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

Meng-Yuan Yang, Jia-Dong Zhong, Xin Li, Geng Tian, Wei-Yang Bai, Yi-Hu Fang, Mo-Chang Qiu, Cheng-Da Yuan, Chun-Fu Yu, Nan Li, Ji-Jian Yang, Yu-Heng Liu, Shi-Hui Yu, Wei-Wei Zhao, Jun-Quan Liu, Yi Sun, Pei-Kuan Cong, Saber Khederzadeh, Pian-Pian Zhao, Yu Qian, Peng-Lin Guan, Jia-Xuan Gu, Si-Rui Gai, Xiang-Jiao Yi, Jian-Guo Tao, Xiang Chen, Mao-Mao Miao, Lan-Xin Lei, Lin Xu, Shu-Yang Xie, Jin-Chen Li, Ji-Feng Guo, David Karasik, Liu Yang, Bei-Sha Tang, Fei Huang and Hou-Feng Zheng ()
Additional contact information
Meng-Yuan Yang: Zhejiang University
Jia-Dong Zhong: the Second Affiliated Hospital of Soochow University
Xin Li: Zhejiang University
Geng Tian: Binzhou Medical University
Wei-Yang Bai: Westlake University
Yi-Hu Fang: Jiangxi Medical College
Mo-Chang Qiu: Jiangxi Medical College
Cheng-Da Yuan: Hangzhou Hospital of Traditional Chinese Medicine
Chun-Fu Yu: Shangrao Municipal Hospital
Nan Li: Westlake University
Ji-Jian Yang: Westlake University
Yu-Heng Liu: Westlake University
Shi-Hui Yu: Ltd
Wei-Wei Zhao: Ltd
Jun-Quan Liu: Ltd
Yi Sun: Ltd
Pei-Kuan Cong: Westlake University
Saber Khederzadeh: Westlake University
Pian-Pian Zhao: Westlake University
Yu Qian: the Second Affiliated Hospital of Soochow University
Peng-Lin Guan: Zhejiang University
Jia-Xuan Gu: Zhejiang University
Si-Rui Gai: Zhejiang University
Xiang-Jiao Yi: Westlake University
Jian-Guo Tao: Zhejiang University
Xiang Chen: the Second Affiliated Hospital of Soochow University
Mao-Mao Miao: Westlake University
Lan-Xin Lei: Medical Biosciences, Imperial College London
Lin Xu: Binzhou Medical University
Shu-Yang Xie: Binzhou Medical University
Jin-Chen Li: Central South University
Ji-Feng Guo: Central South University
David Karasik: Bar-Ilan University
Liu Yang: Fourth Military Medical University
Bei-Sha Tang: Central South University
Fei Huang: Binzhou Medical University
Hou-Feng Zheng: the Second Affiliated Hospital of Soochow University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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 × 10−7), and variant-set analysis further supports the association (Pslide_window = 9.08 × 10−9, Pgene_centric = 5.27 × 10−8). 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.

Date: 2024
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DOI: 10.1038/s41467-024-55147-4

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