Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries.
Gorman BR., Voloudakis G., Igo RP., Kinzy T., Halladay CW., Bigdeli TB., Zeng B., Venkatesh S., Cooke Bailey JN., Crawford DC., Markianos K., Dong F., Schreiner PA., Zhang W., VA Million Veteran Program None., International AMD Genomics Consortium (IAMDGC) None., Hadi T., Anger MD., Stockwell A., Melles RB., Yin J., Choquet H., Kaye R., Patasova K., Patel PJ., Yaspan BL., Jorgenson E., Hysi PG., Lotery AJ., Gaziano JM., Tsao PS., Fliesler SJ., Sullivan JM., Greenberg PB., Wu W-C., Assimes TL., Pyarajan S., Roussos P., Peachey NS., Iyengar SK.
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.