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.
Veterans may be afflicted by a wide range of age-related conditions that impair vision or ocular function. These include primary open angle glaucoma, cataract, and diabetic retinopathy. Our understanding of the underlying disease mechanisms for these and other conditions is incomplete, as is our appreciation for whether the disease process varies across ethnic groups. Genetic studies provide important information regarding these questions. In this project, the Million Veteran Program resources will be used to (a) identify genetic loci related to ocular conditions that are prevalent in the Veteran population; (b) compare susceptibility genes across Veteran populations of European, African or Hispanic heritage and (c) determine if susceptibility genes are shared in multiple ocular disorders, are involved in other systemic disorders, or interact with environmental factors. The information gained in this project will inform the development of new treatments for age-related eye disease.
