Department of Economics and Business Economics

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Frank R Wendt, University of Toronto, Yale University, Veterans Affairs Connecticut Healthcare System
  • ,
  • Miguel Garcia-Argibay, Örebro University
  • ,
  • Brenda Cabrera-Mendoza, Yale University, Veterans Affairs Connecticut Healthcare System
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  • Unnur A Valdimarsdóttir, University of Iceland, Karolinska Institutet, Harvard University
  • ,
  • Joel Gelernter, Yale University, Veterans Affairs Connecticut Healthcare System
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  • Murray B Stein, University of California at San Diego
  • ,
  • Michel G Nivard, Vrije Universiteit Amsterdam
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  • Adam X Maihofer, University of California at San Diego
  • ,
  • Caroline M Nievergelt, University of California at San Diego
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  • Henrik Larsson, Örebro University, Karolinska Institutet
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  • Manuel Mattheisen, Dalhousie University, Ludwig Maximilian University of Munich
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  • Renato Polimanti, Yale University
  • ,
  • Sandra M Meier
  • Post-Traumatic Stress Disorder Working Group of the Psychiatric Genomics Consortium
  • ,
  • Preben Bo Mortensen

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
Pages (from-to)362-369
Number of pages8
Publication statusPublished - Feb 2023

    Research areas

  • ADHD, Causal inference, Comorbidities, Epidemiology, Genome-wide association study, PTSD, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Stress Disorders, Post-Traumatic/genetics, Attention Deficit Disorder with Hyperactivity/epidemiology, Siblings

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