title: Biology-Driven Gene-Gene Interaction Analysis of Age-Related Cataract in the eMERGE Network.
abstract: Bioinformatics approaches to examine gene-gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge-driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty-three SNP-SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)-rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell-to-cell adhesion signaling, cell-cell junction organization, and cell-cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP-SNP models, which included signal transduction and PI3K-Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology-driven method, applicable for any genome-wide association study dataset.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Eberly College of Science, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Hall
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Eberly College of Science, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Shefali S
authors.initials: SS
authors.lastname: Verma
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Eberly College of Science, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Wallace
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Eberly College of Science, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Lucas
authors.affiliation: Marshfield Clinic, Marshfield, Wisconsin, United States of America.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Berg
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Connolly
authors.affiliation: Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.affiliation: Center for Inherited Disease Research, IGM, Johns Hopkins University SOM, Baltimore, Maryland, United States of America.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.affiliation: Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.|Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Marshfield Clinic, Marshfield, Wisconsin, United States of America.
authors.forename: Terrie
authors.initials: T
authors.lastname: Kitchner
authors.affiliation: Geisinger Health System, Danville, Pennsylvania, United States of America.
authors.forename: Helena
authors.initials: H
authors.lastname: Kuivaniemi
authors.affiliation: Group Health Research Institute, Seattle, Washington, United States of America.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Group Health Research Institute, Seattle, Washington, United States of America.
authors.forename: David S
authors.initials: DS
authors.lastname: Carrell
authors.affiliation: Geisinger Health System, Danville, Pennsylvania, United States of America.
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.affiliation: Geisinger Health System, Danville, Pennsylvania, United States of America.
authors.forename: Tamara R
authors.initials: TR
authors.lastname: Vrabec
authors.affiliation: Geisinger Health System, Danville, Pennsylvania, United States of America.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Pendergrass
authors.affiliation: Essentia Rural Health, Duluth, Minnesota, United States of America.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, Eberly College of Science, The Pennsylvania State University, University Park, Pennsylvania, United States of America.|Geisinger Health System, Danville, Pennsylvania, United States of America.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
mesh_terms: D000367:Age Factors; D016022:Case-Control Studies; D002386:Cataract / Q000235:genetics*; D002448:Cell Adhesion; D019295:Computational Biology / Q000379:methods*; D003627:Data Interpretation, Statistical; D057286:Electronic Health Records; D005260:Female; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044382:Population Groups / Q000235:genetics; D015398:Signal Transduction; D012984:Software
keywords: association; complex disease; genetic interaction