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

ABSTRACT: Although numerous common age-related macular 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 extracellular matrix and high-density lipoprotein pathways in the aetiology of AMD.

SUBMITTER: Yu Y 

PROVIDER: S-EPMC6078639 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature