全基因组关联的应用和解释以了解遗传药理学研究——以老年性黄斑变性为例

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:

关键词: 老年性黄斑变性，全基因组关联，配体，遗传药理学，药物基因学，系统，靶点。

摘要: 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.

Cite this article as:

SanGiovanni J.P., Rosen R. and Kaushal S., Application and Interpretation of Genome-Wide Association (GWA) Studies for Informing Pharmacogenomic Research - Examples from the Field of Age-Related Macular Degeneration, Current Molecular Medicine 2014; 14 (7) . https://dx.doi.org/10.2174/1566524014666140811113606