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

  • Isabell Brikell
    Address correspondence to Isabell Brikell, M.Sc., Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Search for articles by this author
  • Laura Ghirardi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Search for articles by this author
  • Brian M. D’Onofrio
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

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

    Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
    Search for articles by this author
  • Søren Dalsgaard
    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
    Search for articles by this author
  • Ralf Kuja-Halkola
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Search for articles by this author
  • Henrik Larsson
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    School of Medical Sciences, Örebro University, Örebro, Sweden
    Search for articles by this author



      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.


      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.


      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).


      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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Russ S.A.
        • Larson K.
        • Halfon N.
        A national profile of childhood epilepsy and seizure disorder.
        Pediatrics. 2012; 129: 256-264
        • Polanczyk G.V.
        • Salum G.A.
        • Sugaya L.S.
        • Caye A.
        • Rohde L.A.
        Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents.
        J Child Psychol Psychiatry. 2015; 56: 345-365
        • Aaberg K.M.
        • Bakken I.J.
        • Lossius M.I.
        • Lund Søraas C.
        • Håberg S.E.
        • Stoltenberg C.
        • et al.
        Comorbidity and childhood epilepsy: A nationwide registry study.
        Pediatrics. 2016; 138
        • Bertelsen E.N.
        • Larsen J.T.
        • Petersen L.
        • Christensen J.
        • Dalsgaard S.
        Childhood epilepsy, febrile seizures, and subsequent risk of ADHD.
        Pediatrics. 2016; 138
        • Hamoda H.M.
        • Guild D.J.
        • Gumlak S.
        • Travers B.H.
        • Gonzalez-Heydrich J.
        Association between attention-deficit/hyperactivity disorder and epilepsy in pediatric populations.
        Expert Rev Neurother. 2009; 9: 1747-1754
        • Williams A.E.
        • Giust J.M.
        • Kronenberger W.G.
        • Dunn D.W.
        Epilepsy and attention-deficit hyperactivity disorder: Links, risks, and challenges.
        Neuropsychiatr Dis Treat. 2016; 12: 287-296
        • Chou I.C.
        • Chang Y.T.
        • Chin Z.N.
        • Muo C.H.
        • Sung F.C.
        • Kuo H.T.
        • et al.
        Correlation between epilepsy and attention deficit hyperactivity disorder: A population-based cohort study.
        PLoS One. 2013; 8: e57926
        • Hesdorffer D.C.
        • Ludvigsson P.
        • Olafsson E.
        • Gudmundsson G.
        • Kjartansson O.
        • Hauser W.A.
        ADHD as a risk factor for incident unprovoked seizures and epilepsy in children.
        Arch Gen Psychiatry. 2004; 61: 731-736
        • Hermann B.
        • Jones J.
        • Dabbs K.
        • Allen C.A.
        • Sheth R.
        • Fine J.
        • et al.
        The frequency, complications and aetiology of ADHD in new onset paediatric epilepsy.
        Brain. 2007; 130: 3135-3148
        • Kanazawa O.
        Reappraisal of abnormal EEG findings in children with ADHD: On the relationship between ADHD and epileptiform discharges.
        Epilepsy Behav. 2014; 41: 251-256
        • Moreno-De-Luca A.
        • Myers S.M.
        • Challman T.D.
        • Moreno-De-Luca D.
        • Evans D.W.
        • Ledbetter D.H.
        Developmental brain dysfunction: Revival and expansion of old concepts based on new genetic evidence.
        Lancet Neurol. 2013; 12: 406-414
        • Hesdorffer D.C.
        • Caplan R.
        • Berg A.T.
        Familial clustering of epilepsy and behavioral disorders: Evidence for a shared genetic basis.
        Epilepsia. 2012; 53: 301-307
        • Gonzalez-Heydrich J.
        • Hamoda H.M.
        • Luna L.
        • Rao S.
        • McClendon J.
        • Rotella P.
        • et al.
