Whole Genome Sequencing Identifies Novel Common and Low-Frequency Variants Associated With Age-Related Macular Degeneration

PURPOSE: To identify associations of common, low-frequency, and rare variants with advanced age-related macular degeneration (AMD) using whole genome sequencing (WGS). METHODS: WGS data were obtained for 2123 advanced AMD patients (participants of clinical trials for advanced AMD) and 2704 controls (participants of clinical trials for asthma [N = 2518] and Alzheimer's disease [N = 186]), and joint genotype calling was performed, followed by quality control of the dataset. Single variant association analyses were performed for all identified common, low-frequency, and rare variants. Gene-based tests were executed for rare and low-frequency variants using SKAT-O and three groups of variants based on putative impact information: (1) all variants, (2) modifier impact variants, and (3) high- and moderate-impact variants. To ascertain independence of the identified associations from previously reported AMD and asthma loci, conditional analyses were performed. RESULTS: Previously identified AMD variants at the CFH, ARMS2/HTRA1, APOE, and C3 loci were associated with AMD at a genome-wide significance level. We identified new single variant associations for common variants near the PARK7 gene and in the long non-coding RNA AC103876.1, and for a rare variant near the TENM3 gene. In addition, gene-based association analyses identified a burden of modifier variants in eight intergenic and gene-spanning regions and of high- and moderate-impact variants in the C3, CFHR5, SLC16A8, and CFI genes. CONCLUSIONS: We describe the largest WGS study in AMD to date. We confirmed previously identified associations and identified several novel associations that are worth exploring in further follow-up studies.