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

Abstract

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.

Figure 1.

Manhattan plots of GWAS results (A) from the initial GWAS with no conditioning, followed by (B) Asthma and (C) AMD conditioning in the next two panels are shown (genes associated after AMD conditioning are listed in Supplementary Table S8). The peaks that reached genome-wide significance are annotated with the gene they belong to.

Figure 2.

LocusZoom plots of (A) intronic rs226251 variant on PARK7, and (B) intergenic rs143255652 near AC103876.1 are shown. Diamond-shaped variant shows the variants of interest (rs226251 and rs143255652, respectively), and dots show other variants in the region; red shows high LD, and blue shows no LD.