title: Application and interpretation of genome-wide association (GWA) studies for informing pharmacogenomic research - examples from the field of age-related macular degeneration.
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.
authors.forename: J P
authors.initials: JP
authors.lastname: SanGiovanni
authors.forename: R
authors.initials: R
authors.lastname: Rosen
authors.affiliation: National Eye Institute, Bethesda, MD 20892-1863, USA. jpsangio@post.harvard.edu.
authors.forename: S
authors.initials: S
authors.lastname: Kaushal
mesh_terms: D018682:GABA Agents / Q000627:therapeutic use; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008268:Macular Degeneration / Q000188:drug therapy / Q000235:genetics; D008957:Models, Genetic; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016896:Treatment Outcome; D014635:Valproic Acid / Q000627:therapeutic use
chemical_list: D018682:GABA Agents; D014635:Valproic Acid