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Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder: A Nationwide Cohort Study

  • Isabell Brikell
    Correspondence
    Address correspondence to Isabell Brikell, M.Sc., Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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  • Laura Ghirardi
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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  • Brian M. D’Onofrio
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Department of Psychological and Brain Sciences, Indiana University, Bloomington
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  • David W. Dunn
    Affiliations
    Department of Psychiatry, Riley Child and Adolescent Psychiatry Clinic, Indiana University School of Medicine, Indiana University Health Physicians, Indianapolis, Indiana
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  • Catarina Almqvist
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
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  • Søren Dalsgaard
    Affiliations
    National Centre for Register-Based Research, Department of Economics, Aarhus University, Aarhus, Denmark

    The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark

    Department for Child and Adolescent Psychiatry, Hospital of Telemark, Kragerø, Norway
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  • Ralf Kuja-Halkola
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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  • Henrik Larsson
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    School of Medical Sciences, Örebro University, Örebro, Sweden
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      Abstract

      Background

      Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are strongly associated; however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Therefore, our goal in this study was to investigate the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence.

      Methods

      We identified 1,899,654 individuals born between 1987 and 2006 via national Swedish registers and linked each individual to his or her biological relatives. We used logistic regression to estimate the association between epilepsy and ADHD within individual and across relatives. Quantitative genetic modeling was used to decompose the cross-disorder covariance into genetic and environmental factors.

      Results

      Individuals with epilepsy had a statistically significant increased risk of ADHD (odds ratio [OR] = 3.47, 95% confidence interval [CI] = 3.33–3.62). This risk increase extended to children whose mothers had epilepsy (OR = 1.85, 95% CI = 1.75–1.96), children whose fathers had epilepsy (OR = 1.64, 95% CI = 1.54–1.74), full siblings (OR = 1.56, 95% CI = 1.46–1.67), maternal half siblings (OR = 1.28, 95% CI = 1.14–1.43), paternal half siblings (OR = 1.10, 95% CI = 0.96–1.25), and cousins (OR = 1.15, 95% CI = 1.10–1.20). The genetic correlation was 0.21 (95% CI = 0.02–0.40) and explained 40% of the phenotypic correlation between epilepsy and ADHD, with the remaining variance largely explained by nonshared environmental factors (49%, nonshared environmental correlation = 0.36, 95% CI = 0.23–0.49). The contribution of shared environmental factors to the cross-disorder overlap was not statistically significant (11%, shared environmental correlation = 0.32, 95% CI = −0.16–0.79).

      Conclusions

      This study demonstrates a strong and etiologically complex association between epilepsy and ADHD, with shared familial factors and risk factors unique to the individual contributing to co-occurrence of the disorders. Our findings suggest that epilepsy and ADHD may share less genetic risk as compared with other neurodevelopmental disorders.

      Keywords

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