Distinctive cross-ancestry genetic architecture for age-related macular degeneration

To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown due to lower lifetime prevalence. We combined genetic and clinical data in the Million Veteran Program with five other cohorts to conduct the first multi-ancestry genome-wide association study of AMD and discovered 63 loci (30 novel). We observe marked cross-ancestry heterogeneity at major risk loci, especially in African-ancestry populations which demonstrate a primary signal in a Major Histocompatibility Complex Class II haplotype and reduced risk at the established CFH and ARMS2/HTRA1 loci. Broadening efforts to include ancestrally-distinct populations helped uncover genes and pathways which boost risk in an ancestry-dependent manner, and are potential targets for corrective therapies. One Sentence Summary robing electronic health record data with genomics unearths novel paths to age-related macular degeneration. ### Competing Interest Statement ADS and BY are employees of Genentech/Roche and hold stock and stock options in Roche. EJ is an employee and stockholder of Regeneron Genetics Center. The rest of the authors declare that they have no competing interests. ### Funding Statement Department of Veterans Affair Office of Research & Development I01BX003364 (NSP) Department of Veterans Affair Office of Research & Development I01BX004557 (NSP) Department of Veterans Affair Office of Research & Development I01BX004189 (PR) Department of Veterans Affair Office of Research & Development I01BX005233 (NSP) Department of Veterans Affair Office of Research & Development I01BX005787 (SJF) National Institutes of Health grant P30EY025585 (B Anand-Apte) National Institutes of Health grant P30EY011373 (IA Pikuleva) National Institutes of Health grant K08MH122911 (GV) National Institutes of Health grant R01AG067025 (PR) National Institutes of Health grant R01AG065582 (PR) National Institutes of Health grant U01MH116442 (PR) National Institutes of Health grant R01MH125246 (PR) National Institutes of Health grant R01AG050986 (PR) National Institutes of Health grant R01EY027004 (HC, EJ) National Institutes of Health grant RC2AG036607(CA Schaefer, NJ Risch) National Institutes of Health grant R01EY022310 (JL Haines, SH Blanton, MA Pericak-Vance) National Institutes of Health grant X01HG006934 (G Abecasis) International Retinal Research Foundation (SKI) Robert Wood Johnson Foundation, Research Program on Genes, Environment and Health Wayne and Gladys Valley Foundation Ellison Medical Foundation Kaiser Permanente Community Benefit Programs Research to Prevent Blindness (Departments of Ophthalmology at Case Western Reserve University; Cleveland Clinic Lerner College of Medicine; University of Buffalo) The UK Biobank Eye and Vision Consortium is supported by grants from Moorfields Eye Charity, The NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, the Alcon Research Institute and the International Glaucoma Association (UK) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Central IRB of the VA Office of Research & Development gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The full summary level association data from the individual population association analyses in MVP will be available via the dbGaP study accession number phs001672.