Shared genetic architecture between major depressive disorder and four digestive diseases in European populations

Patients diagnosed with cholelithiasis, gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and constipation frequently exhibit comorbid major depressive disorder (MDD). Although the underlying mechanisms remain elusive, potential genetic associations have been proposed. Leveraging extensive genome-wide association study databases, the genetic association patterns between MDD and four digestive diseases (cholelithiasis, GERD, IBS, and constipation) were systematically investigated. A hierarchical analytical approach was adopted: linkage disequilibrium score regression (LDSC), genetic covariance analysis (GNOVA), and high-definition likelihood (HDL) were employed to evaluate genome-wide correlations. Regional genetic variation was analyzed using local variation association analysis (LAVA) to pinpoint significant genomic loci. A bivariate causal mixture model (MiXeR) was further applied to quantify genetic overlap. The conditional/conjunctional false discovery rate (cond/conjFDR) approach was utilized to detect shared loci. Tissue-specific enrichment analyses were conducted using linkage disequilibrium score regression for specifically expressed genes (LDSC-SEG) to identify phenotype-relevant tissue distributions. In addition, a genetics-informed cell-type spatial mapping approach was used to generate single-cell-resolution maps of disease-associated cell populations. The findings revealed statistically significant, positive genome-wide genetic correlations between MDD and all four digestive diseases. Multiple chromosomal regions exhibiting shared genetic signals were identified through local variation analysis. Key overlapping genetic loci were uncovered via cond/conjFDR analysis. MiXeR further indicated substantial genetic overlap among these traits. Furthermore, gene enrichment assessments indicated that MDD, constipation, and IBS demonstrated significant tissue-specific enrichment in various brain regions. Genetics-informed cell-type spatial mapping analyses also revealed similar patterns of cell-type-specific distribution across related tissues. This investigation constitutes the first genomic-level evidence of genetic overlap between MDD and the four digestive diseases, elucidating shared loci that may underlie comorbidity mechanisms. These results suggest novel molecular pathways for integrated clinical prevention and therapeutic strategies.