Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration

Abstract

Although numerous common age-relatedmacular degeneration (AMD) alleles have been discovered using genome-wide association studies, substantial disease heritability remains unexplained. We sought to identify additional common and rare variants associated with advanced AMD. A total of 4,332 cases and 25,268 controls of European ancestry from three different populations were genotyped using the Illumina Infinium HumanExome BeadChip. We performed meta-analyses to identify associations with common variants, and single variant and gene-based burden tests to identify rare variants. Two protective, low-frequency, non-synonymous variants were significantly associated with a decrease in AMD risk: A307V in PELI3 (odds ratio [OR]=0.14, P=4.3×10-10) and N1050Y in CFH (OR=0.76, P=6.2×10-12). The new variants have a large effect size, similar to some rare mutations we reported previously in a targeted sequencing study, which remain significant in this analysis: CFH R1210C (OR=18.82, P=3.5×10-07), C3 K155Q (OR=3.27, P=1.5×10-10) and C9 P167S (OR=2.04, P=2.8×10-07). We also identified a strong protective signal for a common variant (rs8056814) near CTRB1 associated with a decrease in AMD risk (logistic regression: OR=0.71, P=1.8×10-07). Suggestive protective loci were identified in the COL4A3 and APOH genes. Our results support the involvement of common and low-frequency protective variants in this vision-threatening condition. This study expands the roles of the innate immune pathway as well as the extracellularmatrix and high-density lipoprotein pathways in the aetiology of AMD.