Understanding the causal relationships of attention-deficit/hyperactivity disorder with mental disorders and suicide attempt: a network Mendelian randomisation study

Christa Meisinger, Dennis Freuer

Attention-deficit/hyperactivity disorder (ADHD) is a lifespan neurodevelopmental condition resulting from complex interactions between genetic and environmental risk factors. There is evidence that ADHD is associated with other mental disorders, but it remains unclear whether and in what way a causal relationship exists. To investigate the direct and indirect causal paths between ADHD and seven common mental disorders. Two-sample network Mendelian randomisation analysis was performed to identify psychiatric disorders causally related to ADHD. Total and direct effects were estimated in an univariable and multivariable setting, respectively. Robustness of results was ensured in three ways: a range of pleiotropy-robust methods, an iterative approach identifying and excluding outliers, and use of up to two genome-wide association studies per outcome to replicate results and calculate subsequently pooled meta-estimates. Genetic liability to ADHD was independently associated with the risk of anorexia nervosa (OR 1.28 (95% CI 1.11 to 1.47); p=0.001). A bidirectional association was found with major depressive disorder (OR 1.09 (95% CI 1.03 to 1.15); p=0.003 in the forward direction and OR 1.76 (95% CI 1.50 to 2.06); p=4×10-12 in the reverse direction). Moreover, after adjustment for major depression disorder, a direct association with both suicide attempt (OR 1.30 (95% CI 1.16 to 1.547); p=2×10-5) and post-traumatic stress disorder (OR 1.18 (95% CI 1.05 to 1.33); p=0.007) was observed. There was no evidence of a relationship with anxiety, bipolar disorder or schizophrenia. This study suggests that ADHD is an independent risk factor for a number of common psychiatric disorders. The risk of comorbid psychiatric disorders in individuals with ADHD needs to be considered both in diagnosis and treatment.