Loss of CFHR5 function reduces the risk for age-related macular degeneration
Mary Pat Reeve,
Stephanie 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,
Mitja Kurki,
Michael E. Talkowski,
Jan O. Korbel,
Kip Connor,
Seppo Meri,
Mark J. Daly () and
Heiko Runz ()
Additional contact information
Mary Pat Reeve: University of Helsinki
Stephanie Loomis: Biogen Inc
Eija Nissilä: University of Helsinki
Thomas W. Soare: insitro Inc.
Tobias Rausch: European Molecular Biological Laboratories (EMBL)
Zhili Zheng: Massachusetts General Hospital
Pietro DELLA BRIOTTA Parolo: Massachusetts General Hospital
Daniel Ben-Isvy: Broad Institute of Harvard and MIT
Elias Aho: University of Helsinki
Emilia Cesetti: University of Helsinki
Yoko Okunuki: Biogen Inc
Helen McLaughlin: Biogen Inc
Johanna Mäkelä: Finnish Biobank Cooperative (FinBB)
Mitja Kurki: University of Helsinki
Michael E. Talkowski: Broad Institute of Harvard and MIT
Jan O. Korbel: European Molecular Biological Laboratories (EMBL)
Kip Connor: Biogen Inc
Seppo Meri: University of Helsinki
Mark J. Daly: University of Helsinki
Heiko Runz: University of Helsinki
Nature Communications, 2025, vol. 16, issue 1, 1-15
Abstract:
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 complement activation capacity and a thicker retinal photoreceptor layer. Our results propose therapeutic downregulation of FHR-5 as promising to prevent or treat AMD.
Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61193-3
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DOI: 10.1038/s41467-025-61193-3
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