Loss of CFHR5 function reduces the risk for age-related macular degeneration

Mary Pat Reeve; Stephanie J. Loomis; Eija Nissilä; Thomas W. Soare; Tobias Rausch; Zhili Zheng; Pietro Della Briotta Parolo; Daniel Ben-Isvy; Elias Aho; Emilia Cesetti; Yoko Okunuki; Helen McLaughlin; Johanna Mäkelä; FinnGen; Mitja Kurki; Michael E. Talkowski; Jan O. Korbel; Kip M. Connor; Seppo Meri; Mark J. Daly; Heiko Runz

doi:10.1038/s41467-025-61193-3

Genetic & Genomic MedicineNature CommunicationsJul 1, 2025

Peer-reviewed journal article

Loss of CFHR5 function reduces the risk for age-related macular degeneration

Mary Pat Reeve iD, Stephanie J. Loomis iD, Eija Nissilä iD, Thomas W. Soare iD, Tobias Rausch iD, Zhili Zheng iD, Pietro Della Briotta Parolo, Daniel Ben-Isvy iD, Elias Aho, Emilia Cesetti iD, Yoko Okunuki iD, Helen McLaughlin, Johanna Mäkelä, FinnGen iD, Mitja Kurki iD, Michael E. Talkowski iD, Jan O. Korbel iD, Kip M. Connor iD, Seppo Meri iD, Mark J. Daly iD, Heiko Runz iD

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Abstract

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 (CFH) 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 CFH haplotypes that convey protection from AMD. We show that beyond CFH, two of these are explained by Finn-enriched frameshift and missense variants in the CFH modulator CFHR5. We demonstrate through a FinnGen sample recall study that CFHR5 variant carriers exhibit dose-dependent reductions in serum levels of the CFHR5 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.