Low bone mineral density as a causal risk factor for cervical and thoracolumbar intervertebral disc degeneration: A Mendelian randomization analysis

Bone mineral density (BMD) is a key indicator of osteoporosis, which may influence the development of intervertebral disc degeneration (IDD). However, the causal relationship and underlying signaling pathways between BMD and IDD remain unclear. Therefore, this study aimed to investigate the potential causal relationship and underlying signaling pathways between BMD and IDD. A two-sample Mendelian randomization (MR) analysis was employed to analyze the causal effects of BMD levels across 3 anatomical sites [total body BMD (TB-BMD), lumbar spine BMD (LS-BMD), and femoral neck BMD (FN-BMD)] on risks of IDD. In this study, IDD was divided into 2 groups, namely cervical IDD (C-IDD) and thoracic/thoracolumbar/lumbosacral IDD (TTL-IDD). Additionally, multivariable MR (MVMR) was applied to explore whether type 2 diabetes (T2D) and body mass index (BMI) would mediate the identification of causal pathways. Moreover, gene ontology (GO) enrichment analysis and expression quantitative trait locus (eQTL) colocalization analyses were utilized to examine the potential mechanisms and shared genes involved in osteoporosis and IDD. The results showed that genetic predispositions to TB-BMD, LS-BMD, and FN-BMD were associated with increased risk of C-IDD. Furthermore, TB-BMD, LS-BMD, and FN-BMD were identified as significant risk factors causally associated with TTL-IDD. The MVMR analysis revealed that even after adjusting for T2D and BMI, lower TB-BMD could significantly increase the odds of C-IDD and TTL-IDD. In the subgroup analysis, a significant causal effect of TB-BMD on TTL-IDD was observed in individuals aged 30 to 45, 45 to 60, and > 60 years. Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) and homeobox C4 (HOXC4) were the most prominent co-located genes illustrated by GO enrichment analysis and eQTL analysis. In conclusion, we found that lower BMD exerts significant causal effects on elevated IDD risk (both C-IDD and TTL-IDD).