SEAD reference panel with 22,134 haplotypes boosts rare variant imputation and genome-wide association analysis in Asian populations

Limited whole genome sequencing (WGS) studies in Asian populations result in a lack of representative reference panels, thus hindering the discovery of ancestry-specific variants. Here, we present the South and East Asian reference Database (SEAD) panel ( https://imputationserver.westlake.edu.cn/ ), which integrates WGS data for 11,067 individuals from various sources across 17 Asian countries. The SEAD panel, comprising 22,134 haplotypes and 88,294,957 variants, demonstrates improved imputation accuracy for South Asian populations compared to 1000 Genomes Project, TOPMed, and ChinaMAP panels, with a higher proportion of well-imputed rare variants. For East Asian populations, SEAD shows concordance comparable to ChinaMAP, but outperforming TOPMed. Additionally, we apply the SEAD panel to conduct a genome-wide association study for total hip (Hip) and femoral neck (FN) bone mineral density (BMD) traits in 5369 genotyped Chinese samples. The single-variant test suggests that rare variants near SNTG1 are associated with Hip BMD (rs60103302, MAF = 0.0092, P = 1.67 × 10<sup>-7</sup>), and variant-set analysis further supports the association (P<sub>slide_window</sub> = 9.08 × 10<sup>-9</sup>, P<sub>gene_centric</sub> = 5.27 × 10<sup>-8</sup>). This association was not reported previously and can only be detected by using Asian reference panels. Preliminary in vitro experiments for one of the rare variants identified provide evidence that it upregulates SNTG1 expression, which could in turn inhibit the proliferation and differentiation of preosteoblasts.

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Publication Details

Journal
Nature Communications
Published
2024-12-30
DOI
https://doi.org/10.1038/s41467-024-55147-4
Citations
12
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
6.05

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article

SEAD reference panel with 22,134 haplotypes boosts rare variant imputation and genome-wide association analysis in Asian populations

Pianpian Zhao, Peng-Lin Guan, Weiwei Zhao, Peikuan Cong et al.
12 citations
Nature Communications
Genetic Associations and Epidemiology
6.05
article

SEAD reference panel with 22,134 haplotypes boosts rare variant imputation and genome-wide association analysis in Asian populations

Pianpian Zhao, Peng-Lin Guan, Weiwei Zhao, Peikuan Cong, Si-Rui Gai, Chun-Fu Yu, Xiangjiao Yi, Jia-Xuan Gu, Mo-Chang Qiu, Jianguo Tao, Saber Khederzadeh, Fei Huang, Hou‐Feng Zheng, Mengyuan Yang, Jifeng Guo, David Karasik, Yu Qian, Yi Sun, Jinchen Li, Beisha Tang, Nan Li, Xin Li, Xiang Chen, Yuheng Liu, Liu Yang, Yi-Hu Fang, Ji-Jian Yang, Shihui Yu, Lin Xu, Jia-Dong Zhong, Jun-Quan Liu, Cheng‐Da Yuan, Shu-Yang Xie, Wei-Yang Bai, Geng Tian, Mao-Mao Miao, Lan-Xin Lei
article en
12 citations

Abstract

Limited whole genome sequencing (WGS) studies in Asian populations result in a lack of representative reference panels, thus hindering the discovery of ancestry-specific variants. Here, we present the South and East Asian reference Database (SEAD) panel ( https://imputationserver.westlake.edu.cn/ ), which integrates WGS data for 11,067 individuals from various sources across 17 Asian countries. The SEAD panel, comprising 22,134 haplotypes and 88,294,957 variants, demonstrates improved imputation accuracy for South Asian populations compared to 1000 Genomes Project, TOPMed, and ChinaMAP panels, with a higher proportion of well-imputed rare variants. For East Asian populations, SEAD shows concordance comparable to ChinaMAP, but outperforming TOPMed. Additionally, we apply the SEAD panel to conduct a genome-wide association study for total hip (Hip) and femoral neck (FN) bone mineral density (BMD) traits in 5369 genotyped Chinese samples. The single-variant test suggests that rare variants near SNTG1 are associated with Hip BMD (rs60103302, MAF = 0.0092, P = 1.67 × 10<sup>-7</sup>), and variant-set analysis further supports the association (P<sub>slide_window</sub> = 9.08 × 10<sup>-9</sup>, P<sub>gene_centric</sub> = 5.27 × 10<sup>-8</sup>). This association was not reported previously and can only be detected by using Asian reference panels. Preliminary in vitro experiments for one of the rare variants identified provide evidence that it upregulates SNTG1 expression, which could in turn inhibit the proliferation and differentiation of preosteoblasts.

Nature CommunicationsVol. 15(1)
Shangrao Normal University (CN), Binzhou Medical University (CN), Bar-Ilan University (IL), Central South University (CN), Shandong University of Aeronautics (CN), Westlake University (CN), Soochow University (CN), First Affiliated Hospital of Jiangxi Medical College (CN), Kingmed Diagnostics (CN), Second Affiliated Hospital of Soochow University (CN), Hangzhou Hospital of Traditional Chinese Medicine (CN), Xijing Hospital (CN), Xiangya Hospital Central South University (CN), Imperial College London (GB), Zhejiang University (CN), Air Force Medical University (CN)
Westlake University, National Natural Science Foundation of China
Life below water
Openalex Percentile: Top 3%
Genetic Associations and Epidemiology
6.05
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