Integrative omics identify NID2 as a therapeutic target linking depression and colorectal cancer in humans.

Depression is frequently comorbid with gastrointestinal malignancies, yet the biological links governing this relationship require precise characterization. Analysis of a prospective colonoscopy cohort (n = 2,857) and National Health and Nutrition Examination Survey data (n = 37,597) shows that major depression is associated with an increased prevalence of colorectal precancerous lesions and cancer risk. Two-sample Mendelian randomization supports a causal effect of depression on colorectal tumorigenesis. By integrating plasma protein quantitative trait loci (pQTL) with colorectal neoplasia genome-wide association data through Bayesian colocalization, we identify nidogen-2 (NID2) as a shared causal mediator. This finding is supported by observed reductions of NID2 levels in plasma and colorectal tissues, alongside consistent transcriptomic and proteomic evidence from public datasets. These results establish NID2 as a biomarker and therapeutic target linking depression to colorectal cancer, providing a molecular framework for understanding how psychological stressors influence oncological progression.