        Elevated rates of ADHD in mothers of children with comorbid ADHD and epilepsy.
        Neuropsychiatry (London). 2012; 2: 385-391
        • Halmoy A.
        • Klungsoyr K.
        • Skjaerven R.
        • Haavik J.
        Pre- and perinatal risk factors in adults with attention-deficit/hyperactivity disorder.
        Biol Psychiatry. 2012; 71: 474-481
        • Ludvigsson J.F.
        • Otterblad-Olausson P.
        • Pettersson B.U.
        • Ekbom A.
        The Swedish personal identity number: Possibilities and pitfalls in healthcare and medical research.
        Eur J Epidemiol. 2009; 24: 659-667
        • National Board of Health and Welfare
        The Swedish Medical Birth Registry: A Summary of Content and quality [Report No. 2003-112-3].
        National Board of Health and Welfare, Stockholm, Sweden2003
        • Ekbom A.
        The Swedish Multi-generation Register.
        Methods Mol Biol. 2011; 675: 215-220
        • World Health Organization
        The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines.
        World Health Organization, Geneva, Switzerland1992
        • Ludvigsson J.F.
        • Andersson E.
        • Ekbom A.
        • Feychting M.
        • Kim J.L.
        • Reuterwall C.
        • et al.
        External review and validation of the Swedish National Inpatient Register.
        BMC Public Health. 2011; 11: 450
        • Wettermark B.
        • Hammar N.
        • Fored C.M.
        • Leimanis A.
        • Otterblad Olausson P.
        • Bergman U.
        • et al.
        The new Swedish Prescribed Drug Register—Opportunities for pharmacoepidemiological research and experience from the first six months.
        Pharmacoepidemiol Drug Saf. 2007; 16: 726-735
        • Statistics Sweden
        Different Families Live in Dfferent Ways—A Survey on Residence and Support of Children After a Separation [Report No. 2014-02-21].
        Statistics Sweden, Stockholm, Sweden2014
        • Yao S.
        • Kuja-Halkola R.
        • Thornton L.M.
        • Runfola C.D.
        • D’Onofrio B.M.
        • Almqvist C.
        • et al.
        Familial liability for eating disorders and suicide attempts: Evidence from a population registry in Sweden.
        JAMA Psychiatry. 2016; 73: 284-291
        • Chen Q.
        • Kuja-Halkola R.
        • Sjolander A.
        • Serlachius E.
        • Cortese S.
        • Faraone S.V.
        • et al.
        Shared familial risk factors between attention-deficit/hyperactivity disorder and overweight/obesity—A population-based familial coaggregation study in Sweden.
        J Child Psychol Psychiatry. 2017; 58: 711-718
        • Neale M.
        • Cardon L.
        Methodology for Genetic Studies of Twins and Families.
        Springer Science & Business Media, New York1992
        • Frisell T.
        • Pawitan Y.
        • Långström N.
        • Lichtenstein P.
        Heritability, assortative mating and gender differences in violent crime: Results from a total population sample using twin, adoption, and sibling models.
        Behav Genet. 2012; 42: 3-18
        • Faraone S.V.
        • Ghirardi L.
        • Kuja-Halkola R.
        • Lichtenstein P.
        • Larsson H.
        The familial co-aggregation of attention-deficit/hyperactivity disorder and intellectual disability: A register-based family study.
        J Am Acad Child Adolesc Psychiatry. 2017; 56: 167-174.e1
        • Neale M.C.
        • Hunter M.D.
        • Pritikin J.N.
        • Zahery M.
        • Brick T.R.
        • Kirkpatrick R.M.
        • et al.
        OpenMx 2.0: Extended structural equation and statistical modeling.
        Psychometrika. 2016; 81: 535-549
        • Efron B.
        • Tibshirani R.
        Bootstrap methods for standard errors, confidence intervals, and other measures of statistical accuracy.
        Statist Sci. 1986; 1: 54-75
        • Hudson J.I.
        • Javaras K.N.
        • Laird N.M.
        • VanderWeele T.J.
        • Pope Jr., H.G.
        • Hernan M.A.
        A structural approach to the familial coaggregation of disorders.
        Epidemiology. 2008; 19: 431-439
      1. Anttila V, Bulik-Sullivan B, Finucane HK, Bras J, Duncan L, Escott-Price V, et al. (2016): Analysis of shared heritability in common disorders of the brain [published online ahead of print Apr 16]. bioRxiv.

