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 Summaryrobing electronic health record data with genomics unearths novel paths to age-related macular degeneration.