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

Author

Listed:
  • Mary Pat Reeve

    (University of Helsinki
    Massachusetts General Hospital
    Broad Institute of Harvard and MIT)

  • 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
    Broad Institute of Harvard and MIT)

  • Pietro DELLA BRIOTTA PAROLO

    (Massachusetts General Hospital
    Broad Institute of Harvard and MIT)

  • Daniel Ben-Isvy

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital
    Harvard Medical School)

  • Elias Aho

    (University of Helsinki)

  • Emilia Cesetti

    (University of Helsinki
    Humanitas University)

  • Yoko Okunuki

    (Biogen Inc)

  • Helen McLaughlin

    (Biogen Inc)

  • Johanna Mäkelä

    (Finnish Biobank Cooperative (FinBB))

  • Mitja Kurki

    (University of Helsinki
    Massachusetts General Hospital
    Broad Institute of Harvard and MIT)

  • Michael E. Talkowski

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital)

  • Jan O. Korbel

    (European Molecular Biological Laboratories (EMBL))

  • Kip Connor

    (Biogen Inc)

  • Seppo Meri

    (University of Helsinki)

  • Mark J. Daly

    (University of Helsinki
    Massachusetts General Hospital
    Broad Institute of Harvard and MIT)

  • Heiko Runz

    (University of Helsinki
    Biogen Inc
    insitro Inc.
    European Molecular Biological Laboratories (EMBL))

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.

Suggested Citation

  • 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 McL, 2025. "Loss of CFHR5 function reduces the risk for age-related macular degeneration," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61193-3
    DOI: 10.1038/s41467-025-61193-3
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