title: eMERGE Phenome-Wide Association Study (PheWAS) identifies clinical associations and pleiotropy for stop-gain variants.
abstract: We explored premature stop-gain variants to test the hypothesis that variants, which are likely to have a consequence on protein structure and function, will reveal important insights with respect to the phenotypes associated with them. We performed a phenome-wide association study (PheWAS) exploring the association between a selected list of functional stop-gain genetic variants (variation resulting in truncated proteins or in nonsense-mediated decay) and an extensive group of diagnoses to identify novel associations and uncover potential pleiotropy.
  
  
  
  In this study, we selected 25 stop-gain variants: 5 stop-gain variants with previously reported phenotypic associations, and a set of 20 putative stop-gain variants identified using dbSNP. For the PheWAS, we used data from the electronic MEdical Records and GEnomics (eMERGE) Network across 9 sites with a total of 41,057 unrelated patients. We divided all these samples into two datasets by equal proportion of eMERGE site, sex, race, and genotyping platform. We calculated single effect associations between these 25 stop-gain variants and ICD-9 defined case-control diagnoses. We also performed stratified analyses for samples of European and African ancestry. Associations were adjusted for sex, site, genotyping platform and the first three principal components to account for global ancestry. We identified previously known associations, such as variants in LPL associated with hyperglyceridemia indicating that our approach was robust. We also found a total of three significant associations with p < 0.01 in both datasets, with the most significant replicating result being LPL SNP rs328 and ICD-9 code 272.1 "Disorder of Lipoid metabolism" (pdiscovery = 2.59x10-6, preplicating = 2.7x10-4). The other two significant replicated associations identified by this study are: variant rs1137617 in KCNH2 gene associated with ICD-9 code category 244 "Acquired Hypothyroidism" (pdiscovery = 5.31x103, preplicating = 1.15x10-3) and variant rs12060879 in DPT gene associated with ICD-9 code category 996 "Complications peculiar to certain specified procedures" (pdiscovery = 8.65x103, preplicating = 4.16x10-3).
  
  
  
  In conclusion, this PheWAS revealed novel associations of stop-gained variants with interesting phenotypes (ICD-9 codes) along with pleiotropic effects.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, PA, USA. anurag.verma@psu.edu.|Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA. anurag.verma@psu.edu.
authors.forename: Anurag
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, PA, USA. szs14@psu.edu.|Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA. szs14@psu.edu.
authors.forename: Shefali S
authors.initials: SS
authors.lastname: Verma
authors.affiliation: Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Pendergrass
authors.affiliation: Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa.
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.affiliation: Case Western Reserve University, Cleveland, OH, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Bush
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, PA, USA.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bradford
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Iftikhar
authors.initials: I
authors.lastname: Kullo
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Suzette J
authors.initials: SJ
authors.lastname: Bielinski
authors.affiliation: National Human Genome Research Institute, Bethesda, MD, USA.
authors.forename: Rongling
authors.initials: R
authors.lastname: Li
authors.affiliation: Vanderbilt University, Nashville, TN, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Marshfield Clinic, Marshfield, WI, USA.
authors.forename: Peggy
authors.initials: P
authors.lastname: Peissig
authors.affiliation: Marshfield Clinic, Marshfield, WI, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Hebbring
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Mariza
authors.initials: M
authors.lastname: De Andrade
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Pennsylvania State University, University Park, PA, USA.|Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa.
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
mesh_terms: D000328:Adult; D003710:Demography; D057286:Electronic Health Records; D058685:Genetic Pleiotropy / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide