Epistatic Gene-Based Interaction Analyses for Glaucoma in eMERGE and NEIGHBOR Consortium.
Primary open angle glaucoma (POAG) is a complex disease and is one of the major leading causes of blindness worldwide. Genome-wide association studies have successfully identified several common variants associated with glaucoma; however, most of these variants only explain a small proportion of the genetic risk. Apart from the standard approach to identify main effects of variants across the genome, it is believed that gene-gene interactions can help elucidate part of the missing heritability by allowing for the test of interactions between genetic variants to mimic the complex nature of biology. To explain the etiology of glaucoma, we first performed a genome-wide association study (GWAS) on glaucoma case-control samples obtained from electronic medical records (EMR) to establish the utility of EMR data in detecting non-spurious and relevant associations; this analysis was aimed at confirming already known associations with glaucoma and validating the EMR derived glaucoma phenotype. Our findings from GWAS suggest consistent evidence of several known associations in POAG. We then performed an interaction analysis for variants found to be marginally associated with glaucoma (SNPs with main effect p-value <0.01) and observed interesting findings in the electronic MEdical Records and GEnomics Network (eMERGE) network dataset. Genes from the top epistatic interactions from eMERGE data (Likelihood Ratio Test i.e. LRT p-value <1e-05) were then tested for replication in the NEIGHBOR consortium dataset. To replicate our findings, we performed a gene-based SNP-SNP interaction analysis in NEIGHBOR and observed significant gene-gene interactions (p-value <0.001) among the top 17 gene-gene models identified in the discovery phase. Variants from gene-gene interaction analysis that we found to be associated with POAG explain 3.5% of additional genetic variance in eMERGE dataset above what is explained by the SNPs in genes that are replicated from previous GWAS studies (which was only 2.1% variance explained in eMERGE dataset); in the NEIGHBOR dataset, adding replicated SNPs from gene-gene interaction analysis explain 3.4% of total variance whereas GWAS SNPs alone explain only 2.8% of variance. Exploring gene-gene interactions may provide additional insights into many complex traits when explored in properly designed and powered association studies.
Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, Pennsylvania, United States of America.|The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
Shefali Setia
SS
Verma
Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
Jessica N
0000-0002-4001-8702
JN
Cooke Bailey
Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, Pennsylvania, United States of America.
Anastasia
A
Lucas
Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, Pennsylvania, United States of America.
Yuki
Y
Bradford
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States of America.
James G
JG
Linneman
Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States of America.
Michael A
MA
Hauser
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America.|Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Louis R
LR
Pasquale
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States of America.
Peggy L
PL
Peissig
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States of America.
Murray H
MH
Brilliant
Essentia Rural Health, Duluth, Minnesota, United States of America.
Catherine A
CA
McCarty
Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
Jonathan L
JL
Haines
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America.
Janey L
JL
Wiggs
Department of Ophthalmology, Geisinger Health System, Danville, Pennsylvania, United States of America.
Tamara R
TR
Vrabec
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
Gerard
0000-0002-7761-0806
G
Tromp
Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, Pennsylvania, United States of America.|Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
Marylyn D
MD
Ritchie
D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide