Title:Application and Interpretation of Genome-Wide Association (GWA) Studies for Informing Pharmacogenomic Research - Examples from the Field of Age-Related Macular Degeneration
Volume: 14
Issue: 7
Author(s): J.P. SanGiovanni, R. Rosen and S. Kaushal
Affiliation:
Keywords:
Age-related macular degeneration, genome wide association, ligand, pharmacogenetic,
pharmacogenomic, system, target.
Abstract: Genome-wide association (GWA) studies apply broad DNA scans on hundreds-of-thousands of
common sequence variants in thousands of people for the purpose of mapping trait- or disease-related loci.
We provide examples of ligand- and target-based studies from the field of age-related macular degeneration
(AMD) to demonstrate the value of the GWA approach in confirmatory and exploratory pharmacogenomics
research. Complementing this genomic analysis, we used a simple biochemical retinal pigment epithelium
(RPE) oxidative, apoptotic high throughput screening (HTS) assay to identify compounds. This ligand-to-targetto
DNA sequence variant-to disease approach provided guidance on rational design of preclinical studies and
identified associations between: 1) valproic acid and advanced AMD-associated genes with the capacity to
alter GABA-succinate signaling (ALDH5A1, CACNA1C, SUCLA2, and GABBR2) and chromatin remodeling
(HDAC9); and 2) Ropinirole and a geographic atrophy-associated gene (DRD3) with the capacity to alter
systems involved in cAMP-PKA signaling. In both applications of our method, the breadth of GWA findings
allowed efficient expansion of results to identify enriched pathways and additional ligands capable of targeting
pathway constituents. A disease associated SNP-to gene-to target-to ligand approach provided guidance to
inform preventive and therapeutic preclinical studies investigating roles of targets in: 1) PPAR-RXR
transcription complex constituents for neovascular AMD; and 2) the stress activated MAPK signaling cascade
constituents for advanced AMD. Our conclusion is that publically available data from GWA studies can be used
successfully with open-access genomics, proteomics, structural chemistry, and pharmacogenomics databases
in an efficient, rational approach to streamline the processes of planning and implementation for confirmatory
and exploratory pre-clinical studies of preventive or therapeutic pharmacologic treatments for complex
diseases.
