Abstract
ObjectiveSchizophrenia is a globally prevalent complex neuropsychiatric disorder that is frequently comorbid with various psychiatric disorders, leading to poor prognoses for affected patients. However, the causal relationships between schizophrenia and these comorbid disorders remain unclear.MethodsWe utilized Mendelian randomization to investigate the causal effects of schizophrenia on eight psychiatric disorders, including alcohol use disorder, anorexia nervosa, anxiety disorders, attention-deficit hyperactivity disorder, autism spectrum disorders, bipolar disorder, depression, and obsessive-compulsive disorder, using data from the Psychiatric Genomics Consortium and other extensive Genome-Wide Association Studies. We employed the inverse variance-weighted method as the primary analysis, complemented by Mendelian randomization-Egger, weighted median, Mendelian randomization-Presso, Steiger filtering, leave-one-out sensitivity analysis, and reverse Mendelian randomization to address potential biases and validate the directionality of the causal relationships.ResultsOur analysis revealed that a genetically predicted one-log unit increase in schizophrenia risk was associated with a 70.7% increase in the odds of bipolar disorder (odds ratio: 1.707, 95% confidence interval: 1.58-1.84). We also found strong evidence regarding a causal relationship of schizophrenia with autism spectrum disorders, showing a 17.4% higher odds (odds ratio: 1.174, 95% confidence interval: 1.11-1.24). Additionally, schizophrenia conferred a 14.5% elevated risk of alcohol use disorder (odds ratio: 1.145, 95% confidence interval: 1.09-1.21), while a statistically significant yet clinically marginal association was observed with depression (odds ratio: 1.004, 95% confidence interval: 1.003-1.006). No causal relationships were detected between schizophrenia and attention-deficit hyperactivity disorder, anorexia nervosa, anxiety disorders, or obsessive-compulsive disorder. Sensitivity analyses reinforced these findings, and reverse Mendelian randomization analyses provided no evidence of reverse causal impacts on schizophrenia from the disorders examined.ConclusionThese findings confirm schizophrenia as a significant genetic risk factor for bipolar disorder, autism spectrum disorders, and alcohol use disorder. Our findings enhance understanding of the interrelationships among psychiatric disorders and offer novel insights into the clinical diagnosis and management of psychiatric comorbidities.