Abstract
Purpose :
Genome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). Whole-exome sequencing (WES) studies allow a more comprehensive analysis of rare, coding variants across all genes of the genome, and will contribute to a better understanding of the underlying disease mechanisms. To date, the number of WES studies in AMD case-control cohorts is still scarce and sample sizes are limited. To scrutinize the role of rare protein-altering variants in AMD etiology, we performed the largest WES study in AMD to date, in a large European cohort consisting of 1,125 AMD cases and 1,361 controls.
Methods :
WES was performed in 2,516 individuals from the European Genetic Database (EUGENDA, 667 AMD cases and 132 healthy controls) and the Rotterdam Study (470 AMD cases and 1,247 controls). After stringent quality control steps, a cohort of 1,125 AMD cases and 1,361 controls was selected for association analyses. Genome-wide single-variant and gene-based association analyses (CMC, VT, SKAT) of WES data was performed. Immunohistochemistry was performed on mouse eye sections using polyclonal anti-COL8A1 antibodies.
Results :
In this study, we detected a burden of rare protein-altering variants in the COL8A1 gene (p=7.07x10-05). The COL8A1 burden is explained by 14 rare protein-altering variants spread across the protein, which are found more often in cases (22/2,250 alleles, 1.0%) than in controls (11/2,722 alleles, 0.4%). The association of rare variants in the COL8A1 gene is independent of the common intergenic variant (rs140647181) near the COL8A1 gene, previously associated with AMD. We demonstrate that COL8A1 localizes at Bruch’s membrane, which has a key role in AMD pathogenesis.
Conclusions :
This study supports a role for protein-altering variants in the COL8A1 gene in AMD pathogenesis, and suggests that the previously observed association of the common intergenic variant is driven by effects on COL8A1. In this study we for the first time demonstrate the presence of COL8A1 in Bruch’s membrane, further supporting the role of COL8A1 variants in AMD pathogenesis. Protein-altering variants in COL8A1 may alter the integrity of Bruch’s membrane, contributing to the accumulation of drusen and the development of AMD.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.