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

被引：122

作者：

Pendergrass, Sarah A. ^{[1
]}

Brown-Gentry, Kristin ^{[2
]}

Dudek, Scott ^{[2
]}

Frase, Alex ^{[1
]}

Torstenson, Eric S. ^{[2
]}

Goodloe, Robert ^{[2
]}

Ambite, Jose Luis ^{[3
]}

Avery, Christy L. ^{[4
]}

Buyske, Steve ^{[5
,6
]}

Buzkova, Petra ^{[7
]}

Deelman, Ewa ^{[3
]}

Fesinmeyer, Megan D. ^{[8
]}

Haiman, Christopher A. ^{[9
]}

Heiss, Gerardo ^{[4
]}

Hindorff, Lucia A. ^{[10
]}

Hsu, Chu-Nan ^{[3
]}

Jackson, Rebecca D. ^{[11
]}

Kooperberg, Charles ^{[8
]}

Le Marchand, Loic ^{[12
]}

Lin, Yi ^{[8
]}

Matise, Tara C. ^{[5
]}

Monroe, Kristine R. ^{[9
]}

Moreland, Larry ^{[13
]}

Park, Sungshim L. ^{[12
]}

Reiner, Alex ^{[8
,14
]}

Wallace, Robert ^{[15
,16
]}

Wilkens, Lynn R. ^{[12
]}

Crawford, Dana C. ^{[2
,17
]}

Ritchie, Marylyn D. ^{[1
]}

机构：

[1] Penn State Univ, Ctr Syst Genom, Dept Biochem & Mol Biol, Eberly Coll Sci,Huck Inst Life Sci, University Pk, PA 16802 USA

[2] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN USA

[3] Univ So Calif, Inst Informat Sci, Marina Del Rey, CA 90292 USA

[4] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[5] Rutgers State Univ, Dept Genet, Piscataway, NJ USA

[6] Rutgers State Univ, Dept Stat, Piscataway, NJ USA

[7] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[8] Fred Hutchinson Canc Res Ctr, Div Publ Hlth, Seattle, WA 98104 USA

[9] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA

[10] NHGRI, NIH, Bethesda, MD 20892 USA

[11] Ohio State Univ, Columbus, OH 43210 USA

[12] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA

[13] Univ Pittsburgh, Pittsburgh, PA USA

[14] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[15] Univ Iowa, Dept Epidemiol, Iowa City, IA USA

[16] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA

[17] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

来源：

PLOS GENETICS | 2013年 / 9卷 / 01期

基金：

美国国家卫生研究院;

关键词：

CORONARY-ARTERY-DISEASE; METABOLIC SYNDROME; LOCI; RISK; DESIGN; REPLICATION; CHOLESTEROL; CONSORTIUM; TRAITS; COHORT;

D O I：

10.1371/journal.pgen.1003087

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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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