Liaw Yi-Ching, Matsuda Koichi, Liaw Yung-Po
Department of Computational Biology and Medical Sciences, Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan.
Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung 40201, Taiwan.
JBMR Plus. 2024 Mar 5;8(5):ziae028. doi: 10.1093/jbmrpl/ziae028. eCollection 2024 May.
The purpose of this study was to identify new independent significant SNPs associated with osteoporosis using data from the Taiwan Biobank (TWBB).
The dataset was divided into discovery (60%) and replication (40%) subsets. Following data quality control, genome-wide association study (GWAS) analysis was performed, adjusting for sex, age, and the top 5 principal components, employing the Scalable and Accurate Implementation of the Generalized mixed model approach. This was followed by a meta-analysis of TWBB1 and TWBB2. The Functional Mapping and Annotation (FUMA) platform was used to identify osteoporosis-associated loci. Manhattan and quantile-quantile plots were generated using the FUMA platform to visualize the results. Independent significant SNPs were selected based on genome-wide significance ( < 5 × 10) and independence from each other (r < 0.6) within a 1 Mb window. Positional, eQTL(expression quantitative trait locus), and Chromatin interaction mapping were 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, -value = 1.15 × 10). Replication of the association was performed in TWBB2, yielding a -value of 6.56 × 10. The meta-analysis of TWBB1 and TWBB2 data demonstrated a highly significant association for SNP rs76140829 (-value = 7.52 × 10). In the positional mapping of rs76140829, 6 genes (, , , , , ) were identified through chromatin interaction mapping in mesenchymal stem cells.
Our GWAS analysis using the Taiwan Biobank dataset unveils rs76140829 in the 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.
本研究旨在利用台湾生物银行（TWBB）的数据，鉴定与骨质疏松症相关的新的独立显著单核苷酸多态性（SNP）。
数据集被分为发现集（60%）和复制集（40%）。在进行数据质量控制后，采用广义混合模型方法的可扩展且准确的实现方式，进行全基因组关联研究（GWAS）分析，并对性别、年龄和前5个主成分进行校正。随后对TWBB1和TWBB2进行荟萃分析。使用功能映射与注释（FUMA）平台来鉴定与骨质疏松症相关的基因座。使用FUMA平台生成曼哈顿图和分位数 - 分位数图以直观展示结果。基于全基因组显著性（<5×10）以及在1兆碱基窗口内彼此独立（r<0.6）来选择独立显著的SNP。使用位置映射、表达定量性状基因座（eQTL）和染色质相互作用映射将SNP定位到基因。
共有29084名个体（3154例骨质疏松症病例和25930名对照）用于GWAS分析（TWBB1数据），18918名个体（1917例病例和17001名对照）用于复制研究（TWBB2数据）。我们在TWBB1中鉴定出一个与骨质疏松症相关的新的独立显著SNP，主效SNP为rs76140829（次要等位基因频率 = 0.055，P值 = 1.15×10）。在TWBB2中对该关联进行复制，得到的P值为6.56×10。对TWBB1和TWBB2数据的荟萃分析表明SNP rs76140829具有高度显著的关联性（P值 = 7.52×10）。在rs76140829的位置映射中，通过间充质干细胞中的染色质相互作用映射鉴定出6个基因（，，，，，）。
我们使用台湾生物银行数据集进行的GWAS分析揭示了基因中的rs76140829是与骨质疏松症相关的关键风险变异体。这一发现扩展了我们对骨质疏松症遗传基础的理解，并突出了该SNP在间充质干细胞中的潜在调控作用。
