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. Prior genetics studies have implicated the CFH locus, which contains CFH and the five CFHR1-5 genes, in AMD. While the CFH gene has been robustly linked with AMD risk, the potential additional role of the five CFHR genes remains unclear, with strong linkage disequilibrium across the locus hindering the identification of individual gene contributions. Investigation of 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 the association of rare (MAF<1%) predicted loss-of-function (pLOF) and predicted-damaging missense variants with AMD. When adjusting for CFH-region variants previously established to independently associate with AMD, we find that CFHR5 rare variant burden significantly associates with decreased risk of AMD (OR=0.75, p=7x10-4), and that this association is primarily driven by pLOF variants. Furthermore, the association of CFHR5 rare variants with AMD protection is estimated as stronger for individuals carrying the CFH Y402H variant, which increases AMD risk (interaction p=0.04). We also identify increased thinning of the outer segment of the photoreceptor layer of the retina to be a strong predictor of AMD and find that CFHR5 rare variant burden significantly associates with increased thickness of this retinal layer (+0.34 SD, p=4x10-4). These findings suggest CFHR5 inhibition as a potential therapeutic approach for AMD.