Abstract
Transcriptome-wide association studies (TWAS) systematically investigate the association of genetically predicted gene expression with disease risk, providing an effective approach to identify novel susceptibility genes. Osteoporosis is the most common metabolic bone disease, associated with reduced bone mineral density (BMD) and increased risk of osteoporotic fractures, whereas genetic factors explain approximately 70% of the variance in phenotypes associated with bone. BMD is commonly assessed using dual-energy X-ray absorptiometry (DXA) to obtain measurements (g/cm(2)) of areal BMD. However, quantitative computed tomography (QCT) measured 3D volumetric BMD (vBMD) (g/cm(3)) has important advantages compared with DXA since it can evaluate cortical and trabecular microstructural features of bone quality, which can be used to directly predict fracture risk. Here, we performed the first TWAS for volumetric BMD (vBMD) by integrating genome-wide association studies (GWAS) data from two independent cohorts, namely the Framingham Heart Study (FHS, n = 3298) and the Osteoporotic Fractures in Men (MrOS, n = 4641), with tissue-specific gene expression data from the Genotype-Tissue Expression (GTEx) project. We first used stratified linkage disequilibrium (LD) score regression approach to identify 12 vBMD-relevant tissues, for which vBMD heritability is enriched in tissue-specific genes of the given tissue. Focusing on these tissues, we subsequently leveraged GTEx expression reference panels to predict tissue-specific gene expression levels based on the genotype data from FHS and MrOS. The associations between predicted gene expression levels and vBMD variation were then tested by MultiXcan, an innovative TWAS method that integrates information available across multiple tissues. We identified 70 significant genes associated with vBMD, including some previously identified osteoporosis-related genes such as LYRM2 and NME8, as well as some novel loci such as DNAAF2 and SPAG16. Our findings provide novel insights into the pathophysiological mechanisms of osteoporosis and highlight several novel vBMD-associated genes that warrant further investigation.