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.

为了在全球范围内有效减少年龄相关性黄斑生成 （AMD） 引起的视力丧失，有必要了解其在不同人群中的遗传结构。一个关键因素，非洲和西班牙裔/拉丁裔血统的 AMD 风险概况在很大程度上仍然未知。我们将 Million Veteran Program 中的数据与其他 5 个队列相结合，进行了 AMD 的第一次多血统全基因组关联研究，发现了 63 个位点（30 个新基因位点）。我们在主要风险位点观察到明显的交叉血统异质性，尤其是在非洲血统人群中，这些人在主要组织相容性复合体 II 类单倍型中表现出主要信号，并且在已建立的 CFH 和 ARMS2/HTRA1 位点的风险降低。剖析混合个体的当地血统，我们发现非洲血统单倍型中 CFH 风险等位基因的边际效应大小明显较小。扩大工作范围以纳入祖先不同的人群有助于发现以祖先依赖性方式增加风险的基因和途径，并且是矫正疗法的潜在目标。