Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders. Evidence indicates both disorders co-occur with a high frequency, in 20–50% of children with ADHD meeting criteria for ASD and in 30-80% of ASD children meeting criteria for ADHD. This review will provide an overview on all available studies [family based, twin, candidate gene, linkage, and genome wide association (GWA) studies] shedding light on the role of shared genetic underpinnings of ADHD and ASD. It is concluded that family and twin studies do provide support for the hypothesis that ADHD and ASD originate from partly similar familial/genetic factors. Only a few candidate gene studies, linkage studies and GWA studies have specifically addressed this co-occurrence, pinpointing to some promising pleiotropic genes, loci and single nucleotide polymorphisms (SNPs), but the research field is in urgent need for better designed and powered studies to tackle this complex issue. We propose that future studies examining shared familial etiological factors for ADHD and ASD use a family-based design in which the same phenotypic (ADHD and ASD), candidate endophenotypic, and environmental measurements are obtained from all family members. Multivariate multi-level models are probably best suited for the statistical analysis.

[1]  Robert T. Schultz,et al.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes , 2009, Nature.

[2]  E. Hatchwell,et al.  Association of a Monoamine Oxidase-A Gene Promoter Polymorphism With ADHD and Anxiety in Boys With Autism Spectrum Disorder , 2009, Journal of autism and developmental disorders.

[3]  O. Kwon,et al.  Protein kinase A-dependent phosphorylation of B/K protein , 2006, Experimental & Molecular Medicine.

[4]  M. Gill,et al.  Association analysis of the monoamine oxidase A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: Preferential transmission of the MAO‐A 941G allele to affected children , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[5]  A. Meyer-Lindenberg,et al.  Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis , 2010, Molecular Psychiatry.

[6]  R. Delorme,et al.  Psychiatric and psychosocial problems in adults with normal-intelligence autism spectrum disorders , 2009, BMC psychiatry.

[7]  R. Prediger,et al.  Environmental enrichment improves cognitive deficits in Spontaneously Hypertensive Rats (SHR): Relevance for Attention Deficit/Hyperactivity Disorder (ADHD) , 2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[8]  R. Oades Dopamine-serotonin interactions in attention-deficit hyperactivity disorder (ADHD). , 2008, Progress in brain research.

[9]  J. Wickens,et al.  Neurobiology of ADHD , 2009, Neuropharmacology.

[10]  L Eugene Arnold,et al.  Treatment of inattention, overactivity, and impulsiveness in autism spectrum disorders. , 2008, Child and adolescent psychiatric clinics of North America.

[11]  S. Spence,et al.  A genomewide screen of 345 families for autism-susceptibility loci. , 2003, American journal of human genetics.

[12]  J Sergeant,et al.  The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes , 2006, Molecular Psychiatry.

[13]  J. Thome,et al.  Dopamine D3 receptor gene polymorphism and violent behavior: relation to impulsiveness and ADHD-related psychopathology , 2003, Journal of Neural Transmission.

[14]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[15]  C. Francks,et al.  Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism. , 2002, American journal of human genetics.

[16]  S. Faraone,et al.  Should the diagnosis of Attention-Deficit/ Hyperactivity disorder be considered in children with Pervasive Developmental Disorder? , 2001 .

[17]  B. Maher Personal genomes: The case of the missing heritability , 2008, Nature.

[18]  G. Lehmkuhl,et al.  What Do We Know about the Serotonergic Genetic Heterogeneity in Attention-Deficit/Hyperactivity and Autistic Disorders? , 2007, Psychopathology.

[19]  Benjamin M. Neale,et al.  Genome-wide association studies in ADHD , 2009, Human Genetics.

[20]  D. Pinto,et al.  Structural variation of chromosomes in autism spectrum disorder. , 2008, American journal of human genetics.

[21]  D. Loesch,et al.  Autism Spectrum Disorders and Attention-Deficit/Hyperactivity Disorder in Boys with the Fragile X Premutation , 2006, Journal of developmental and behavioral pediatrics : JDBP.

[22]  A comparison of univariate, bivariate, and trivariate whole-genome linkage screens of genetically correlated electrophysiological endophenotypes , 2005, BMC Genetics.

