Identification of a novel genetic variant associated with osteoporosis: insights from the Taiwan biobank study

Abstract

The purpose of this study was to identify new independent significant SNPs associated with osteoporosis using data from the Taiwan Biobank (TWBB). The TWBB dataset was divided into two subsets: We first used 60% of the data as discovery data, and 40% as replication data. Following data quality control measures, GWAS analysis was conducted using an additive genetic model adjusted for sex, age, and the top 5 principal components, employing the Scalable and Accurate Implementation of the Generalized mixed model (SAIGE) approach. The meta-analysis of TWBB1 and TWBB2 was further carried out. The Functional Mapping and Annotation (FUMA) platform was used to identify genetic loci associated with osteoporosis based on GWAS summary statistics. Manhattan and quantile-quantile plots were generated using the FUMA platform to visualize the association results. Independent significant single nucleotide polymorphisms (SNPs) were selected based on genome-wide significance (P < 5 × 10−8) and independence from each other (r2 < 0.6) within a 1 Mb window. Results from GWAS typically do not directly translate into causal variants because the majority of hits are in non-coding or intergenic regions. Positional, eQTL and Chromatin interaction mapping are used to map SNPs to genes. A total of 29 084 individuals (3154 osteoporosis cases and 25 930 controls) were used for GWAS analysis (TWBB1 data), and 18 918 individuals (1917 cases and 17 001 controls) were utilized for replication studies (TWBB2 data). We identified a new independent significant SNP for osteoporosis in TWBB1, with the lead SNP rs76140829 (minor allele frequency = 0.055, P-value = 1.15 × 10-08). This SNP is located within the VTI1A gene on chromosome 10, specifically in its intronic region (10q25.2). Replication of the association was performed in TWBB2, yielding a P-value of 6.56 × 10-3. The meta-analysis of TWBB1 and TWBB2 data demonstrated a highly significant association for SNP rs76140829 (P-value = 7.52 × 10-10). In the positional mapping of rs76140829, six genes (HABP2, RP11-481H12.1, RNU7-165P, RP11-139 K1.2, RP11-57H14.3, and RP11-214 N15.5) were identified through chromatin interaction mapping in mesenchymal stem cells, indicating potential regulatory involvement. Our GWAS analysis using the Taiwan Biobank dataset unveils rs76140829 in the VTI1A gene as a key risk variant associated with osteoporosis. This finding expands our understanding of the genetic basis of osteoporosis and highlights the potential regulatory role of this SNP in mesenchymal stem cells. Further research on the associated genes may contribute to future advancements in personalized treatments and drug development for osteoporosis.