Genetic Association Study Using GWAS and Mendelian Randomization to Central Nervous System Comorbidities Between Multisite Chronic Pain and Major Depressive Disorder

Multisite chronic pain (MCP) and major depressive disorder (MDD) exhibit significant clinical relevance. However, the central nervous system comorbidity mechanism and the shared genetic risk mechanisms remain poorly elucidated. This study aims to systematically investigate the neurobiological and genetic correlation features between MCP and MDD. Leveraging a multidimensional genetic framework, we integrated GWAS data for MCP (UK Biobank, UKB), MDD (Psychiatric Genomics Consortium, PGC), and ENIGMA neuroimaging data to investigate their genetic-neurobiological interplay. Initially, genome-wide genetic correlations were evaluated using Linkage Disequilibrium Score Regression (LDSC). Next, the GWAS Pairwise (GWAS-PW) method was employed to identify local genetic association regions, complemented by functional annotation through the FUMA platform. Lastly, Mendelian randomization (MR) mediation models were applied to explore the mediating effects of brain structure. LDSC analysis revealed a significant genetic correlation between MCP and MDD (rg = 0.53, P = 4.1×10 -45 ). GWAS-PW method identified 18 genomic regions associated with both MCP and MDD. FUMA functional annotation prioritized seven key genes (e.g., DCC and TCF4) implicated in neurodevelopmental and synaptic regulation pathways. Additionally, mendelian mediation analysis of specific brain regions, such as the isthmus cingulate cortex, play a mediating role in the comorbid pathogenesis of MCP and MDD. This study revealed that MCP-MDD comorbidity arises from genome-wide shared neurodevelopmental loci, structural abnormalities, and dysregulated coordination among the default mode, central executive, and sensorimotor networks, collectively forming its neurobiological basis. Schematic flowchart of the genetic analysis pipeline investigating the shared genetic architecture between Major Depressive Disorder (MDD) and Multisite chronic pain (MCP) • First genome-wide evidence for significant genetic correlation between multisite chronic pain and major depressive disorder (rg = 0.53, p = 4.1×10 −45 ). • 18 pleiotropic loci identified via GWAS-PW analysis, implicating neurodevelopmental pathways (e.g., DCC, TCF4). • Mendelian randomization revealed structural abnormalities in the isthmus cingulate cortex mediate bidirectional MCP-MDD comorbidity. • Multidimensional framework integrating GWAS, neuroimaging, and causal mediation models deciphers shared neurobiological mechanisms.