Genetic analysis of familial AMD cohort identifies genes associated with disease susceptibility

Abstract

Purpose : Age-related macular degeneration (AMD) continues to present a major challenge to the vision field. With over 11 million patients in the US and 190 million worldwide, AMD is the third leading cause of vision loss in the world. Despite more than 150 years of research at-least 50% of the heritability of AMD remains unclear. Our goal is to take advantage of familial clustering of AMD to gain a better understanding of the genetic factors contributing to AMD development.

Methods : Patients with familial history of AMD seen at the Casey Eye Institute were recruited for the study. Medical and ophthalmologic data and blood samples were collected. DNA was isolated from blood samples, and whole exome/genome sequencing was performed on 554 AMD patients and controls from 127 families. FASTQ files were aligned against human reference genome GRCh38 using BWA (Version 0.7.17). Variants were called by GATK (Version 3.8-1), and annotated with ANNOVAR. Variant and segregation filters were applied to retain only rare and potentially pathogenic variants segregating within at least one family.

Results : Combining classic genetic approaches and bioinformatic tools, we were able to verify associations in 11 previously reported genes, including well established genes such as complement factors, but also newly identified genes such as DCHS2 and DNAH14. This corresponds to only 13% of our families suggesting that there are other contributing genetic factors within our cohort. Notably, 4 genes were found to segregate in more than one family, while the remaining were each found only in one family, underlining the challenges in identification of rare genetic factors. We then performed systematic analysis of WES data to identify segregating rare variants in genes not previously associated with AMD. This analysis yielded 5869 genes. Next, we filtered the list to genes which segregated in 3 or more families, resulting in 330 genes. To identify high confidence candidates, we investigated if they overlaped known AMD loci or belonged to a distinct pathway. This highlighted 2 pathways previously not associated with AMD, lipid transport and sphingolipids. Additional experiments to validate these findings are underway.

Conclusions : We performed genetic analysis on a large familial AMD cohort. Our results corroborate other familial studies and provide new insights in to the molecular pathways contributing to AMD.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.