title: Phenome-wide association study (PheWAS) for detection of pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network.
abstract: 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.
authors: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, Eberly College of Science, The Huck Institutes of the Life Sciences, University Park, Pennsylvania, United States of America.
authors: Sarah A
authors: SA
authors: Pendergrass
authors: Kristin
authors: K
authors: Brown-Gentry
authors: Scott
authors: S
authors: Dudek
authors: Alex
authors: A
authors: Frase
authors: Eric S
authors: ES
authors: Torstenson
authors: Robert
authors: R
authors: Goodloe
authors: Jose Luis
authors: JL
authors: Ambite
authors: Christy L
authors: CL
authors: Avery
authors: Steve
authors: S
authors: Buyske
authors: Petra
authors: P
authors: Bůžková
authors: Ewa
authors: E
authors: Deelman
authors: Megan D
authors: MD
authors: Fesinmeyer
authors: Christopher A
authors: CA
authors: Haiman
authors: Gerardo
authors: G
authors: Heiss
authors: Lucia A
authors: LA
authors: Hindorff
authors: Chu-Nan
authors: CN
authors: Hsu
authors: Rebecca D
authors: RD
authors: Jackson
authors: Charles
authors: C
authors: Kooperberg
authors: Loic
authors: L
authors: Le Marchand
authors: Yi
authors: Y
authors: Lin
authors: Tara C
authors: TC
authors: Matise
authors: Kristine R
authors: KR
authors: Monroe
authors: Larry
authors: L
authors: Moreland
authors: Sungshim L
authors: SL
authors: Park
authors: Alex
authors: A
authors: Reiner
authors: Robert
authors: R
authors: Wallace
authors: Lynn R
authors: LR
authors: Wilkens
authors: Dana C
authors: DC
authors: Crawford
authors: Marylyn D
authors: MD
authors: Ritchie
mesh_terms: D002118:Calcium / Q000097:blood; D003324:Coronary Artery Disease / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006454:Hemoglobins / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000235:genetics; D017350:N-Acetylgalactosaminyltransferases; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D002118:Calcium; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006454:Hemoglobins; D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase
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