To investigate cross-ancestry genetics of complex traits, we conducted a phenome-wide analysis of loci with heterogeneous effects across African, Admixed-American, Central/South Asian, East Asian, European, and Middle Eastern participants of UK Biobank (N=441,331). Testing 843 phenotypes, we identified 82 independent genomic regions mapping variants showing genome-wide significant (GWS) associations (p<5x10-8) in the trans-ancestry meta-analysis and GWS heterogeneity among the ancestry-specific effects. These included: i) loci with GWS association in one ancestry and concordant but heterogeneous effects among the other ancestries; ii) loci with a GWS association in one ancestry group and an experiment-wide significant discordant effect (p<6.1x10-4) in at least another ancestry. Since the trans-ancestry GWS associations were mostly driven by the European-ancestry sample size, we investigated the differences of allele frequency (Delta-AF) and linkage-disequilibrium regulome tagging (Delta-LD) between European populations and the other ancestries. Within loci with concordant effects, the degree of heterogeneity was associated with European - Middle Eastern Delta-AF (p=9.04x10-6) and Delta-LD of European populations with respect to African, Admixed-American, and Central/South Asian groups (p=8.21x10-4, p=7.17x10-4, and p=2.16x10-3, respectively). Within loci with discordant effects, Delta-AF and Delta-LD of European populations with respect to African and Central/South Asian ancestries was associated with the degree of heterogeneity (Delta-AF: p=7.69x10-3 and p=5.31x10-3, Delta-LD: p=0.016 and p=2.65x10-4, respectively). Considering the traits associated with cross-ancestry heterogeneous loci, we observed enrichments for blood biomarkers (p=5.7x10-35) and physical appearance (p=1.38x10-4). This suggests that these specific phenotypic domains may present considerable cross-ancestry heterogeneity due to large allele frequency and LD variation among worldwide populations.

中文翻译：

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通过跨祖先全基因组关联研究确定的等位基因频率在群体间的差异与基因座的异质性相关

为了研究复杂性状的跨祖先遗传学，我们对英国生物库的非洲人，美国混血儿，中亚/南亚，东亚，欧洲和中东参与者（N = 441,331）进行了具有异质性影响的基因座的全基因组分析）。通过测试843个表型，我们确定了82个独立的基因组区域，这些图谱变异显示了跨谱系荟萃分析中的全基因组显着（GWS）关联（p <5x10-8）和GWS异质性。其中包括：i）在一个祖先与GWS协会相关的基因座，而在其他祖先之间却产生了协调但异质的影响；ii）一个血统中具有GWS关联的基因座，并且至少另一个血统中具有实验范围内的显着不一致效应（p <6.1x10-4）。由于跨祖先的GWS协会主要由欧洲祖先的样本量驱动，因此我们调查了欧洲人群与其他祖先之间的等位基因频率（Delta-AF）和连锁不平衡调控标签（Delta-LD）的差异。在具有一致影响的基因座内，异质性程度与欧洲人-非洲，美国混血儿和中亚/南亚人群的欧洲-中东Delta-AF（p = 9.04x10-6）和Delta-LD相关（分别为p = 8.21x10-4，p = 7.17x10-4和p = 2.16x10-3）。在具有不一致影响的基因座中，欧洲人口相对于非洲和中亚/南亚祖先的Delta-AF和Delta-LD与异质性程度相关（Delta-AF：p = 7.69x10-3和p = 5.31x10- 3，Delta-LD：分别为p ＝ 0.016和p ＝ 2.65×10-4。考虑到与跨祖先异质基因座相关的性状，我们观察到血液生物标志物（p = 5.7x10-35）和物理外观（p = 1.38x10-4）的富集。这表明由于世界各地人群之间较大的等位基因频率和LD变异，这些特定的表型结构域可能呈现出相当大的跨祖先异质性。