Shared genetic architecture between major depressive disorder and inflammatory bowel disease: Insights from...

Major depressive disorder (MDD) and inflammatory bowel disease (IBD) exhibit clinical associations, yet the cross-disease genetic links and shared mechanisms between them remain unclear. This study aims to explore the genetic associations between MDD and IBD and identify the shared risk loci, potential key tissues, and related genetic mechanisms.

Leveraging large-scale genome-wide association study (GWAS) summary statistics, we employed linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) methods to comprehensively evaluate the genetic correlation between MDD and IBD. We further conducted cross-trait pleiotropy analysis to identify shared pleiotropic loci and genes. Additionally, to explore potential associations between complex traits, we performed a series of functional annotation and tissue-specific analyses. Moreover, drug targets were explored via the SMR method. Finally, we employed immunological colocalization methods to investigate the immunological associations between these diseases.

Our findings highlight a robust genetic correlation between MDD and IBD, including both UC and CD. A total of 1,604 potential pleiotropic loci were identified at the genome-wide significance level (P < 5 × 10^-8). Additionally, annotation analysis revealed 45 leading risk SNPs, among which 5 (rs9074, rs2477077, rs12427851, rs16841904, rs56059718) passed the causal colocalization test. Shared loci including 1q31.3, 3p21.31, and 6p22.1 have been identified. Gene-level analysis pinpointed pleiotropic genes such as BSN, DAG1, DENND1B, MED24, NICN1, and PSMD3. Pathway analysis revealed that the positive regulation of RNA metabolic process, T cell activation, FOXP3 target genes, and macromolecule biosynthetic processes play critical roles in these diseases. Gene-level tissue enrichment analysis indicated that pleiotropic mechanisms are pivotal in whole blood, spleen, brain (cerebellum and cerebellar hemisphere), and EBV-transformed lymphocytes. Finally, phenotype-level immunological colocalization analysis uncovered the immunological mediatory role of CD45 in the association between MDD and UC.

This study provides evidence of a significant genetic correlation between MDD and IBD, and sheds light on the multilayered immune regulatory mechanisms underlying their comorbidity. These insights may have important implications for the prevention and management of patients with comorbid MDD and IBD.