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<p>Accurate genotype imputation is essential for large-scale genetic studies and precision medicine. While East Asian (EAS)-specific reference panels like ChinaMAP and CHN100k have been developed, most studies still rely on multi-ancestry panels like TOPMed due to the large sample size. However, their performance in underrepresented groups like Southeast Asians remains unclear. Using high-coverage whole-genome sequencing and SNP-array data from 8,316 Chinese and Thai individuals, we systematically evaluate six state-of-the-art reference panels for genotype imputation. Our results show that EAS-specific panels outperformed multi-ancestry panels for East and Southeast Asian populations. For example, ChinaMAP achieves a mean heterozygosity concordance rate above 0.90 without R<sup>2</sup> filtering, whereas TOPMed requires an R<sup>2</sup> threshold of 0.60-0.70 to achieve comparable results. Notably, we find that recent positive selection drives regional disparities in imputation accuracy, as illustrated by the olfactory receptor gene cluster. More importantly, our results indicate that the choice of reference panel and R<sup>2</sup> thresholds have a significant impact on polygenic risk score estimation for disease prediction. These findings provide valuable guidelines for improving genotype imputation in East and Southeast Asian populations and underscore the need for ancestrally diverse reference panels to support globally equitable genomic research.</p>

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Imputation disparities driven by recent selection and their impact on disease risk estimation in East and Southeast Asian populations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Dingyang Li,
  • Pattarin Tangtanatakul,
  • Yao Lei,
  • Xiaoxi Liu,
  • Hsi-Yuan Huang,
  • Yang-Chi-Dung Lin,
  • Chengjia Li,
  • Yidan Chen,
  • Lizhi Cai,
  • Jinglu Zhao,
  • Prapaporn Pisitkul,
  • Thanitta Suangtamai,
  • Jinhan Yu,
  • Yihang Zhou,
  • Yuan Xu,
  • Yue Xiao,
  • Punna Kunhapan,
  • Rui Sun,
  • Guangjun Yu,
  • Hao Sun,
  • Nattiya Hirankarn,
  • Yuki Ishikawa,
  • Chikashi Terao,
  • Kwangwoo Kim,
  • Sang-Cheol Bae,
  • Meiying Wang,
  • Hsien-Da Huang,
  • Wanling Yang,
  • Yong-Fei Wang

摘要

Accurate genotype imputation is essential for large-scale genetic studies and precision medicine. While East Asian (EAS)-specific reference panels like ChinaMAP and CHN100k have been developed, most studies still rely on multi-ancestry panels like TOPMed due to the large sample size. However, their performance in underrepresented groups like Southeast Asians remains unclear. Using high-coverage whole-genome sequencing and SNP-array data from 8,316 Chinese and Thai individuals, we systematically evaluate six state-of-the-art reference panels for genotype imputation. Our results show that EAS-specific panels outperformed multi-ancestry panels for East and Southeast Asian populations. For example, ChinaMAP achieves a mean heterozygosity concordance rate above 0.90 without R2 filtering, whereas TOPMed requires an R2 threshold of 0.60-0.70 to achieve comparable results. Notably, we find that recent positive selection drives regional disparities in imputation accuracy, as illustrated by the olfactory receptor gene cluster. More importantly, our results indicate that the choice of reference panel and R2 thresholds have a significant impact on polygenic risk score estimation for disease prediction. These findings provide valuable guidelines for improving genotype imputation in East and Southeast Asian populations and underscore the need for ancestrally diverse reference panels to support globally equitable genomic research.