Table5_Dissecting Generalizability and Actionability of Disease-Associated Genes From 20 Worldwide Ethnolinguistic Cultural Groups.XLS

Findings resulting from whole-genome sequencing (WGS) have markedly increased due to the massive evolvement of sequencing methods and have led to further investigations such as clinical actionability of genes, as documented by the American College of Medical Genetics and Genomics (ACMG). ACMG’s actionable genes (ACGs) may not necessarily be clinically actionable across all populations worldwide. It is critical to examine the actionability of these genes in different populations. Here, we have leveraged a combined WES from the African Genome Variation and 1000 Genomes Project to examine the generalizability of ACG and potential actionable genes from four diseases: high-burden malaria, TB, HIV/AIDS, and sickle cell disease. Our results suggest that ethnolinguistic cultural groups from Africa, particularly Bantu and Khoesan, have high genetic diversity, high proportion of derived alleles at low minor allele frequency (0.0–0.1), and the highest proportion of pathogenic variants within HIV, TB, malaria, and sickle cell diseases. In contrast, ethnolinguistic cultural groups from the non-Africa continent, including Latin American, Afro-related, and European-related groups, have a high proportion of pathogenic variants within ACG than most of the ethnolinguistic cultural groups from Africa. Overall, our results show high genetic diversity in the present actionable and known disease-associated genes of four African high-burden diseases, suggesting the limitation of transferability or generalizability of ACG. This supports the use of personalized medicine as beneficial to the worldwide population as well as actionable gene list recommendation to further foster equitable global healthcare. The results point out the bias in the knowledge about the frequency distribution of these phenotypes and genetic variants associated with some diseases, especially in African and African ancestry populations.

随着测序技术的迅猛发展，全基因组测序（whole-genome sequencing, WGS）的研究成果显著增多，进而催生了基因临床可操作性等相关研究，正如美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics, ACMG）所记载的那样。ACMG可操作基因（ACMG’s actionable genes, ACGs）未必适用于全球所有人群的临床场景，因此在不同人群中评估此类基因的可操作性具有重要意义。本研究借助非洲基因组变异项目（African Genome Variation）与千人基因组计划（1000 Genomes Project）的合并全外显子组测序（whole exome sequencing, WES）数据，评估了ACMG可操作基因以及四种高负担疾病（高负担疟疾、结核病（TB, tuberculosis）、艾滋病（HIV/AIDS）与镰状细胞病（sickle cell disease））相关潜在可操作基因的可推广性。研究结果显示，非洲的民族语言文化群体——尤其是班图人（Bantu）与科伊桑人（Khoesan）——拥有极高的遗传多样性，在0.0~0.1的次要等位基因频率区间内，衍生等位基因占比颇高，且在艾滋病、结核病、疟疾与镰状细胞病相关的致病变异占比位居全球前列。与之形成对比的是，非非洲大陆的民族语言文化群体（包括拉丁美洲裔、非洲相关族群与欧洲相关族群），其ACMG可操作基因内的致病变异占比高于多数非洲民族语言文化群体。总体而言，本研究结果表明，针对四种非洲高负担疾病的现有可操作基因与已知疾病关联基因均呈现出极高的遗传多样性，这提示ACMG可操作基因的可转移性与可推广性存在局限。该结论印证了个性化医疗对全球人群的益处，同时也呼吁优化可操作基因列表的推荐标准，以进一步推动全球医疗公平。本研究结果同时揭示了当前对部分疾病相关表型与遗传变异频率分布的认知偏差，这一偏差在非洲人群及非洲血统人群中尤为显著。