A comprehensive Mendelian randomization study revealed extensive bidirectional causal relationships between major depressive disorder and numerous common diseases, with genetic predisposition to major depressive disorder showing broader and more pronounced effects than the reverse relationship.
The study, published in Translational Psychiatry, analyzed data from 807,553 individuals with major depressive disorder (MDD) and explored associations with 877 disease phenotypes from the FinnGen database.
The researchers found genetic liability to MDD was causally associated with 324 disease phenotypes, including 46 psychiatric and behavioral disorders, 18 neurological diseases, 44 respiratory diseases, 40 digestive diseases, 18 circulatory diseases, 37 genitourinary diseases, 66 musculoskeletal and connective diseases, and 22 endocrine diseases.
"Our findings confirmed the extensive and significant causal role of genetic predisposition to MDD in contributing to human disease phenotypes, which were more pronounced than those seen in the reverse analysis of the causal influences of other diseases on MDD," the authors wrote.
In the reverse analysis, genetic components of 51 diseases were causally associated with MDD risk, including 5 infectious diseases, 11 neurological diseases, 14 oncological diseases, and 5 psychiatric and behavioral disorders. The study identified bidirectional causal associations between MDD and 15 diseases.
Among psychiatric disorders, MDD showed the strongest causal impact on personality disorders. Another significant causal effect was observed with fibromyalgia.
The researchers employed inverse variance weighting as their primary analytical method, supplemented by weighted median and MR-Egger approaches for sensitivity analyses. The study found minimal evidence of heterogeneity and pleiotropy in most MR analyses.
The authors concluded that "physicians should be adept at identifying and promptly diagnosing and treating comorbid depression."
The study highlights several potential mechanistic pathways linking MDD with various conditions, including shared inflammatory pathways, autonomic nervous system dysfunction, and neuroendocrine disturbances involving the hypothalamic-pituitary-adrenal axis.
The limitations acknowledged by the researchers include potential pleiotropy concerns, though sensitivity analyses suggested minimal impact, and the focus on European ancestry data, which may limit generalizability to other populations.
The study was supported by various institutions, including the Suzhou Key Laboratory, Suzhou Key Technologies Program, and the Suzhou Clinical Medical Center for mood disorders. All authors declared no competing interests.