Epistatic Gene-Based Interaction Analyses for Glaucoma in eMERGE and NEIGHBOR Consortium

Autor: Rex Chisholm, Joel Schuman, Melanie Myers, Jessica Cooke Bailey, ANDREA HARTZLER, Kenzie Cameron, Jennifer Pacheco, Adam Gordon, Sayoko E Moroi, Catherine McCarty, Helena Kuivaniemi, Paul Lichter, Luke Rasmussen, MARCELLA DEVOTO, Josh Denny, Suzette Bielinski, Gerard Tromp, Stuart Scott, Peter Tarczy-Hornoch, Jean-Sébastien Hulot, Rion Pendergrass
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
Cancer Research
Eye Diseases
Gene Expression
Social Sciences
Genome-wide association study
0302 clinical medicine
Sociology
Missing heritability problem
Consortia
Medicine and Health Sciences
Myopia
Genetics (clinical)
Genetics
Visual Impairments
Genomics
Explained variation
3. Good health
Phenotype
Female
Anatomy
Glaucoma
Open-Angle
Research Article
lcsh:QH426-470
Single-nucleotide polymorphism
Biology
Polymorphism
Single Nucleotide
03 medical and health sciences
Ocular System
Genome-Wide Association Studies
Humans
Molecular Biology
Ecology
Evolution
Behavior and Systematics
Genetic association
Biology and Life Sciences
Computational Biology
Epistasis
Genetic
Human Genetics
Glaucoma
Genome Analysis
Human genetics
lcsh:Genetics
Ophthalmology
030104 developmental biology
Genetic Loci
Case-Control Studies
Genetics of Disease
030221 ophthalmology & optometry
Epistasis
Eyes
Head
Genome-Wide Association Study
Zdroj: PLoS Genetics
PLoS Genetics, Vol 12, Iss 9, p e1006186 (2016)
ISSN: 1553-7404
Popis: 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
Author Summary The complex nature of primary-open angle glaucoma (POAG) has left researchers exploring the genetic architecture and searching for the missing heritability using a number of different study designs. Over the past decade, many studies have been conducted to explain the etiology of POAG; however, a high proportion of estimated heritability still remains unexplained. GWA studies for POAG have identified significant associations but these associations have only explained a small proportion of the genetic risk (odds ratios range between 1–3). In this paper, we sought to confirm the primary genome-wide significant associations that have been discovered so far for glaucoma in phenotypes developed from EMR data in an effort to show that EMR data can be a powerful resource for finding genetic variants influencing POAG susceptibility. Next, we tested for statistical interactions, which can be presented as an important tool in an attempt to explain POAG heritability. We used a reduced list of variants filtered by marginal main effect analysis to look for epistatic interactions. We present our results from replication of gene-based interaction analyses performed in eMERGE and the NEIGHBOR consortium data. Using expression data and annotations from various publicly available databases, the most significant genes that replicated in our analyses show expression in the eye and trabecular meshwork. Analysis for estimation of genetic variance explained by significant associations from previous GWAS and replicated variants from gene-based interactions suggest that these explain 5.6% of variance in eMERGE dataset and also explain 3.4% variance in NEIGHBOR dataset.
Databáze: OpenAIRE
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