Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA.
Department of Computer Science, UCLA, Los Angeles, CA, USA.
Nat Genet. 2023 Apr;55(4):549-558. doi: 10.1038/s41588-023-01338-6. Epub 2023 Mar 20.
Individuals of admixed ancestries (for example, African Americans) inherit a mosaic of ancestry segments (local ancestry) originating from multiple continental ancestral populations. This offers the unique opportunity of investigating the similarity of genetic effects on traits across ancestries within the same population. Here we introduce an approach to estimate correlation of causal genetic effects (r) across local ancestries and analyze 38 complex traits in African-European admixed individuals (N = 53,001) to observe very high correlations (meta-analysis r = 0.95, 95% credible interval 0.93-0.97), much higher than correlation of causal effects across continental ancestries. We replicate our results using regression-based methods from marginal genome-wide association study summary statistics. We also report realistic scenarios where regression-based methods yield inflated heterogeneity-by-ancestry due to ancestry-specific tagging of causal effects, and/or polygenicity. Our results motivate genetic analyses that assume minimal heterogeneity in causal effects by ancestry, with implications for the inclusion of ancestry-diverse individuals in studies.
具有混合血统的个体(例如非裔美国人)继承了源自多个大陆祖先群体的祖先片段(局部血统)的马赛克。这为在同一人群中研究不同血统的遗传对特征的影响相似性提供了独特的机会。在这里,我们介绍了一种估计跨局部血统因果遗传效应相关性(r)的方法,并分析了非洲裔欧洲裔混合个体中的 38 种复杂特征(N=53001),观察到非常高的相关性(荟萃分析 r=0.95,95%置信区间 0.93-0.97),远高于跨大陆血统的因果效应相关性。我们使用基于回归的方法从边际全基因组关联研究汇总统计数据中复制了我们的结果。我们还报告了现实情况下,由于因果效应的特定血统标记和/或多基因性,基于回归的方法会导致遗传异质性膨胀的情况。我们的结果激发了遗传分析,这些分析假设遗传因果效应的异质性最小,这对在研究中纳入具有不同血统的个体具有重要意义。