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

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.

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Publication Details

Journal
Communications Biology
Published
2025-11-21
DOI
https://doi.org/10.1038/s42003-025-09214-1
Citations
1
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
1.82

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article

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

Hsi‐Yuan Huang, Yih‐Sharng Chen, Jinhan Yu, Hao Sun et al.
1 citations
Communications Biology
Genetic Associations and Epidemiology
1.82
article

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

Hsi‐Yuan Huang, Yih‐Sharng Chen, Jinhan Yu, Hao Sun, Yuki Ishikawa, Chikashi C. Terao, Dingyang Li, Lizhi Cai, Rui Sun, Sang‐Cheol Bae, Kwang-Woo Kim, Wanling Yang, Hsien‐Da Huang, Chengjia Li, Guangjun Yu, Punna Kunhapan, Prapaporn Pisitkun, Nattiya Hirankarn, Meiying Wang, Thanitta Suangtamai, Pattarin Tangtanatakul, Yang-Chi-Dung Lin, Xiaoxi Liu, Yongfei Wang, Jinglu Zhao, Lei Yao, Yue Xiao, Yanglin Zhou, Yuan Xu
article en
1 citations

Abstract

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.

Communications BiologyVol. 8(1)
Ministry of Public Health (TH), University of Shizuoka (JP), Chulalongkorn University (TH), Mahidol University (TH), University of Health and Allied Sciences (GH), Queen Mary Hospital (CN), Kyung Hee University (KR), Chinese University of Hong Kong, Shenzhen (CN), Department of Medical Sciences (TH), Shizuoka General Hospital (JP), Ramathibodi Hospital (TH), Hanyang University Seoul Hospital (KR), RIKEN Center for Integrative Medical Sciences (JP), Shenzhen Second People's Hospital (CN), Hanyang University (KR), University of Hong Kong (HK)
National Research Foundation, National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, National Research Foundation of Korea, Chinese University of Hong Kong, Guangdong Science and Technology Department, Sanming Project of Medicine in Shenzhen
Openalex Percentile: Top 11%
Genetic Associations and Epidemiology
1.82
DOIOpen Access PDFOpenAlex
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