[23]  Patrick F. Sullivan,et al.  A framework for interpreting genome-wide association studies of psychiatric disorders , 2009, Molecular Psychiatry.

[24]  Joshua M. Korn,et al.  Association between microdeletion and microduplication at 16p11.2 and autism , 2008 .

[25]  B. Franke,et al.  Neuropsychological endophenotype approach to genome-wide linkage analysis identifies susceptibility loci for ADHD on 2q21.1 and 13q12.11. , 2008, American journal of human genetics.

[26]  M. Rutter,et al.  Comorbidity in child psychopathology: concepts, issues and research strategies. , 1991, Journal of child psychology and psychiatry, and allied disciplines.

[27]  J. Smoller,et al.  Molecular Genetics of Attention-Deficit/Hyperactivity Disorder , 2005, Biological Psychiatry.

[28]  E. Hatchwell,et al.  Association of ADHD, tics, and anxiety with dopamine transporter (DAT1) genotype in autism spectrum disorder. , 2008, Journal of child psychology and psychiatry, and allied disciplines.

[29]  R. Ebstein,et al.  Family-based and association studies of monoamine oxidase A and attention deficit hyperactivity disorder (ADHD): preferential transmission of the long promoter-region repeat and its association with impaired performance on a continuous performance test (TOVA) , 2002, Molecular Psychiatry.

[30]  O. Ousley,et al.  Attention-deficit hyperactivity disorder symptoms in a clinic sample of children and adolescents with pervasive developmental disorders. , 2006, Journal of child and adolescent psychopharmacology.

[31]  C. Gillberg,et al.  Co–existing disorders in ADHD – implications for diagnosis and intervention , 2004, European Child & Adolescent Psychiatry.

[32]  Joshua M. Korn,et al.  Association between microdeletion and microduplication at 16p11.2 and autism. , 2008, The New England journal of medicine.

[33]  J. Buitelaar,et al.  Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study. , 2006, Journal of child and adolescent psychopharmacology.

[34]  Robert T. Schultz,et al.  Common genetic variants on 5p14.1 associate with autism spectrum disorders , 2009, Nature.

[35]  B. Handen,et al.  Efficacy of Methylphenidate Among Children with Autism and Symptoms of Attention-Deficit Hyperactivity Disorder , 2000, Journal of autism and developmental disorders.

[36]  L. Sikich,et al.  Early Pharmacological Treatment of Autism: A Rationale for Developmental Treatment , 2007, Biological Psychiatry.

[37]  S. Faraone,et al.  A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population , 2009, Molecular Psychiatry.

[38]  John A. Sweeney,et al.  Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes , 2009, PLoS genetics.

[39]  Ravinesh A. Kumar,et al.  Novel Submicroscopic Chromosomal Abnormalities Detected in Autism Spectrum Disorder , 2008, Biological Psychiatry.

[40]  Nicholas G Martin,et al.  Evidence for Shared Genetic Influences on Self-Reported ADHD and Autistic Symptoms in Young Adult Australian Twins , 2008, Twin Research and Human Genetics.

[41]  S. Santangelo,et al.  Autism and serotonin transporter gene polymorphisms: A systematic review and meta‐analysis , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[42]  K. Chaudhuri,et al.  MAOA promoter polymorphism and attention deficit hyperactivity disorder (ADHD) in indian children , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[43]  K Konrad,et al.  A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs , 2006, Molecular Psychiatry.

[44]  J. Biederman,et al.  Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. , 1991, The American journal of psychiatry.

[45]  Martin H. Schmidt,et al.  Interaction of dopamine transporter genotype with prenatal smoke exposure on ADHD symptoms. , 2008, The Journal of pediatrics.

[46]  B. Franke,et al.  Dopamine and serotonin transporter genotypes moderate sensitivity to maternal expressed emotion: the case of conduct and emotional problems in attention deficit/hyperactivity disorder. , 2009, Journal of child psychology and psychiatry, and allied disciplines.

[47]  P L Pearson,et al.  A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. , 2003, American journal of human genetics.

[48]  J. Steyaert,et al.  What’s new in autism? , 2008, European Journal of Pediatrics.

[49]  T. Uchiyama,et al.  The clinical necessity for assessing Attention Deficit/Hyperactivity Disorder (AD/HD) symptoms in children with high-functioning Pervasive Developmental Disorder (PDD) , 2004, European Child & Adolescent Psychiatry.

