Gouveia Mateus H, Meeks Karlijn A C, Borda Victor, Leal Thiago P, Kehdy Fernanda S G, Mogire Reagan, Doumatey Ayo P, Tarazona-Santos Eduardo, Kittles Rick A, Mata Ignacio F, O'Connor Timothy D, Adeyemo Adebowale A, Shriner Daniel, Rotimi Charles N
Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD, USA.
Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD, USA; Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Am J Hum Genet. 2025 Jun 5;112(6):1286-1301. doi: 10.1016/j.ajhg.2025.04.012.
The All of Us Research Program (All of Us) seeks to accelerate biomedical research and address the underrepresentation of minorities by recruiting over 1 million participants across the United States. A key question is how self-identification with discrete, predefined race and ethnicity categories compares to genetic variation at continental and subcontinental levels. To contextualize the genetic variation in All of Us, we analyzed ∼2 million common variants from 230,016 unrelated whole genomes using classical population genetics methods alongside reference panels such as the 1000 Genomes Project, Human Genome Diversity Project, and Simons Genome Diversity Project. Our analysis reveals that participants within self-identified race and ethnicity groups exhibit gradients of genetic variation rather than discrete clusters. The distributions of continental and subcontinental ancestries show considerable variation within race and ethnicity, both nationally and across states, reflecting the historical impacts of US colonization, the transatlantic slave trade, and recent migrations. All of Us samples filled most gaps along the top five principal components of genetic variation in current global reference panels. Notably, Hispanic or Latino participants spanned much of the three-way (African, Native American, and European) admixture spectrum. Ancestry was significantly associated with body mass index (BMI) and height even after adjusting for socio-environmental covariates. In particular, West-Central and East African ancestries showed opposite associations with BMI. This study emphasizes the importance of assessing subcontinental ancestries, as the continental approach is insufficient to control for confounding in genetic association studies.
“我们所有人”研究项目（简称“我们所有人”）旨在通过在美国招募超过100万名参与者来加速生物医学研究，并解决少数族裔代表性不足的问题。一个关键问题是，与大陆和次大陆层面的基因变异相比，自我认同离散的、预先定义的种族和族裔类别情况如何。为了将“我们所有人”中的基因变异情况置于具体背景中，我们使用经典群体遗传学方法，结合诸如千人基因组计划、人类基因组多样性计划和西蒙斯基因组多样性计划等参考数据集，分析了来自230,016个无关全基因组的约200万个常见变异。我们的分析表明，自我认同的种族和族裔群体中的参与者呈现出基因变异梯度，而非离散的聚类。大陆和次大陆血统的分布在全国和各州的种族和族裔内部都表现出相当大的差异，反映了美国殖民、跨大西洋奴隶贸易和近期移民的历史影响。“我们所有人”的样本填补了当前全球参考数据集中基因变异前五个主成分中的大部分空白。值得注意的是，西班牙裔或拉丁裔参与者涵盖了大部分三元（非洲、美洲原住民和欧洲）混合谱系。即使在调整了社会环境协变量之后，血统与体重指数（BMI）和身高仍显著相关。特别是，中西部和东非血统与BMI呈现出相反的关联。这项研究强调了评估次大陆血统的重要性，因为大陆层面的方法不足以控制基因关联研究中的混杂因素。