        • Lo-Castro A.
        • Curatolo P.
        Epilepsy associated with autism and attention deficit hyperactivity disorder: Is there a genetic link?.
        Brain Dev. 2014; 36: 185-193
        • Lichtenstein P.
        • Carlstrom E.
        • Rastam M.
        • Gillberg C.
        • Anckarsater H.
        The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood.
        Am J Psychiatry. 2010; 167: 1357-1363
        • Reiersen A.M.
        • Constantino J.N.
        • Grimmer M.
        • Martin N.G.
        • Todd R.D.
        Evidence for shared genetic influences on self-reported ADHD and autistic symptoms in young adult Australian twins.
        Twin Res Hum Genet. 2008; 11: 579-585
        • Ronald A.
        • Simonoff E.
        • Kuntsi J.
        • Asherson P.
        • Plomin R.
        Evidence for overlapping genetic influences on autistic and ADHD behaviours in a community twin sample.
        J Child Psychol Psychiatry. 2008; 49: 535-542
        • Ghirardi L.
        • Brikell I.
        • Kuja-Halkola R.
        • Freitag C.M.
        • Franke B.
        • Asherson P.
        • et al.
        The familial co-aggregation of ASD and ADHD: A register-based cohort study.
        Mol Psychiatry. 2017; ([published online ahead of print Feb 28])
        • Sun Y.
        • Vestergaard M.
        • Pedersen C.B.
        • Christensen J.
        • Basso O.
        • Olsen J.
        Gestational age, birth weight, intrauterine growth, and the risk of epilepsy.
        Am J Epidemiol. 2008; 167: 262-270
        • D’Onofrio B.M.
        • Class Q.A.
        • Rickert M.E.
        • Larsson H.
        • Långström N.
        • Lichtenstein P.
        Preterm birth and mortality and morbidity: A population-based quasi-experimental study.
        JAMA Psychiatry. 2013; 70: 1231-1240
        • Peljto A.L.
        • Barker-Cummings C.
        • Vasoli V.M.
        • Leibson C.L.
        • Hauser W.A.
        • Buchhalter J.R.
        • et al.
        Familial risk of epilepsy: A population-based study.
        Brain. 2014; 137: 795-805
        • Bromley R.
        The treatment of epilepsy in pregnancy: The neurodevelopmental risks associated with exposure to antiepileptic drugs.
        Reprod Toxicol. 2016; 64: 203-210
        • Pal D.K.
        • Durner M.
        • Klotz I.
        • Dicker E.
        • Shinnar S.
        • Resor S.
        • et al.
        Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy.
        Brain Dev. 2006; 28: 92-98
        • Mattsson P.
        • Tomson T.
        • Eriksson Ö.
        • Brännström L.
        • Weitoft G.R.
        Sociodemographic differences in antiepileptic drug prescriptions to adult epilepsy patients.
        Neurology. 2010; 74: 295-301
        • Nilsson L.
        • Tomson T.
        • Farahmand B.Y.
        • Diwan V.
        • Persson P.G.
        Cause-specific mortality in epilepsy: A cohort study of more than 9,000 patients once hospitalized for epilepsy.
        Epilepsia. 1997; 38: 1062-1068
        • Skoglund C.
        • Chen Q.
        • D’Onofrio B.M.
        • Lichtenstein P.
        • Larsson H.
        Familial confounding of the association between maternal smoking during pregnancy and ADHD in offspring.
        J Child Psychol Psychiatry. 2014; 55: 61-68
        • Linnet K.M.
        • Wisborg K.
        • Secher N.J.
        • Thomsen P.H.
        • Obel C.
        • Dalsgaard S.
        • et al.
        Coffee consumption during pregnancy and the risk of hyperkinetic disorder and ADHD: A prospective cohort study.
        Acta Paediatr. 2009; 98: 173-179
        • Mohr-Jensen C.
        • Vinkel Koch S.
        • Briciet Lauritsen M.
        • Steinhausen H.C.
        The validity and reliability of the diagnosis of hyperkinetic disorders in the Danish Psychiatric Central Research Registry.
        Eur Psychiatry. 2016; 35: 16-24
        • Larsson H.
        • Chang Z.
        • D’Onofrio B.M.
        • Lichtenstein P.
        The heritability of clinically diagnosed attention deficit hyperactivity disorder across the lifespan.
        Psychol Med. 2014; 44: 2223-2229
        • Skoglund C.
        • Chen Q.
        • Franck J.
        • Lichtenstein P.
        • Larsson H.
        Attention-deficit/hyperactivity disorder and risk for substance use disorders in relatives.
        Biol Psychiatry. 2015; 77: 880-886
        • Larsson H.
        • Ryden E.
        • Boman M.
        • Langstrom N.
        • Lichtenstein P.
        • Landen M.
        Risk of bipolar disorder and schizophrenia in relatives of people with attention-deficit hyperactivity disorder.
        Br J Psychiatry. 2013; 203: 103-106
        • Chang Z.
        • Lichtenstein P.
        • D’Onofrio B.M.
        • Sjölander A.
        • Larsson H.
        Serious transport accidents in adults with attention-deficit/hyperactivity disorder and the effect of medication: A population-based study.
        JAMA Psychiatry. 2014; 71: 319-325
        • Faraone S.V.
        • Asherson P.
        • Banaschewski T.
        • Biederman J.
        • Buitelaar J.K.
        • Ramos-Quiroga J.A.
        • et al.
        Attention-deficit/hyperactivity disorder.
        Nat Rev Dis Primers. 2015; 1: 15020
        • Faraone S.V.
        • Biederman J.
        • Wozniak J.
        Examining the comorbidity between attention deficit hyperactivity disorder and bipolar I disorder: A meta-analysis of family genetic studies.
        Am J Psychiatry. 2012; 169: 1256-1266
        • Leitner Y.
        The co-occurrence of autism and attention deficit hyperactivity disorder in children—What do we know?.
        Front Hum Neurosci. 2014; 8: 268
        • Christensen J.
        • Vestergaard M.
        • Olsen J.
        • Sidenius P.
        Validation of epilepsy diagnoses in the Danish National Hospital Register.
        Epilepsy Res. 2007; 75: 162-170

      CHORUS Manuscript

      View Open Manuscript