Abstract

Although >20 common frequency age-related macular degeneration (AMD) alleles have been discovered with genome-wide association studies, substantial disease heritability remains unexplained. In this study we sought to identify additional variants, both common and rare, that have an association with advanced AMD. We genotyped 4,332 cases and 25,268 controls of European ancestry from three different populations using the Illumina Infinium HumanExome BeadChip. We performed meta-analyses to identify associations with common variants and performed single variant and gene-based burden tests to identify associations with rare variants. Two protective, low frequency, non-synonymous variants A307V in PELI3 (odds ratio [OR]=0.14, P=4.3x10-10) and N1050Y in CFH (OR=0.76, Pconditional=1.6x10-11) were significantly associated with a decrease in risk of AMD. Additionally, we identified an enrichment of protective alleles in PELI3 using a burden test (OR=0.14). The new variants have a large effect size, similar to rare mutations we reported previously in a targeted sequencing study, which remain significant in this analysis: CFH R1210C (OR=18.82, P=3.5x10-07), C3 K155Q (OR=3.27, P=1.5x10-10), and C9 P167S (OR=2.04, P=2.8x10-07). 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 = 1.8x10-07; Firth corrected OR = 0.64, P = 9.6x10-11). This study supports the involvement of both common and low frequency protective variants in AMD. It also may expand the role of the high-density lipoprotein pathway and branches of the innate immune pathway, outside that of the complement system, in the etiology of AMD.