Novel Insight into the Therapeutic Targets for Spinal Degenerative Diseases Gained by a Post-Genome-Wide Association Study.

Abstract

Degenerative spinal diseases are a group of conditions that affect the structure and function of the spine, which can severely impact patient prognosis. Elucidating the druggable genes governing degenerative spinal diseases plays a pivotal role. GWAS data on degenerative spinal diseases, druggable genes, and eQTL data were acquired and Mendelian Randomization (MR) analysis was conducted. Colocalization analysis was performed and the side effects or additional indications of the identified drug targets was assessed using a phenome-wide association study. Finally, the differential expression of druggable genes in different cell subtypes of osteoporosis and intervertebral disc degeneration was analyzed, and molecular docking of actionable drugs for target genes was performed. In total, 31 druggable genes associated with osteoporosis and 22 druggable genes associated with spinal stenosis were identified. Four genes reached significant colocalization in blood for osteoporosis and eleven genes showed colocalization in spinal stenosis blood. Besides GPX1, KLRC2, and TCF19, the other 13 potential therapeutic targets for spinal degenerative diseases had no significant adverse effects. Furthermore, it was found that PAK4 and ESR1 were highly expressed in mesenchymal stem cells (MSCs) derived from bone marrow (BM-MSCs) in osteoporosis samples. SORCS2 expression was higher in nucleus pulposus cells (NPCs) in samples with severe than in samples with mild intervertebral disc degeneration. Lastly, drug analysis supported Fostamatinib might be potential therapeutics for osteoporosis and spinal stenosis by inhibiting PAK4 and PI4KB, respectively. In conclusion, our research suggested that PAK4, ESR1, and PI4KB might be promising targets for spinal degenerative diseases, and the effectiveness of Fostamatinib in these diseases warrants further investigation.