Journal Article

Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries

Cooke Bailey, Jessica N., Markianos, Kyriacos, Tsao, Philip S., Patasova, Karina, Choquet, Hélène, Hysi, Pirro G., Schreiner, Patrick A., Melles, Ronald B., Stockwell, Amy, Assimes, Themistocles L., Iyengar, Sudha K., Venkatesh, Sanan, Patel, Praveen J., Anger, Matthew D., Yin, Jie, Gorman, Bryan R., Voloudakis, Georgios, Yaspan, Brian L., Crawford, Dana C., Zhang, Wen, Bigdeli, Tim B., Greenberg, Paul B., Zeng, Biao, Sullivan, Jack M., Igo, Robert P., Peachey, Neal S., Kinzy, Tyler, Roussos, Panos, Hadi, Tamer, Halladay, Christopher W., Lotery, Andrew J., Kaye, Rebecca, Dong, Frederick, Pyarajan, Saiju, Gaziano, J. Michael, Jorgenson, Eric, Fliesler, Steven J., Wu, Wen-Chih

2024

Overview

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. Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 45/43 / 631/208 / 631/208/457 / Age / Age related diseases / Aged / Agriculture / Alcohol / Animal Genetics and Genomics / Biobanks / Biomedical and Life Sciences / Biomedicine / Black People - genetics / Cancer Research / Cholesterol / Complement Factor H - genetics / Disease / Electronic health records / Eye diseases / Female / Gene Function / Gene loci / Genetic analysis / Genetic diversity / Genetic Predisposition to Disease / Genome-wide association studies / Genome-Wide Association Study / Genomes / Genomics / Haplotypes / Health risk assessment / Heterogeneity / High density lipoprotein / High-Temperature Requirement A Serine Peptidase 1 - genetics / Hispanic Americans / Hispanic or Latino - genetics / Human Genetics / Humans / Macular degeneration / Macular Degeneration - genetics / Major histocompatibility complex / Male / Meta-analysis / Polymorphism, Single Nucleotide / Population genetics / Populations / Proteins / Proteins - genetics / Risk management / Risk reduction / Veterans