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The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery.

TitleThe use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery.
Publication TypeJournal Article
Year of Publication2011
AuthorsPendergrass SA, Brown-Gentry K, Dudek SM, Torstenson ES, Ambite JL, Avery CL, Buyske S, Cai C, Fesinmeyer MD, Haiman C, Heiss G, Hindorff LA, Hsu C-N, Jackson RD, Kooperberg C, Le Marchand L, Lin Y, Matise TC, Moreland L, Monroe K, Reiner AP, Wallace R, Wilkens LR, Crawford DC, Ritchie MD
JournalGenet Epidemiol
Volume35
Issue5
Pagination410-22
Date Published2011 Jul
ISSN1098-2272
KeywordsContinental Population Groups, Databases, Genetic, Ethnic Groups, Genetic Association Studies, Genetic Variation, Genome-Wide Association Study, Humans, Models, Genetic, Models, Statistical, Phenotype, Polymorphism, Single Nucleotide
Abstract

The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI)-supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well-replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community.

DOI10.1002/gepi.20589
Alternate JournalGenet Epidemiol
PubMed ID21594894
PubMed Central IDPMC3116446
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
M01-RR00425 / RR / NCRR NIH HHS / United States
N01WH32102 / WH / WHI NIH HHS / United States
N01-HC-45205 / HC / NHLBI NIH HHS / United States
N01WH421030 / WH / WHI NIH HHS / United States
U01 HL041642 / HL / NHLBI NIH HHS / United States
N01-HC-05187 / HC / NHLBI NIH HHS / United States
N01WH421013 / WH / WHI NIH HHS / United States
U01CA98758 / CA / NCI NIH HHS / United States
U01 HG004803-01 / HG / NHGRI NIH HHS / United States
U01 HL65520 / HL / NHLBI NIH HHS / United States
U01 HG004801-01 / HG / NHGRI NIH HHS / United States
N01WH421012 / WH / WHI NIH HHS / United States
N01WH421016 / WH / WHI NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
N01WH32112 / WH / WHI NIH HHS / United States
N01WH32101 / WH / WHI NIH HHS / United States
U01 HL041654 / HL / NHLBI NIH HHS / United States
U01 HG004798-01 / HG / NHGRI NIH HHS / United States
N01WH421026 / WH / WHI NIH HHS / United States
N01WH421020 / WH / WHI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
U01 HG004790 / HG / NHGRI NIH HHS / United States
N01-HC-48047 / HC / NHLBI NIH HHS / United States
U01 HL65521 / HL / NHLBI NIH HHS / United States
N01HC48049 / HL / NHLBI NIH HHS / United States
N01WH32119 / WH / WHI NIH HHS / United States
N01WH32105 / WH / WHI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
U01 HG004802 / HG / NHGRI NIH HHS / United States
N01HC45205 / HL / NHLBI NIH HHS / United States
U01 HL41642 / HL / NHLBI NIH HHS / United States
N01WH421024 / WH / WHI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01HC65236 / HL / NHLBI NIH HHS / United States
U01CA136792 / CA / NCI NIH HHS / United States
U01HG004803 / HG / NHGRI NIH HHS / United States
N01HC65235 / HL / NHLBI NIH HHS / United States
N01WH32106 / WH / WHI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
N01-HC-95095 / HC / NHLBI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
N01WH42108 / WH / WHI NIH HHS / United States
N01-HC65237 / HC / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
U01 HL041652 / HL / NHLBI NIH HHS / United States
U01HG004802 / HG / NHGRI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
N01HC65234 / HL / NHLBI NIH HHS / United States
N01WH32113 / WH / WHI NIH HHS / United States
N01-HC-48050 / HC / NHLBI NIH HHS / United States
U01 HL41654 / HL / NHLBI NIH HHS / United States
N01WH421021 / WH / WHI NIH HHS / United States
N01WH421017 / WH / WHI NIH HHS / United States
N01WH32118 / WH / WHI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
N01WH421019 / WH / WHI NIH HHS / United States
N01HC65233 / HL / NHLBI NIH HHS / United States
N01WH42109 / WH / WHI NIH HHS / United States
N01WH421014 / WH / WHI NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01HC95095 / HL / NHLBI NIH HHS / United States
U01 HL41652 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01WH32122 / WH / WHI NIH HHS / United States
N01HC65237 / HL / NHLBI NIH HHS / United States
U01 HG004803 / HG / NHGRI NIH HHS / United States
N01WH421010 / WH / WHI NIH HHS / United States
N01WH42107 / WH / WHI NIH HHS / United States
N01-HC65233 / HC / NHLBI NIH HHS / United States
N01WH32111 / WH / WHI NIH HHS / United States
P01 CA033619 / CA / NCI NIH HHS / United States
N01-HC-48049 / HC / NHLBI NIH HHS / United States
U01HG004798-01 / HG / NHGRI NIH HHS / United States
U01HG004798 / HG / NHGRI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01 HC045134 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01WH421029 / WH / WHI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
N01WH421022 / WH / WHI NIH HHS / United States
N01-HC65234 / HC / NHLBI NIH HHS / United States
U01 HG004790-01 / HG / NHGRI NIH HHS / United States
N01-HC65236 / HC / NHLBI NIH HHS / United States
M01 RR000425 / RR / NCRR NIH HHS / United States
N01HC48050 / HL / NHLBI NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
N01HC05187 / HL / NHLBI NIH HHS / United States
U01HG004801 / HG / NHGRI NIH HHS / United States
R37CA54281 / CA / NCI NIH HHS / United States
N01WH32109 / WH / WHI NIH HHS / United States
N01HC48047 / HL / NHLBI NIH HHS / United States
U01 CA098758 / CA / NCI NIH HHS / United States
U01 HG004802-01 / HG / NHGRI NIH HHS / United States
N01WH32108 / WH / WHI NIH HHS / United States
U01 HL065521 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
U01HG004790 / HG / NHGRI NIH HHS / United States
U01 HG004798 / HG / NHGRI NIH HHS / United States
N01WH421015 / WH / WHI NIH HHS / United States
N01WH421011 / WH / WHI NIH HHS / United States
U01HL080295 / HL / NHLBI NIH HHS / United States
N01WH421018 / WH / WHI NIH HHS / United States
N01WH32100 / WH / WHI NIH HHS / United States
N01-HC-48048 / HC / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
N01WH421031 / WH / WHI NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
U01 CA136792 / CA / NCI NIH HHS / United States
N01WH32115 / WH / WHI NIH HHS / United States
N01WH421023 / WH / WHI NIH HHS / United States
N01-HC65235 / HC / NHLBI NIH HHS / United States
R37 CA054281 / CA / NCI NIH HHS / United States
N01WH44221 / WH / WHI NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States
N01WH421032 / WH / WHI NIH HHS / United States
U01 HL065520 / HL / NHLBI NIH HHS / United States
N01WH421025 / WH / WHI NIH HHS / United States
P01CA33619 / CA / NCI NIH HHS / United States
N01HC48048 / HL / NHLBI NIH HHS / United States
N01WH24152 / WH / WHI NIH HHS / United States
R01 CA63 / CA / NCI NIH HHS / United States
U01 HG004801 / HG / NHGRI NIH HHS / United States