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

Sarah A. Pendergrass, Kristin Brown-Gentry, Scott Dudek, Alex Frase, Eric S. Torstenson, Robert Goodloe, Jose Luis Ambite, Christy L. Avery, Steve Buyske, Petra Bůžková, Ewa Deelman, Megan D. Fesinmeyer, Christopher A. Haiman, Gerardo Heiss, Lucia A. Hindorff, Chu Nan Hsu, Rebecca D. Jackson, Charles Kooperberg, Loic Le Marchand, Yi LinTara C. Matise, Kristine R. Monroe, Larry Moreland, Sungshim L. Park, Alex Reiner, Robert Wallace, Lynn R. Wilkens, Dana C. Crawford, Marylyn Deriggi Ritchie

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere1003087
JournalPLoS genetics
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2013

Fingerprint

pleiotropy
epidemiology
Genomics
phenotype
genomics
Epidemiology
Phenotype
Population
Genetic Association Studies
African Americans
nationalities and ethnic groups
single nucleotide polymorphism
Single Nucleotide Polymorphism
African American
Ethnic Groups
noninsulin-dependent diabetes mellitus
Type 2 Diabetes Mellitus
polymorphism
genotype
diabetes

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Pendergrass, S. A., Brown-Gentry, K., Dudek, S., Frase, A., Torstenson, E. S., Goodloe, R., ... Ritchie, M. D. (2013). Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network. PLoS genetics, 9(1), [e1003087]. https://doi.org/10.1371/journal.pgen.1003087
Pendergrass, Sarah A. ; Brown-Gentry, Kristin ; Dudek, Scott ; Frase, Alex ; Torstenson, Eric S. ; Goodloe, Robert ; Ambite, Jose Luis ; Avery, Christy L. ; Buyske, Steve ; Bůžková, Petra ; Deelman, Ewa ; Fesinmeyer, Megan D. ; Haiman, Christopher A. ; Heiss, Gerardo ; Hindorff, Lucia A. ; Hsu, Chu Nan ; Jackson, Rebecca D. ; Kooperberg, Charles ; Le Marchand, Loic ; Lin, Yi ; Matise, Tara C. ; Monroe, Kristine R. ; Moreland, Larry ; Park, Sungshim L. ; Reiner, Alex ; Wallace, Robert ; Wilkens, Lynn R. ; Crawford, Dana C. ; Ritchie, Marylyn Deriggi. / Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network. In: PLoS genetics. 2013 ; Vol. 9, No. 1.
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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.",
author = "Pendergrass, {Sarah A.} and Kristin Brown-Gentry and Scott Dudek and Alex Frase and Torstenson, {Eric S.} and Robert Goodloe and Ambite, {Jose Luis} and Avery, {Christy L.} and Steve Buyske and Petra Bůžkov{\'a} and Ewa Deelman and Fesinmeyer, {Megan D.} and Haiman, {Christopher A.} and Gerardo Heiss and Hindorff, {Lucia A.} and Hsu, {Chu Nan} and Jackson, {Rebecca D.} and Charles Kooperberg and {Le Marchand}, Loic and Yi Lin and Matise, {Tara C.} and Monroe, {Kristine R.} and Larry Moreland and Park, {Sungshim L.} and Alex Reiner and Robert Wallace and Wilkens, {Lynn R.} and Crawford, {Dana C.} and Ritchie, {Marylyn Deriggi}",
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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, L, Park, SL, Reiner, A, Wallace, R, Wilkens, LR, Crawford, DC & Ritchie, MD 2013, 'Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network', PLoS genetics, vol. 9, no. 1, e1003087. https://doi.org/10.1371/journal.pgen.1003087

Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network. / Pendergrass, Sarah A.; Brown-Gentry, Kristin; Dudek, Scott; Frase, Alex; Torstenson, Eric S.; Goodloe, Robert; Ambite, Jose Luis; Avery, Christy L.; Buyske, Steve; Bůžková, Petra; Deelman, Ewa; Fesinmeyer, Megan D.; Haiman, Christopher A.; Heiss, Gerardo; Hindorff, Lucia A.; Hsu, Chu Nan; Jackson, Rebecca D.; Kooperberg, Charles; Le Marchand, Loic; Lin, Yi; Matise, Tara C.; Monroe, Kristine R.; Moreland, Larry; Park, Sungshim L.; Reiner, Alex; Wallace, Robert; Wilkens, Lynn R.; Crawford, Dana C.; Ritchie, Marylyn Deriggi.

In: PLoS genetics, Vol. 9, No. 1, e1003087, 01.01.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network

AU - Pendergrass, Sarah A.

AU - Brown-Gentry, Kristin

AU - Dudek, Scott

AU - Frase, Alex

AU - Torstenson, Eric S.

AU - Goodloe, Robert

AU - Ambite, Jose Luis

AU - Avery, Christy L.

AU - Buyske, Steve

AU - Bůžková, Petra

AU - Deelman, Ewa

AU - Fesinmeyer, Megan D.

AU - Haiman, Christopher A.

AU - Heiss, Gerardo

AU - Hindorff, Lucia A.

AU - Hsu, Chu Nan

AU - Jackson, Rebecca D.

AU - Kooperberg, Charles

AU - Le Marchand, Loic

AU - Lin, Yi

AU - Matise, Tara C.

AU - Monroe, Kristine R.

AU - Moreland, Larry

AU - Park, Sungshim L.

AU - Reiner, Alex

AU - Wallace, Robert

AU - Wilkens, Lynn R.

AU - Crawford, Dana C.

AU - Ritchie, Marylyn Deriggi

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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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