92: Loss of CFHR5 Function Lowers AMD Risk

Nature Communications - A FinnGen-based genetic and functional study identifies CFHR5 loss-of-function variants as independently protective against age-related macular degeneration and links reduced FHR-5 to altered complement activity and preserved photoreceptor structure. Key terms: CFHR5, age-related macular degeneration, FinnGen, complement system, FHR-5. Study Highlights:A GWAS and fine-mapping in 12,495 AMD cases and 461,686 controls deconvoluted four protective CFH-region haplotypes, two of which are driven by CFHR5 coding variants enriched in Finns. Carriers of a CFHR5 frameshift show dose-dependent loss of circulating FHR-5 and reduced FHR-2 and FHR-4 levels confirmed by SomaScan and Western blot. Functional assays indicate increased classical and alternative complement pathway activation capacity in CFHR5 frameshift homozygotes. UK Biobank retinal OCT analyses show CFHR5 loss-of-function carriers have photoreceptor layer changes consistent with protection from AMD. Conclusion:Genetic loss of CFHR5 function reduces FHR-5 levels, modulates complement activation, associates with protective retinal morphology, and identifies FHR-5 downregulation as a promising therapeutic target for AMD. Music:Enjoy the music based on this article at the end of the episode. Article title:Loss of CFHR5 function reduces the risk for age-related macular degeneration Journal:Nature Communications DOI:10.1038/s41467-025-61193-3 Reference:https://doi.org/10.1038/s41467-025-61193-3 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/cfhr5-loss-reduces-amd-risk QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-31. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the sections describing CFHR5 loss-of-function (fs), dose-dependent FHR-5 reduction and FHR-2/FHR-4 reductions, increased CP/AP complement activation, thicker photoreceptor layers on OCT, recall-by-genotype proteomics, and therapeutic implications; excluded non-scientific intro/outro and unrelated material.- transcript topics: Overview of age-related macular degeneration (AMD) and forms; CFH/CFHR gene locus and CFHR5 focus; FinnGen cohort, population bottlenecks, and fine-mapping; CFHR5 frameshift variant and dose-dependent protein reductions; Proteomics: SomaScan measurements of FHR proteins; Complement pathways activation (classical, alternative, LP) QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 5- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- CFHR5 frameshift (fs) variant carriers show dose-dependent reductions in FHR-5 serum levels- CFHR5 fs carriers also exhibit reduced levels of FHR-2 and FHR-4- CFHR5 fs carriers have higher capacity to activate classical and alternative complement pathways- CFHR5 fs carriers show thicker/healthier photoreceptor layers on OCT imaging- Recall-by-genotype study in FinnGen with ~399 participants; AMD protection linked to CFHR5 fs- CFH haplotypes contribute major AMD risk...