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Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network

Pendergrass, SA and Brown-Gentry, K and Dudek, S and Frase, A and Torstenson, ES and Goodloe, R and Ambite, JL and Avery, CL and Buyske, S and Bůžková, P and Deelman, E and Fesinmeyer, MD and Haiman, CA and Heiss, G and Hindorff, LA and Hsu, CN and Jackson, RD and Kooperberg, C and Le Marchand, L and Lin, Y and Matise, TC and Monroe, KR and Moreland, L and Park, SL and Reiner, A and Wallace, R and Wilkens, LR and Crawford, DC and Ritchie, MD (2013) Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network. PLoS Genetics, 9 (1). ISSN 1553-7390

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Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype-phenotype associations, 26 represented phenotypes closely related to previously known genotype-phenotype associations, and 33 represented potentially novel genotype-phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Pendergrass, SA
Brown-Gentry, K
Dudek, S
Frase, A
Torstenson, ES
Goodloe, R
Ambite, JL
Avery, CL
Buyske, S
Bůžková, P
Deelman, E
Fesinmeyer, MD
Haiman, CA
Heiss, G
Hindorff, LA
Hsu, CN
Jackson, RD
Kooperberg, C
Le Marchand, L
Lin, Y
Matise, TC
Monroe, KR
Moreland, Llwm5@pitt.eduLWM5
Park, SL
Reiner, A
Wallace, R
Wilkens, LR
Crawford, DC
Ritchie, MD
Date: 1 January 2013
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 9
Number: 1
DOI or Unique Handle: 10.1371/journal.pgen.1003087
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
ISSN: 1553-7390
Other ID: NLM PMC3561060
PubMed Central ID: PMC3561060
PubMed ID: 23382687
Date Deposited: 28 Mar 2013 15:16
Last Modified: 27 Jan 2019 03:55


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