Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Am J Hum Genet. 2024 Oct 3;111(10):2117-2128. doi: 10.1016/j.ajhg.2024.07.021. Epub 2024 Aug 26.
Multi-ancestry genome-wide association studies (GWASs) have highlighted the existence of variants with ancestry-specific effect sizes. Understanding where and why these ancestry-specific effects occur is fundamental to understanding the genetic basis of human diseases and complex traits. Here, we characterized genes differentially expressed across ancestries (ancDE genes) at the cell-type level by leveraging single-cell RNA-sequencing data in peripheral blood mononuclear cells for 21 individuals with East Asian (EAS) ancestry and 23 individuals with European (EUR) ancestry (172,385 cells); then, we tested whether variants surrounding those genes were enriched in disease variants with ancestry-specific effect sizes by leveraging ancestry-matched GWASs of 31 diseases and complex traits (average n ∼ 90,000 and ∼ 267,000 in EAS and EUR, respectively). We observed that ancDE genes tended to be cell-type specific and enriched in genes interacting with the environment and in variants with ancestry-specific disease effect sizes, which suggests cell-type-specific, gene-by-environment interactions shared between regulatory and disease architectures. Finally, we illustrated how different environments might have led to ancestry-specific myeloid cell leukemia 1 (MCL1) expression in B cells and ancestry-specific allele effect sizes in lymphocyte count GWASs for variants surrounding MCL1. Our results imply that large single-cell and GWAS datasets from diverse ancestries are required to improve our understanding of human diseases.
多血统全基因组关联研究（GWAS）强调了具有血统特异性效应大小的变体的存在。了解这些血统特异性效应发生的位置和原因对于理解人类疾病和复杂特征的遗传基础至关重要。在这里，我们通过利用来自东亚（EAS）血统的 21 个人和欧洲（EUR）血统的 23 个人的外周血单核细胞的单细胞 RNA 测序数据，在细胞类型水平上对表达不同血统的基因（ancDE 基因）进行了特征描述（172385 个细胞）；然后，我们通过利用与 31 种疾病和复杂特征相关的匹配血统 GWAS 来测试这些基因周围的变体是否富集了具有血统特异性效应大小的疾病变体（EAS 和 EUR 中的平均 n 分别约为 90000 和 267000）。我们观察到 ancDE 基因往往具有细胞类型特异性，并富集了与环境相互作用的基因和具有血统特异性疾病效应大小的变体，这表明调控和疾病结构之间存在细胞类型特异性、基因与环境的相互作用。最后，我们说明了不同的环境如何导致 B 细胞中髓样细胞白血病 1（MCL1）表达的血统特异性和围绕 MCL1 的变体的淋巴细胞计数 GWAS 中等位基因效应大小的血统特异性。我们的研究结果表明，需要来自不同血统的大型单细胞和 GWAS 数据集来提高我们对人类疾病的认识。
