Imputation Disparities Driven by Recent Selection and Their Impact on Disease Risk Estimation in East and Southeast Asian Populations
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Using data consisting of 8,316 individuals, we evaluated performance of genotype imputation across six state-of-the-art reference panels for Chinese and Thai populations. A substantial proportion of variants identified through whole-genome sequencing, especially low-frequency variants, remained undetected by these panels. In Chinese samples, the TOPMed panel required an R2 threshold of 0.60-0.70 to achieve comparable imputation accuracy of the ChinaMAP panel without R2 filtering, challenging the standard practice of applying a fixed R2 threshold in downstream analyses. A region containing an olfactory receptor gene cluster highlighted how recent selection contributes to imputation disparities and demonstrated the importance of ancestry-matched reference panels. Additionally, reference panel selection and R² thresholds were shown to significantly impact 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 of ancestrally diverse reference panels to support globally equitable genomic research.
