Rare predicted loss-of-function and damaging missense variants in CFHR5 associate with protection from age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness among older adults worldwide, but treatment options are limited. Genetics studies have implicated the CFH locus, containing CFH and five CFHR genes, CFHR1-5, in AMD. While CFH has been robustly linked with AMD risk, potential additional roles for the CFHR genes remain unclear, obscured by strong linkage disequilibrium across the locus. Investigating rare coding variants can help to identify causal genes in such regions. We used whole-exome sequencing data from 406,952 UK Biobank participants to examine AMD associations with genes at the CFH locus. For each gene, we used burden testing to examine associations of rare (minor-allele frequency [MAF] < 1%) predicted loss-of-function (pLoF) and predicted damaging missense variants with AMD. We considered "broadly defined AMD" (ICD-10 35.3; n_cases = 10,700) and "strictly defined AMD" (dry or wet AMD; n_cases = 346). Adjusting for CFH-region variants known to independently associate with AMD, we find that CFHR5 rare variant burden significantly associates with a decreased risk of broadly defined AMD (odds ratio [OR] = 0.75, p = 7 × 10^-4), with this association primarily driven by pLoF variants. Furthermore, the association of CFHR5 rare variants with AMD protection is estimated to be stronger for individuals with the CFH rs1061170 AMD risk allele (p.Tyr402His [p.Y402H]; interaction p = 0.04). Corresponding analyses of strict AMD were underpowered. However, we observe that thinning of the photoreceptor layer outer segment strongly predicts strict AMD and find that CFHR5 rare variant burden is significantly associated with increased thickness of this retinal layer (+0.34 SD, p = 4 × 10^-4, n = 45,365). These findings suggest CFHR5 inhibition as a potential therapeutic approach for AMD.