[50]  F. Castellanos,et al.  Attention-Deficit/Hyperactivity Disorder and Comorbid Disruptive Behavior Disorders: Evidence of Pleiotropy and New Susceptibility Loci , 2007, Biological Psychiatry.

[51]  G. Baird,et al.  Impact of comorbid autism spectrum disorders on stimulant response in children with attention deficit hyperactivity disorder: a retrospective and prospective effectiveness study. , 2006, Child: care, health and development.

[52]  J. Gilbert,et al.  A Genome‐wide Association Study of Autism Reveals a Common Novel Risk Locus at 5p14.1 , 2009, Annals of human genetics.

[53]  E. Hatchwell,et al.  Association of COMT (Val158Met) and BDNF (Val66Met) Gene Polymorphisms with Anxiety, ADHD and Tics in Children with Autism Spectrum Disorder , 2009, Journal of autism and developmental disorders.

[54]  R. Hagerman,et al.  A new look at XXYY syndrome: Medical and psychological features , 2008, American journal of medical genetics. Part A.

[55]  G. Dawson,et al.  Evidence for multiple loci from a genome scan of autism kindreds , 2006, Molecular Psychiatry.

[56]  C. Francks,et al.  A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. , 2003, American journal of human genetics.

[57]  M. Lauritsen,et al.  The genetics of autism , 2001, Acta psychiatrica Scandinavica.

[58]  P. Visscher,et al.  Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome? , 2007, Diabetologia.

[59]  P. Michie,et al.  A Multivariate Electrophysiological Endophenotype, from a Unitary Cohort, Shows Greater Research Utility than Any Single Feature in the Western Australian Family Study of Schizophrenia , 2006, Biological Psychiatry.

[60]  P. Asherson,et al.  Attention–Deficit Hyperactivity Disorder in the post–genomic era , 2004, European child & adolescent psychiatry.

[61]  C. Gillberg,et al.  Autism, ADHD, mental retardation and behavior problems in 100 individuals with 22q11 deletion syndrome. , 2009, Research in developmental disabilities.

[62]  I. Craig The importance of stress and genetic variation in human aggression , 2007, BioEssays : news and reviews in molecular, cellular and developmental biology.

[63]  J. Buitelaar,et al.  PDD Symptoms in ADHD, an Independent Familial Trait? , 2009, Journal of abnormal child psychology.

[64]  Cisca Wijmenga,et al.  Gene-Network Analysis Identifies Susceptibility Genes Related to Glycobiology in Autism , 2009, PloS one.

[65]  M. Daly,et al.  Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders , 2008, Journal of Medical Genetics.

[66]  S. Bölte,et al.  Attention Deficit Hyperactivity Disorder Symptoms in Pervasive Developmental Disorders: Association with Autistic Behavior Domains and Coexisting Psychopathology , 2007, Psychopathology.

[67]  I. Waldman,et al.  Candidate gene studies of ADHD: a meta-analytic review , 2009, Human Genetics.

[68]  D. S. Parker,et al.  Challenges in phenotype definition in the whole-genome era: multivariate models of memory and intelligence , 2009, Neuroscience.

[69]  I. Gottesman,et al.  Psychiatric endophenotypes and the development of valid animal models , 2006, Genes, brain, and behavior.

[70]  G. Baird,et al.  Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. , 2008, Journal of the American Academy of Child and Adolescent Psychiatry.

[71]  A. Lu,et al.  A quantitative trait locus analysis of social responsiveness in multiplex autism families. , 2007, The American journal of psychiatry.

[72]  J. Gilbert,et al.  Examination of association to autism of common genetic variationin genes related to dopamine , 2008, Autism research : official journal of the International Society for Autism Research.

[73]  J. Constantino,et al.  Deficits in reciprocal social behavior in male twins: evidence for a genetically independent domain of psychopathology. , 2003, Journal of the American Academy of Child and Adolescent Psychiatry.

[74]  B. Neale,et al.  Comorbidity of tic disorders & ADHD , 2007, European Child & Adolescent Psychiatry.

[75]  S. Smalley,et al.  Social Functioning Difficulties in ADHD: Association with PDD Risk , 2009, Clinical child psychology and psychiatry.

