title: The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery.
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.
authors: Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37232-0700, USA.
authors: S A
authors: SA
authors: Pendergrass
authors: K
authors: K
authors: Brown-Gentry
authors: S M
authors: SM
authors: Dudek
authors: E S
authors: ES
authors: Torstenson
authors: J L
authors: JL
authors: Ambite
authors: C L
authors: CL
authors: Avery
authors: S
authors: S
authors: Buyske
authors: C
authors: C
authors: Cai
authors: M D
authors: MD
authors: Fesinmeyer
authors: C
authors: C
authors: Haiman
authors: G
authors: G
authors: Heiss
authors: L A
authors: LA
authors: Hindorff
authors: C-N
authors: CN
authors: Hsu
authors: R D
authors: RD
authors: Jackson
authors: C
authors: C
authors: Kooperberg
authors: L
authors: L
authors: Le Marchand
authors: Y
authors: Y
authors: Lin
authors: T C
authors: TC
authors: Matise
authors: L
authors: L
authors: Moreland
authors: K
authors: K
authors: Monroe
authors: A P
authors: AP
authors: Reiner
authors: R
authors: R
authors: Wallace
authors: L R
authors: LR
authors: Wilkens
authors: D C
authors: DC
authors: Crawford
authors: M D
authors: MD
authors: Ritchie
references: Am J Epidemiol. 1989 Apr;129(4):687-702
references: 2646917
references: Nat Genet. 2007 Oct;39(10):1181-6
references: 17898773
references: Ann Epidemiol. 1991 Feb;1(3):263-76
references: 1669507
references: Proc Natl Acad Sci U S A. 2009 May 12;106(19):7933-8
references: 19383797
references: BMC Med Genet. 2007;8 Suppl 1:S1
references: 17903291
references: Nature. 2007 Jul 26;448(7152):470-3
references: 17611496
references: Am J Epidemiol. 2011 Oct 1;174(7):849-59
references: 21836165
references: Am J Epidemiol. 2000 Feb 15;151(4):346-57
references: 10695593
references: Neuroscience. 2009 Nov 24;164(1):30-42
references: 19344640
references: Nature. 2010 Aug 5;466(7307):714-9
references: 20686566
references: Adv Genet. 2008;60:293-308
references: 18358325
references: Am J Hum Genet. 2010 Apr 9;86(4):560-72
references: 20362271
references: Paediatr Perinat Epidemiol. 2005 Jul;19(4):264-75
references: 15958149
references: Control Clin Trials. 1998 Feb;19(1):61-109
references: 9492970
references: Bioinformatics. 2010 May 1;26(9):1205-10
references: 20335276
references: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references: 19474294
references: Genet Med. 2003 Jan-Feb;5(1):35-42
references: 12544474
references: Am J Epidemiol. 1990 Dec;132(6):1141-55
references: 2260546
references: Clin Pharmacol Ther. 2008 Sep;84(3):362-9
references: 18500243
references: Per Med. 2007 May;4(2):175-182
references: 29788633
references: J Investig Med. 2010 Jun;58(5):700-6
references: 20216460
references: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11694-9
references: 17609372
references: Control Clin Trials. 1987 Dec;8(4 Suppl):68S-73S
references: 3440391