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The Relationship of Attention-deficit/Hyperactivity Disorder with Post-traumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study.

  • Author Footnotes
    ∗ Shared First-authorship
    Frank R. Wendt
    Footnotes
    ∗ Shared First-authorship
    Affiliations
    Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA

    Department of Anthropology, University of Toronto, Toronto, Ontario, Canada
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  • Author Footnotes
    ∗ Shared First-authorship
    Miguel Garcia-Argibay
    Footnotes
    ∗ Shared First-authorship
    Affiliations
    School of Medical Sciences, Örebro University, Örebro, Sweden
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  • Brenda Cabrera-Mendoza
    Affiliations
    Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
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  • Unnur A. Valdimarsdóttir
    Affiliations
    Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
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  • Joel Gelernter
    Affiliations
    Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
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  • Murray B. Stein
    Affiliations
    Department of Psychiatry, UC San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA

    Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA

    Veterans Affairs San Diego Healthcare System, San Diego, California, USA
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  • Michel G. Nivard
    Affiliations
    Department of Biological Psychology, Faculty of Behaviour and Movement Sciences, VU University, Amsterdam, The Netherlands
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  • Adam X. Maihofer
    Affiliations
    Department of Psychiatry, UC San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA

    Veterans Affairs San Diego Healthcare System, San Diego, California, USA

    Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
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  • Post-Traumatic Stress Disorder Working Group of the Psychiatric Genomics Consortium
  • Caroline M. Nievergelt
    Affiliations
    Department of Psychiatry, UC San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA

    Veterans Affairs San Diego Healthcare System, San Diego, California, USA

    Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA
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  • Author Footnotes
    # Shared Last-authorship
    Henrik Larsson
    Footnotes
    # Shared Last-authorship
    Affiliations
    School of Medical Sciences, Örebro University, Örebro, Sweden

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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  • Author Footnotes
    # Shared Last-authorship
    Manuel Mattheisen
    Footnotes
    # Shared Last-authorship
    Affiliations
    Department of Psychiatry, Dalhousie University, Halifax, NS, Canada
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  • Author Footnotes
    # Shared Last-authorship
    Renato Polimanti
    Correspondence
    Correspondence to Renato Polimanti, PhD. Yale University School of Medicine, Department of Psychiatry. VA CT 116A2, 950 Campbell Avenue, West Haven, CT 06516, USA. Phone: +1 (203) 932-5711 x5745. Fax: +1 (203) 937-3897.
    Footnotes
    # Shared Last-authorship
    Affiliations
    Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
    Search for articles by this author
  • Author Footnotes
    # Shared Last-authorship
    Sandra Meier
    Footnotes
    # Shared Last-authorship
    Affiliations
    Department of Psychiatry, Dalhousie University, Halifax, NS, Canada
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  • Author Footnotes
    ∗ Shared First-authorship
    # Shared Last-authorship

      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 this relationship.

      Methods

      Linkage Disequilibrium Score Regression and two-sample Mendelian randomization (MR) were used to test for genetic correlation (rg) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and six 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 rg (rg range, 0.43-0.52; P < .001). ADHD genetic liability was causally linked with increased risk for PTSD (Beta=0.367, 95% confidence interval (CI), 0.186-0.552, P=7.68x10-5). This result was not affected by heterogeneity, horizontal pleiotropy (MR Egger intercept=4.34x10-4, P=0.961), 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

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