CIDR- Custom Exome Chip Genotyping in POAG (WIGGS)

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Primary open angle glaucoma (POAG) is a significant cause of blindness worldwide. The etiology of POAG is poorly understood and primary prevention is not possible. Current treatments can slow but do not cure this progressive neuropathy. The overall goal of our research is to elucidate the pathogenesis of primary openangle glaucoma (POAG) making it possible to implement effective screening and prevention strategies and to develop novel therapies. POAG is a clinically and genetically complex condition with significant heritability. Linkage and association studies have identified interesting POAG susceptibility genes, however these genes only account for a small fraction of the overall disease heritability and mainly have relatively modest (if any) functional effects. Previously we formed two collaborative consortia contributing 3,517 POAG cases and 3,631 controls for GWA studies, the NEIGHBOR consortium (NEI Glaucoma Human genetic collaboration) and the GLAUGEN study (Glaucoma genes and environment). While our meta analysis revealed important common variants associated with POAG the actual disease susceptibility variants in these genomic regions are not yet known. Additionally rare genetic variation, not detected by the GWAS, is also likely to contribute to POAG. The purpose of this proposal is to add whole exome data to the NEIGHBOR and GLAUGEN datasets using the Illumina HumanExome BeadChip with added content relevant to POAG. The immediate goals of this proposal are: 1) Obtain high quality human exome data for all available NEIGHBOR and GLAUGEN samples (3517 cases and 3611 controls)? 2) Perform association analyses to identify variants contributing to POAG? 3) Confirm novel associations in an independent dataset and through in vitro and animal models as appropriate. Adding exome data will make it possible to conduct a comprehensive analysis of genetic risk factors contributing to POAG by assessing contributions of both common and rare genetic variants. This work will be an important step toward the development of gene based screening tests and novel therapies targeted to the molecular events responsible for the disease. Public Health Rlevance: Glaucoma is an intraocular pressure (IOP) related progressive optic neuropathy that ultimately leads to blindness. Permanent visual field loss from glaucoma is a condition of public health significance worldwide, affecting millions of people. The etiology of glaucoma is poorly understood and effective means of primary prevention and curative therapies are not available. The overall goal of our research is to elucidate the molecular pathogenesis of glaucoma making it possible to implement effective screening and prevention strategies and to develop novel therapies. The purpose of this proposal is to extend the genetic analysis of two large glaucoma cohorts (the GLAUGEN and NEIGHBOR genomewide association studies) by adding exome data from Illumina HumanExome BeadChip which will make it possible to identify high impact functional genetic defects that contribute to this blinding disease.