Understanding the Molecular and Biological Basis of GWAS Findings in AMD

We aim to integrate the GWAS findings with functional genomics to elucidate the mechanistic understanding of the genetic causes of AMD. The interpretation of GWAS findings remains challenging as the majority of disease-associated variants reside in the non-coding genome.

Age-related macular degeneration (AMD) is a major cause of irreversible vision loss resulting from the death of light-sensing photoreceptors primarily in the macular region of the retina. Worldwide, 200 million people are affected by AMD, and the prevalence may double by 2050. Genome-wide associated studies (GWAS) have identified multiple genetic loci associated with AMD. However, the interpretation of GWAS findings remains a major challenge as the majority of disease-associated variants reside outside the protein-coding regions and we have limited understanding of how associated variants translate into disease pathogenesis.

In this proposal, we will integrate the GWAS findings with transcriptome and epigenome data to identify underlying causal variants, regulatory elements, and target genes to address major gaps in mechanistic understanding of the causes of AMD. Additionally, we will characterize the cis-regulatory landscape in non-human primates to gain insights into the primate-specific regulatory circuitry that can ultimately serve as a template for developing primate models of AMD.

AMD has substantial genetic basis that has been successfully demonstrated through several GWAS. However, this information has not been exhausted for understanding the mechanistic basis of the disease or to provide new opportunities for therapeutic discovery. Our approach to systematically characterize gene expression across cell types and the regulatory elements that control them is aimed to provide an innovative strategy to explore the molecular mechanisms through which non-coding genetic variants affect AMD risk.

Our project is aimed at obtaining a mechanistic understanding of the biology underlying genetic associations that could potentially uncover novel gene and pathways for therapeutic interventions. Our findings provide a systems-level understanding of the disease, and tools and resources generated will also be relevant for functional genomic dissection of other related complex ocular diseases. Finally, these findings will eventually improve clinical interpretation of GWAS studies in risk prediction and clinical trials practices.