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Leveraging the local genetic structure for trans-ancestry association mapping
American Journal of Human Genetics ( IF 9.8 ) Pub Date : 2022-06-16 , DOI: 10.1016/j.ajhg.2022.05.013
Jiashun Xiao 1 , Mingxuan Cai 1 , Xinyi Yu 1 , Xianghong Hu 1 , Gang Chen 2 , Xiang Wan 3 , Can Yang 1
Affiliation  

Over the past two decades, genome-wide association studies (GWASs) have successfully advanced our understanding of the genetic basis of complex traits. Despite the fruitful discovery of GWASs, most GWAS samples are collected from European populations, and these GWASs are often criticized for their lack of ancestry diversity. Trans-ancestry association mapping (TRAM) offers an exciting opportunity to fill the gap of disparities in genetic studies between non-Europeans and Europeans. Here, we propose a statistical method, LOG-TRAM, to leverage the local genetic architecture for TRAM. By using biobank-scale datasets, we showed that LOG-TRAM can greatly improve the statistical power of identifying risk variants in under-represented populations while producing well-calibrated p values. We applied LOG-TRAM to the GWAS summary statistics of various complex traits/diseases from BioBank Japan, UK Biobank, and African populations. We obtained substantial gains in power and achieved effective correction of confounding biases in TRAM. Finally, we showed that LOG-TRAM can be successfully applied to identify ancestry-specific loci and the LOG-TRAM output can be further used for construction of more accurate polygenic risk scores in under-represented populations.



中文翻译:

利用本地遗传结构进行跨祖先关联映射

在过去的二十年里,全基因组关联研究 (GWAS) 成功地促进了我们对复杂性状遗传基础的理解。尽管 GWAS 取得了丰硕的发现,但大多数 GWAS 样本都是从欧洲人群中收集的,并且这些 GWAS 经常因缺乏祖先多样性而受到批评。跨血统关联作图 (TRAM) 提供了一个令人兴奋的机会来填补非欧洲人和欧洲人之间遗传研究中的差异空白。在这里,我们提出了一种统计方法 LOG-TRAM,以利用 TRAM 的局部遗传架构。通过使用生物样本库规模的数据集,我们表明 LOG-TRAM 可以极大地提高识别代表性不足人群中风险变异的统计能力,同时产生校准良好的 p 值。我们将 LOG-TRAM 应用于来自日本生物银行、英国生物银行和非洲人群的各种复杂性状/疾病的 GWAS 汇总统计数据。我们获得了显着的功率增益,并实现了对 TRAM 中混杂偏差的有效校正。最后,我们表明 LOG-TRAM 可以成功地应用于识别祖先特定基因座,并且 LOG-TRAM 输出可以进一步用于在代表性不足的人群中构建更准确的多基因风险评分。

更新日期:2022-06-16
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