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

Bryan R. Gorman, Georgios Voloudakis, Robert P. Igo, Tyler Kinzy, Christopher W. Halladay, Tim B. Bigdeli, Biao Zeng, Sanan Venkatesh, Jessica N. Cooke Bailey, Dana C. Crawford, Kyriacos Markianos, Frederick Dong, Patrick A. Schreiner, Wen Zhang, VA Million Veteran Program, International AMD Genomics Consortium (IAMDGC), Alex W. Hewitt, Jamie E. Craig, David A. Mackey, Stewart LakeJanette Hall, Emmanuelle Souzeau, David J. Hunter, Kathryn P. Burdon, Tamer Hadi, Matthew D. Anger, Amy Stockwell, Ronald B. Melles, Jie Yin, Hélène Choquet, Rebecca Kaye, Karina Patasova, Praveen J. Patel, Brian L. Yaspan, Eric Jorgenson, Pirro G. Hysi, Andrew J. Lotery, J. Michael Gaziano, Philip S. Tsao, Steven J. Fliesler, Jack M. Sullivan, Paul B. Greenberg, Wen Chih Wu, Themistocles L. Assimes, Saiju Pyarajan, Panos Roussos, Neal S. Peachey, Sudha K. Iyengar

Research output: Contribution to journalArticlepeer-review

Abstract

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 languageEnglish
Pages (from-to)2659-2671
Number of pages13
JournalNature Genetics
Volume56
Issue number12
DOIs
Publication statusPublished - Dec 2024

Keywords

  • Genetics
  • Population genetics
  • Macular degeneration

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