Population-level genetic studies are overwhelmingly biased toward European ancestries. Transferring genetic predictions from European ancestries to other ancestries results in a substantial loss of accuracy. Yet, it remains unclear how much various genetic factors, such as causal effect differences, linkage disequilibrium (LD) differences, or allele frequency differences, contribute to the loss of prediction accuracy across ancestries. In this study, we used gene expression levels in lymphoblastoid cell lines to understand how much each genetic factor contributes to lowered portability of gene expression prediction from European to African ancestries. We found that cis-genetic effects on gene expression are highly similar between European and African individuals. However, we found that allele frequency differences of causal variants have a striking impact on prediction portability. For example, portability is reduced by more than 32% when the causal cis-variant is common (minor allele frequency, MAF >5%) in European samples (training population) but is rarer (MAF <5%) in African samples (prediction population). While large allele frequency differences can decrease portability through increasing LD differences, we also determined that causal allele frequency can significantly impact portability when the impact from LD is substantially controlled. This observation suggests that improving statistical fine-mapping alone does not overcome the loss of portability resulting from differences in causal allele frequency. We conclude that causal cis-eQTL effects are highly similar in European and African individuals, and allele frequency differences have a large impact on the accuracy of gene expression prediction.

中文翻译：

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等位基因频率影响淋巴母细胞样细胞系中基因表达预测的交叉祖先可移植性。


种群水平的遗传研究压倒性地偏向于欧洲血统。将遗传预测从欧洲祖先转移到其他祖先会导致准确性的大幅损失。然而，目前尚不清楚各种遗传因素，如因果效应差异、连锁不平衡 （LD） 差异或等位基因频率差异，在多大程度上导致了跨祖先预测准确性的丧失。在这项研究中，我们使用淋巴母细胞样细胞系中的基因表达水平来了解每个遗传因素在多大程度上导致基因表达预测从欧洲到非洲祖先的可移植性降低。我们发现欧洲和非洲个体之间顺式遗传对基因表达的影响高度相似。然而，我们发现因果变异的等位基因频率差异对预测可移植性有显着影响。例如，当因果顺式变异在欧洲样本（训练人群）中很常见（次要等位基因频率，MAF >5%）但在非洲样本（预测人群）中更罕见（MAF <5%）时，可移植性降低 32% 以上。虽然较大的等位基因频率差异可以通过增加 LD 差异来降低可移植性，但我们还确定，当 LD 的影响得到基本控制时，因果等位基因频率会显着影响可移植性。这一观察结果表明，仅改进统计精细映射并不能克服因果等位基因频率差异而导致的可移植性损失。我们得出结论，因果顺式-eQTL 效应在欧洲和非洲个体中高度相似，等位基因频率差异对基因表达预测的准确性有很大影响。