Gene Expression and RNA Splicing Imputation Identifies Novel Candidate Genes Associated with Osteoporosis
Yong Liu, Hui Shen, Jonathan Greenbaum, Anqi Liu, Kuan‐Jui Su, Li-Shu Zhang, Lei Zhang, Qing Tian, Honggang Hu, Jinsheng He, Hong‐Wen Deng
Abstract
CONTEXT: Though genome-wide association studies (GWASs) have identified hundreds of genetic variants associated with osteoporosis related traits, such as bone mineral density (BMD) and fracture, it remains a challenge to interpret their biological functions and underlying biological mechanisms. OBJECTIVE: Integrate diverse expression quantitative trait loci and splicing quantitative trait loci data with several powerful GWAS datasets to identify novel candidate genes associated with osteoporosis. DESIGN, SETTING, AND PARTICIPANTS: Here, we conducted a transcriptome-wide association study (TWAS) for total body BMD (TB-BMD) (n = 66 628 for discovery and 7697 for validation) and fracture (53 184 fracture cases and 373 611 controls for discovery and 37 857 cases and 227 116 controls for validation), respectively. We also conducted multi-SNP-based summarized mendelian randomization analysis to further validate our findings. RESULTS: In total, we detected 88 genes significantly associated with TB-BMD or fracture through expression or ribonucleic acid splicing. Summarized mendelian randomization analysis revealed that 78 of the significant genes may have potential causal effects on TB-BMD or fracture in at least 1 specific tissue. Among them, 64 genes have been reported in previous GWASs or TWASs for osteoporosis, such as ING3, CPED1, and WNT16, as well as 14 novel genes, such as DBF4B, GRN, TMUB2, and UNC93B1. CONCLUSIONS: Overall, our findings provide novel insights into the pathogenesis mechanisms of osteoporosis and highlight the power of a TWAS to identify and prioritize potential causal genes.