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

Abstract

Background: 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.

Objective: To investigate the direct and indirect causal paths between ADHD and seven common mental disorders.

Methods: 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.

Results: 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.

Conclusions: This study suggests that ADHD is an independent risk factor for a number of common psychiatric disorders.

Clinical implications: The risk of comorbid psychiatric disorders in individuals with ADHD needs to be considered both in diagnosis and treatment.

Keywords: Depression & mood disorders; Eating disorders; Schizophrenia & psychotic disorders; Suicide & self-harm.

Figure 1

Effect estimates in the form of odds ratios (ORs) and 95% confidence intervals representing the impact of attention-deficit/hyperactivity disorder on the risk of psychiatric outcomes. Estimates derived from meta-analyses based on two Mendelian randomisation studies per outcome (except suicide and major depression disorder). The results should be interpreted based on the Bonferroni corrected threshold of 0.007.

Figure 2

Results from network Mendelian randomisation analyses testing causal effects of major depression disorder or anorexia nervosa on the risk of psychiatric outcomes. Estimates are given in the form of odds ratios (ORs) and 95% confidence intervals. Estimates derived from meta-analyses based on two Mendelian randomisation studies per phenotype (except the outcomes suicide and major depression disorder). Results should be interpreted based on the Bonferroni corrected threshold of 0.007.

Figure 3

Summary of the findings of this study based on two-sample Mendelian randomisation (MR) analyses. Effect estimates of the associations between ADHD and both suicide attempt and PTSD resulted from multivariable MR analyses after adjusting for MDD. Estimates are given in the form of odds ratios (ORs) and 95% confidence intervals. ADHD, attention-deficit/hyperactivity disorder; AN, anorexia nervosa; MDD, major depressive disorder; PTSD, post-traumatic stress disorder.