title: Detection of pleiotropy through a Phenome-wide association study (PheWAS) of epidemiologic data as part of the Environmental Architecture for Genes Linked to Environment (EAGLE) study.
abstract: We performed a Phenome-wide association study (PheWAS) utilizing diverse genotypic and phenotypic data existing across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC), and accessed by the Epidemiological Architecture for Genes Linked to Environment (EAGLE) study. We calculated comprehensive tests of association in Genetic NHANES using 80 SNPs and 1,008 phenotypes (grouped into 184 phenotype classes), stratified by race-ethnicity. Genetic NHANES includes three surveys (NHANES III, 1999-2000, and 2001-2002) and three race-ethnicities: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950). We identified 69 PheWAS associations replicating across surveys for the same SNP, phenotype-class, direction of effect, and race-ethnicity at p<0.01, allele frequency >0.01, and sample size >200. Of these 69 PheWAS associations, 39 replicated previously reported SNP-phenotype associations, 9 were related to previously reported associations, and 21 were novel associations. Fourteen results had the same direction of effect across more than one race-ethnicity: one result was novel, 11 replicated previously reported associations, and two were related to previously reported results. Thirteen SNPs showed evidence of pleiotropy. We further explored results with gene-based biological networks, contrasting the direction of effect for pleiotropic associations across phenotypes. One PheWAS result was ABCG2 missense SNP rs2231142, associated with uric acid levels in both non-Hispanic whites and Mexican Americans, protoporphyrin levels in non-Hispanic whites and Mexican Americans, and blood pressure levels in Mexican Americans. Another example was SNP rs1800588 near LIPC, significantly associated with the novel phenotypes of folate levels (Mexican Americans), vitamin E levels (non-Hispanic whites) and triglyceride levels (non-Hispanic whites), and replication for cholesterol levels. The results of this PheWAS show the utility of this approach for exposing more of the complex genetic architecture underlying multiple traits, through generating novel hypotheses for future research.
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Hall
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Anurag
authors.initials: A
authors.lastname: Verma
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Brown-Gentry
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Goodloe
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Boston
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Bob
authors.initials: B
authors.lastname: McClellan
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Cara
authors.initials: C
authors.lastname: Sutcliffe
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Holly H
authors.initials: HH
authors.lastname: Dilks
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Nila B
authors.initials: NB
authors.lastname: Gillani
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Hailing
authors.initials: H
authors.lastname: Jin
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Mayo
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Allen
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schnetz-Boutaud
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Pendergrass
mesh_terms: D000328:Adult; D004777:Environment; D015340:Epidemiologic Research Design; D005006:Ethnicity / Q000235:genetics / Q000706:statistics & numerical data; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D009749:Nutrition Surveys; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D014481:United States / Q000453:epidemiology