The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study

Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship.

Methods: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r_g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons).

Results: ADHD and PTSD had consistent r_g (r_g range, 0.43-0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186-0.552; p = 7.68 × 10^-5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10^-4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98-3.53).

Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

Keywords: ADHD; Causal inference; Comorbidities; Epidemiology; Genome-wide association study; PTSD.

Figure 1.. ADHD and PTSD Mendelian Randomization Results

(A) Casual effect of attention deficit hyperactivity disorder (ADHD) on posttraumatic stress disorder (PTSD) phenotypes (left), and PTSD phenotypes on ADHD (right). All estimates lack evidence of heterogeneity and horizontal pleiotropy among the genetic instruments. For clarity, inverse variance weighted (IVW) and MR robust adjusted profile score (MR-RAPS, which accounts for weak genetic instruments) estimates are shown graphically and estimates across MR methods are provided in eTable 4. Odds ratios and 95% confidence interval (CI) are reported for each MR test. The number of SNPs contributing to each genetic instrument is shown in parenthesis for each PTSD trait on the y-axis. Asterisks indicate significance after multiple testing correction accounting for all trait pairs and all MR causal inference methods applied (6 PTSD traits x 2 directions tested x 6 MR methods = 72 tests). (B) a directed acyclic diagram of multivariable MR results for ADHD and PTSD including bidirectional paths to covariates (green arrows) and direct causal paths to mediators (blue arrows) of the ADHD-PTSD relationship. All mediators and covariate traits were included in a single MVMR analysis. G indicates subsets of SNPs associated with one or more of the exposures. U indicates the effect of an unobserved confounder.

Figure 2.. Effect of ADHD on PTSD based on a Population-based Sibling Comparison Design.

Hazard ratio and 95% confidence interval (CI) for the association between attention deficit hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD).