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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. We combined 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. Dissecting local ancestry in admixed individuals, we find significantly smaller marginal effect sizes for CFH risk alleles in African ancestry haplotypes. Broadening efforts to include ancestrally distinct populations helped uncover genes and pathways that boost risk in an ancestry-dependent manner and are potential targets for corrective therapies.

Original publication

DOI

10.1038/s41588-024-01764-0

Type

Journal article

Journal

Nat Genet

Publication Date

12/2024

Volume

56

Pages

2659 - 2671

Keywords

Macular Degeneration, Genome-Wide Association Study, Humans, Haplotypes, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Hispanic or Latino, Black People, Male, Complement Factor H, Female, Aged, High-Temperature Requirement A Serine Peptidase 1, Proteins, White