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

Abstract

Abstract Here, we present the South and East Asian Reference Database (SEAD) reference panel (https://imputationserver.westlake.edu.cn/), 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 (Pslide_window=1.08×10− 8, Pgene_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.