Deciphering Genetic and Environmental Influences on Visual Disorders in the Million Veteran Program

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Abstract The VA Million Veteran Program (MVP) provides access to genotyping and longitudinal clinical data for more than 616,000 Veterans, thereby offering an unparalleled opportunity to define the genetic basis of complex diseases. In this project, we will examine age-related eye conditions that are of high relevance to the Veterans Health Administration (primary open angle glaucoma, diabetic retinopathy, Fuchs endothelial corneal dystrophy, cataract, myopia, aqueous tear deficiency) that are prevalent in the Veteran population with distinct adverse effects on vision and demands on system resources. In Aim 1, we will perform single variant analysis for each ocular phenotype, towards identification of common and rare variants. This genetic analysis will be conducted following development of a robust algorithm to identify Cases with a condition and Controls without that condition. This algorithm will be based on International Classification of Diseases (ICD) codes. Separate genome wide association studies (GWAS) will be conducted on MVP enrollees of European-American (EA), African-American (AA) or Hispanic- American (HA) descent, with descent confirmed by Principal Component Analysis. For many of these conditions, this will be the first GWAS ever conducted or will be the first trans-ethnic GWAS. This work will follow-on our successful analysis of age-related macular degeneration (AMD), where we noted marked differences in the genetic basis of EA as compared to AA and HA Veterans. In Aim 2, we will use PheWAS analysis to understand the interrelationships between different ocular diseases, between ocular diseases and other conditions and between ocular diseases and quantitative physiological traits. The MVP biobank provides an unprecedented opportunity to examine the genetic basis for eye diseases that impact Veteran populations and to determine how eye diseases and other medical conditions are related via shared gene variants or genetic profiles. Through the identification of new relationships between ocular traits and other diseases or physiologic measures, this project will address an important gap in the ocular genetics field.