SEAD: an augmented reference panel with 22,134 haplotypes boosts the rare variants imputation and GWAS analysis in Asian population

Meng-Yuan Yang,Jia-Dong Zhong, Xin Li,Wei-Yang Bai,Cheng-Da Yuan,Mo-Chang Qiu,Ke-Qi Liu, 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 Liao, Lan-Xin Lei,Lin Xu,Shu-Yang Xie,Geng Tian,Jin-Chen Li,Ji-Feng Guo,David Karasik,Liu Yang,Bei-Sha Tang,Fei Huang,Hou-Feng Zheng

medrxiv（2023）

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摘要

Here, we present the South and East Asian Reference Database (SEAD) reference panel (), which comprises whole genome sequencing data from 11,067 individuals across 17 countries in Asia. The SEAD panel, which excludes singleton variants, consists of 22,134 haplotypes and 80,367,720 variants. Firstly, we assessed the concordance rate in global populations using HGDP datasets, notably, the SEAD panel showed advantage in East Asia, Central and South Asia, and Oceania populations. When imputing the disease-associated variants of Asian population, the SEAD panel displayed a distinct preponderance in imputing low-frequency and rare variants. In imputation of Chinese population, the SEAD panel imputed a larger number of well-imputed sites across all minor allele frequency (MAF) bins. Additionally, the SEAD panel exhibited higher imputation accuracy for shared sites in all MAF bins. Finally, we applied the augmented SEAD panel to conduct a discovery and replication genome-wide association study (GWAS) for hip and femoral neck (FN) bone mineral density (BMD) traits within the 5,369 Westlake BioBank for Chinese (WBBC) samples. The single-variant test suggests that rare variants near SNTG1 gene are associated with hip BMD (rs60103302, MAF=0.0091, P =4.79×10-8). The spatial clustering analysis also suggests the association of this gene ( P slide_window=1.08×10-8, P gene_centric=4.72×10-8). The gene and variants achieved a suggestive level for FN BMD. This gene was not reported previously, and the preliminary experiment demonstrated that the identified rare variant can upregulate the SNTG1 expression, which in turn inhibits the proliferation and differentiation of preosteoblast. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the "Pioneer" and "Leading Goose" R&D Program of Zhejiang (#2023C03164), the National Natural Science Foundation of China (#82370887), the Chinese National Key Technology R&D Program, Ministry of Science and Technology (#2021YFC2501702), and the funds from the Westlake Laboratory of Life Sciences and Biomedicine (#202208014). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: NA I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes GWAS summary statistics for hip and femoral neck (FN) bone mineral density (BMD)from Westlake biobank for Chinese

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