Investigating the Causal Relationship and Shared Genetic Basis Between Major Depression Disorder and Eight Types of Gastrointestinal Diseases.

Background: Previous studies on the causal relationship or shared genetic basis between major depression disorder (MDD) and gastrointestinal (GI) diseases covered either a limited range and not comprehensive enough. Methods: We used linkage disequilibrium score regression (LDSC) to estimate the heritability for nine traits and the genetic correlation (r g ) between MDD and eight GI diseases, respectively. We further conducted a two-sample Mendelian randomization (MR) analysis to identify the causal relationship between MDD and eight GI diseases. Finally, based on the result of MR, we performed stratified LDSC (S-LDSC) to estimate the partitioned heritability and significantly enriched tissues, transcriptome-wide association study (TWAS) to define shared genes, and colocalization analysis to define the pleiotropic single-nucleotide polymorphisms (SNPs) and genes. Results: For the heritability, heritability of all nine traits was significant. For genetic correlation, six GI diseases showed significant correlations with MDD. For the result of MR, we revealed the causal relationship between MDD and acute appendicitis (OR = 1.09), irritable bowel syndrome (IBS) (OR = 1.14), and ulcer of esophagus (OR = 1.24). Additionally, we found no significant overlapping tissues after S-LDSC. Finally, we defined three shared genes: PRSS16, ZNF602P, and ZNF204P by TWAS and nine pleiotropic genes C4A, FLOT1, LINC00243, MICB, and PRSS16 by colocalization analysis between MDD and acute appendicitis. Conclusions: Our findings provided the evidence of genetic association, causal relationship, and shared pleiotropic genes between MDD and GI diseases especially acute appendicitis, offering new insights into our understanding of their shared genetic basis.