[76]  L. Peltonen,et al.  A heterogeneity-based genome search meta-analysis for autism-spectrum disorders , 2006, Molecular Psychiatry.

[77]  J. Grisel Quantitative Trait Locus Analysis , 2000, Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism.

[78]  B. Franke,et al.  Autism symptoms in Attention-Deficit/Hyperactivity Disorder: A Familial trait which Correlates with Conduct, Oppositional Defiant, Language and Motor Disorders , 2009, Journal of autism and developmental disorders.

[79]  J. Hattori,et al.  Are pervasive developmental disorders and attention-deficit/hyperactivity disorder distinct disorders? , 2006, Brain and Development.

[80]  Kenny Q. Ye,et al.  Strong Association of De Novo Copy Number Mutations with Autism , 2007, Science.

[81]  P. Rowlandson,et al.  An interagency service delivery model for autistic spectrum disorders and attention deficit hyperactivity disorder. , 2009, Child: care, health and development.

[82]  Sarah Curran,et al.  A Common Variant in DRD3 Receptor Is Associated with Autism Spectrum Disorder , 2009, Biological Psychiatry.

[83]  M. Munafo,et al.  Gene × Environment Interactions at the Serotonin Transporter Locus , 2009, Biological Psychiatry.

[84]  Rebecca F. Halperin,et al.  Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12 , 2008, Molecular Psychiatry.

[85]  P Bolton,et al.  Variable expression of the autism broader phenotype: findings from extended pedigrees. , 2000, Journal of child psychology and psychiatry, and allied disciplines.

[86]  Lin He,et al.  Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). , 2006, Human molecular genetics.

[87]  C. McDougle,et al.  Open-label atomoxetine for attention-deficit/ hyperactivity disorder symptoms associated with high-functioning pervasive developmental disorders. , 2006, Journal of child and adolescent psychopharmacology.

[88]  B. Herpertz-Dahlmann,et al.  Molecular genetic aspects of attention-deficit/hyperactivity disorder , 2004, Neuroscience & Biobehavioral Reviews.

[89]  J. Swanson,et al.  Sequence variants of the DRD4 gene in autism: Further evidence that rare DRD4 7R haplotypes are ADHD specific , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[90]  C. Freitag,et al.  The genetics of autistic disorders and its clinical relevance: a review of the literature , 2007, Molecular Psychiatry.

[91]  D. Geschwind,et al.  A genomewide screen for autism susceptibility loci. , 2001, American journal of human genetics.

[92]  N. Freimer,et al.  Endophenotypes for psychiatric disorders: ready for primetime? , 2006, Trends in genetics : TIG.

[93]  Thomas Bourgeron,et al.  Mapping autism risk loci using genetic linkage and chromosomal rearrangements , 2007, Nature Genetics.

[94]  J Miller,et al.  A high-density SNP genome-wide linkage scan in a large autism extended pedigree , 2009, Molecular Psychiatry.

[95]  S. Cichon,et al.  Genomewide association studies: history, rationale, and prospects for psychiatric disorders. , 2009, The American journal of psychiatry.

[96]  B. Franke,et al.  Meta‐analysis of genome‐wide linkage scans of attention deficit hyperactivity disorder , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[97]  J. Buitelaar,et al.  ADHD: strategies to unravel its genetic architecture. , 2005, Journal of neural transmission. Supplementum.

[98]  Jefferson Prince,et al.  Catecholamine Dysfunction in Attention-Deficit/Hyperactivity Disorder: An Update , 2008, Journal of clinical psychopharmacology.

[99]  C. Gillberg,et al.  The impact of ADHD and autism spectrum disorders on temperament, character, and personality development. , 2006, The American journal of psychiatry.

[100]  Aribert Rothenberger,et al.  Genome‐wide association scan of attention deficit hyperactivity disorder , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[101]  R. Plomin,et al.  Evidence for overlapping genetic influences on autistic and ADHD behaviours in a community twin sample. , 2008, Journal of child psychology and psychiatry, and allied disciplines.

[102]  J. Sinzig,et al.  Attention Deficit/Hyperactivity Disorder in Children and Adolescents With Autism Spectrum Disorder , 2009, Journal of attention disorders.