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

Isabell Brikell, Laura Ghirardi, Brian M. D'Onofrio, David Dunn, Catarina Almqvist, Søren Dalsgaard, Ralf Kuja-Halkola, Henrik Larsson

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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.

Original languageEnglish (US)
Pages (from-to)173-180
Number of pages8
JournalBiological Psychiatry
Volume83
Issue number2
DOIs
StatePublished - Jan 15 2018

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Attention Deficit Disorder with Hyperactivity
Epilepsy
Cohort Studies
Confidence Intervals
Odds Ratio
Siblings
Mothers
Fathers
Logistic Models

Keywords

  • ADHD
  • Comorbidity
  • Epilepsy
  • Genetics
  • Neurodevelopment
  • Risk factors

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder : A Nationwide Cohort Study. / Brikell, Isabell; Ghirardi, Laura; D'Onofrio, Brian M.; Dunn, David; Almqvist, Catarina; Dalsgaard, Søren; Kuja-Halkola, Ralf; Larsson, Henrik.

In: Biological Psychiatry, Vol. 83, No. 2, 15.01.2018, p. 173-180.

Research output: Contribution to journalArticle

Brikell, I, Ghirardi, L, D'Onofrio, BM, Dunn, D, Almqvist, C, Dalsgaard, S, Kuja-Halkola, R & Larsson, H 2018, 'Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder: A Nationwide Cohort Study', Biological Psychiatry, vol. 83, no. 2, pp. 173-180. https://doi.org/10.1016/j.biopsych.2017.08.006
Brikell, Isabell ; Ghirardi, Laura ; D'Onofrio, Brian M. ; Dunn, David ; Almqvist, Catarina ; Dalsgaard, Søren ; Kuja-Halkola, Ralf ; Larsson, Henrik. / Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder : A Nationwide Cohort Study. In: Biological Psychiatry. 2018 ; Vol. 83, No. 2. pp. 173-180.
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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.",
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AU - Brikell, Isabell

AU - Ghirardi, Laura

AU - D'Onofrio, Brian M.

AU - Dunn, David

AU - Almqvist, Catarina

AU - Dalsgaard, Søren

AU - Kuja-Halkola, Ralf

AU - Larsson, Henrik

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N2 - 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.

AB - 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.

KW - ADHD

KW - Comorbidity

KW - Epilepsy

KW - Genetics

KW - Neurodevelopment

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