Loss of function reduces the risk for age-related macular degeneration.

Age-related macular degeneration (AMD) is a prevalent cause of vision loss in the elderly with limited therapeutic options. A single chromosomal region around the complement factor H gene () is reported to explain nearly 25% of genetic AMD risk. Here, we used association testing, statistical finemapping and conditional analyses in 12,495 AMD cases and 461,686 controls to deconvolute four major haplotypes that convey protection from AMD. We show that beyond , two of these are explained by Finn-enriched frameshift and missense variants in the modulator . We demonstrate through a FinnGen sample recall study that variant carriers exhibit dose-dependent reductions in serum levels of the gene product FHR-5 and two functionally related proteins at the locus. Genetic reduction in FHR-5 correlates with higher preserved activities of the classical and alternative complement pathways. Our results propose therapeutic downregulation of FHR-5 as promising to prevent or treat AMD.