Supplementary Material for: Interoceptive Neural Circuits Mediating the Progression from Somatic Diseases to Comorbid Depression

Introduction: Somatic diseases comorbid with depression exacerbate the health burden. The interoceptive neural circuit (INC) might mediate brain-body connections. We aimed to assess the causal relationship between somatic diseases, the INC, and depression. Methods: We conducted Mendelian randomization (MR) analysis to determine the following: 1) the causal effect of four categories of systemic somatic diseases (ulcerative colitis, essential hypertension, chronic pain, and type 2 diabetes) on the INC’s morphology; 2) the causal effect of INC morphology on depression; and 3) the INC’s mediating role between somatic diseases and depression. A replication analysis confirmed the results above in other GWAS datasets. An extended analysis further validated the predictive role of the INC for depression in another systemic disease (asthma). Results: We found all four systemic somatic diseases resulted in morphological changes in the INC, with shared reduced left ventral diencephalon (L-VDC). The morphological alterations of the INC increased depression risk, with the bilateral ventral thalamus most impacted. The L-VDC volume mediated the relationship between somatic diseases and depression, a finding validated across different datasets. The mediating role of the L-VDC in the relationship between somatic diseases and depression remains present in asthma. Conclusion: The INC, particularly the L-VDC, plays a crucial role in the pathogenesis of depression and the intersection of somatic diseases. The INC mediates the progression from somatic diseases to comorbid depression, suggesting that interventions targeting the INC may prevent and alleviate the burden of comorbid somatic diseases and depression.