美国凯斯西储大学Sudha K. Iyengar等研究人员合作发现，全基因组关联分析识别出不同种族中年龄相关性黄斑变性的遗传结构。相关论文于2024年12月2日在线发表在《自然—遗传学》杂志上。

据研究人员介绍，为了在全球范围内有效地减少因年龄相关性黄斑生成（AMD）而导致的视力丧失，了解其在不同人群中的遗传结构是必要的。一个关键因素，非洲和西班牙/拉丁裔祖先的AMD风险概况，在很大程度上仍然未知。

研究人员结合百万老兵计划的数据与其他五个队列，进行了首次多种族全基因组关联研究（GWAS）并发现了63个位点（其中30个是新发现的）。研究人员观察到在主要风险位点存在显著的跨种族异质性。

特别是在非洲裔种群中，显示出主要信号集中在主要组织相容性复合体II类单倍型，同时在已知的CFH和ARMS2/HTRA1位点上风险较低。

通过分析混合种族个体的局部祖先，研究人员发现非洲裔单倍型中的CFH风险等位基因的边际效应显著较小。

通过将努力范围扩大到包括不同种族的群体，研究人员揭示了以种族依赖的方式增强风险的基因和通路，并为潜在的纠正疗法提供了靶点。

附：英文原文

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

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

Issue&Volume: 2024-12-02

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.

DOI: 10.1038/s41588-024-01764-0

Source: https://www.nature.com/articles/s41588-024-01764-0