue number4
DOIs
StatePublished - Apr 23 2012
Externally publishedYes

Fingerprint

African Americans
genotyping
Single Nucleotide Polymorphism
loci
Genes
ancestry
Quality control
Genome-Wide Association Study
gene frequency
quality control
Gene Frequency
Quality Control
genomics
sampling
genome
Genome
genes
Population

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Evaluation of the metabochip genotyping array in african americans and implications for fine mapping of gwas-identified loci : The PAGE study. / 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; 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.

In: PloS one, Vol. 7, No. 4, e35651, 23.04.2012.

Research output: Contribution to journalArticle

Buyske, S, Wu, Y, Carty, CL, Cheng, I, Assimes, TL, Dumitrescu, L, Hindorff, LA, Mitchell, S, Ambite, JL, Boerwinkle, E, Buzkova, P, Carlson, CS, Cochran, B, Duggan, D, Eaton, CB, Fesinmeyer, MD, Franceschini, N, Haessler, J, Jenny, N, Kang, HM, Kooperberg, C, Lin, Y, Marchand, L, Matise, TC, Robinson, JG, Rodriguez, C, Schumacher, FR, Voight, BF, Young, A, Manolio, TA, Mohlke, KL, Haiman, CA, Peters, U, Crawford, DC & North, KE 2012, 'Evaluation of the metabochip genotyping array in african americans and implications for fine mapping of gwas-identified loci: The PAGE study', PloS one, vol. 7, no. 4, e35651. https://doi.org/10.1371/journal.pone.0035651
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 ; 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. / Evaluation of the metabochip genotyping array in african americans and implications for fine mapping of gwas-identified loci : The PAGE study. In: PloS one. 2012 ; Vol. 7, No. 4.
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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 = 3.5×10 -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.",
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AU - Buyske, Steven

AU - Wu, Ying

AU - Carty, Cara L.

AU - Cheng, Iona

AU - Assimes, Themistocles L.

AU - Dumitrescu, Logan

AU - Hindorff, Lucia A.

AU - Mitchell, Sabrina

AU - Ambite, Jose Luis

AU - Boerwinkle, Eric

AU - Buzkova, Petra

AU - Carlson, Chris S.

AU - Cochran, Barbara

AU - Duggan, David

AU - Eaton, Charles B.

AU - Fesinmeyer, Megan D.

AU - Franceschini, Nora

AU - Haessler, Jeffrey

AU - Jenny, Nancy

AU - Kang, Hyun Min

AU - Kooperberg, Charles

AU - Lin, Yi

AU - Marchand, Loic

AU - Matise, Tara C.

AU - Robinson, Jennifer G.

AU - Rodriguez, Carlos

AU - Schumacher, Fredrick R.

AU - Voight, Benjamin F.

AU - Young, Alicia

AU - Manolio, Teri A.

AU - Mohlke, Karen L.

AU - Haiman, Christopher A.

AU - Peters, Ulrike

AU - Crawford, Dana C.

AU - North, Kari E.

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