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

Abstract

Here, we present the South and East Asian reference Database (SEAD) 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 88,294,957 variants. The SEAD panel demonstrated higher accuracy compared to 1kGP, TOPMed and ChinaMAP in South Asian population. And as the proportion of South Asian ancestry increased, the proportion of low-frequency and rare well-imputed variants imputed using the SEAD panel progressively increased, whereas those imputed with TOPMed panel significantly decreased. Additionally, when imputing the East Asian population, the SEAD showed comparable concordance in imputation with ChinaMAP panel, while the TOPMed panel was inferior. 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) genotyped samples. The single-variant test suggests that rare variants near SNTG1 gene are associated with hip BMD (rs60103302, MAF=0.0092, P=1.67x10-7). The variant-set analysis also suggests the association of this gene (Pslide_window=9.08x10-9, Pgene_centric=5.27x10-8). The gene and variants achieved a suggestive level for FN BMD. This gene was not reported previously and can only be detected by using Asian reference panel. The preliminary experiment in-vitro demonstrated that the identified rare variant could upregulate the SNTG1 expression, which in turn inhibits the proliferation and differentiation of preosteoblast.