Exploring spinal degenerative diseases therapy targets through druggability genes: a Mendelian randomization study

As society ages, the prevalence of spinal degenerative diseases (SDDs) is rising, creating significant life and financial burdens for patients and their families. This study employs mendelian randomization (MR) to identify therapeutic targets for SDDs management. Two sample mendelian randomization (TSMR) analyses were conducted to investigate the causal relationships between multiple genes and various SDDs, including osteoporosis (OP), spinal canal stenosis (SCS), and prolapsed disc/slipped disc (PD/SD). To enhance the robustness of the findings, summary data-based MR (SMR) analyses were performed, complemented by Bayesian co-localization, which provided strong evidential support for the results. Additionally, the potential therapeutic applications were assessed through estimates of druggability. Our findings reveal several target genes linked to the risk of SDDs. Notably, ESR1 was positively and causally associated with the risk of osteoporosis (OR: 1.011, 95% CI: 1.008-1.016, P_FDR = 2.41 × 10^-8). Conversely, high expression of HTT was associated with a reduced risk of spinal canal stenosis (OR: 0.693, 95% CI: 0.589-0.816, P_FDR = 1.06 × 10^-5). Furthermore, high expression of PIK3C2A was linked to increased risk of spinal canal stenosis (OR: 1.086, 95% CI: 1.056-1.117, P_FDR = 9.01 × 10^-9). In conclusion, this study identifies several potential therapeutic targets related to SDDs and offers new insights for the development of therapeutic agents aimed at managing these conditions.