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

• Published in: Nature communications 2024-12, Vol.15 (1), p.10839
• Main Authors: Yang, Meng-Yuan, Zhong, Jia-Dong, Li, Xin, Tian, Geng, Bai, Wei-Yang, Fang, Yi-Hu, Qiu, Mo-Chang, Yuan, Cheng-Da, Yu, Chun-Fu, Li, Nan, Yang, Ji-Jian, Liu, Yu-Heng, Yu, Shi-Hui, Zhao, Wei-Wei, Liu, Jun-Quan, Sun, Yi, Cong, Pei-Kuan, Khederzadeh, Saber, Zhao, Pian-Pian, Qian, Yu, Guan, Peng-Lin, Gu, Jia-Xuan, Gai, Si-Rui, Yi, Xiang-Jiao, Tao, Jian-Guo, Chen, Xiang, Miao, Mao-Mao, Lei, Lan-Xin, Xu, Lin, Xie, Shu-Yang, Li, Jin-Chen, Guo, Ji-Feng, Karasik, David, Yang, Liu, Tang, Bei-Sha, Huang, Fei, Zheng, Hou-Feng
• Format: Article
• Language: English
• Subjects: 45/23; 45/43; 631/208/205/2138; 631/208/726/649/2219; Asian People - genetics; Association analysis; Biomedical materials; Bone Density - genetics; Bone mineral density; Databases, Genetic; Gene sequencing; Genetic diversity; Genetic variance; Genome, Human; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomic analysis; Haplotypes; Hip; Humanities and Social Sciences; Humans; Mice; multidisciplinary; Panels; Polymorphism, Single Nucleotide; Population genetics; Population studies; Populations; Science; Science (multidisciplinary); Whole Genome Sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-55147-4

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 ( P slide_window  = 9.08 × 10 −9 , P gene_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. Limited whole genome sequencing (WGS) of Asian populations results in a lack of representative reference panels, hindering imputation of Asian ancestry-specific genetic variants. Here the authors use WGS data from 11,067 individuals across 17 Asian countries to create a new reference panel which shows improved imputation accuracy for South Asian populations.