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

Post-Traumatic Stress Disorder Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalBiological Psychiatry
DOIs
Publication statusPublished - 1 Aug 2022

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (Grant Nos. R21 DC018098 , R33 DA047527 , and F32 MH122058 ), Canadian Institute for Health Research Canadian Research Chairs stipend (Grant No. 1024586), National Institute of Mental Health (Grant No. R01MH120219 [to MGN]), The Netherlands Organisation for Health Research and Development (Zon MW) (Grant Nos. 849200011 and 531003014 [to MGN]), Dutch Research Council (NOW) Veni Grant (Grant No. VI.Veni.191G.030 [to MGN]), and Jacobs Foundation Fellowship Program (to MGN). Financial support for the PGC PTSD was provided by Cohen Veterans Bioscience, Stanley Center for Psychiatric Research at the Broad Institute, One Mind, and National Institute of Mental Health (Grant Nos. R01MH106595 , R01MH124847 , and R01MH124851 ). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Publisher Copyright:
© 2022 Society of Biological Psychiatry

Other keywords

  • ADHD
  • Causal inference
  • Comorbidities
  • Epidemiology
  • Genome-wide association study
  • PTSD

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