Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior.

[1]  J. Swanson,et al.  High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder , 2003, Molecular Psychiatry.

[2]  J N Giedd,et al.  Lack of an association between a dopamine-4 receptor polymorphism and attention-deficit/hyperactivity disorder: genetic and brain morphometric analyses , 1998, Molecular Psychiatry.

[3]  J. Buitelaar,et al.  Deficient response inhibition as a cognitive endophenotype of ADHD. , 2003, Journal of the American Academy of Child and Adolescent Psychiatry.

[4]  L. Leamy,et al.  Morphometric studies in inbred and hybrid house mice. II. Patterns in the variances. , 1982, The Journal of heredity.

[5]  M. W. Jones A comparative review of rodent prefrontal cortex and working memory. , 2002, Current molecular medicine.

[6]  J. Tallman,et al.  II. Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor-selective ligand [3H]NGD 94-1. , 1997, The Journal of pharmacology and experimental therapeutics.

[7]  T. Achenbach Manual for the child behavior checklist/4-18 and 1991 profile , 1991 .

[8]  J. Swanson,et al.  Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention‐deficit/hyperactivity disorder (ADHD): Increased prevalence of the 2‐repeat allele , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[9]  P. Goldman-Rakic,et al.  Increased volume and glial density in primate prefrontal cortex associated with chronic antipsychotic drug exposure , 1999, Biological Psychiatry.

[10]  A. Diamond,et al.  Genetic and neurochemical modulation of prefrontal cognitive functions in children. , 2004, The American journal of psychiatry.

[11]  J. Swanson,et al.  Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. , 1996, Molecular psychiatry.

[12]  J. Swanson,et al.  The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. , 2004, American journal of human genetics.

[13]  R. De La Garza,et al.  [3H]PNU‐101958, a D4 dopamine receptor probe, accumulates in prefrontal cortex and hippocampus of non‐human primate brain , 2000, Synapse.

[14]  J. Lieberman,et al.  Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. , 1994, The American journal of psychiatry.

[15]  Mary L Marazita,et al.  Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis , 2002, Psychiatric genetics.

[16]  C. Edelbrock,et al.  Child Behavior Checklist (CBCL) , 1983 .

[17]  J. Seibyl,et al.  Prediction of dopamine transporter binding availability by genotype: a preliminary report. , 2000, The American journal of psychiatry.

[18]  Jan K Buitelaar,et al.  Magnetic resonance imaging of boys with attention-deficit/hyperactivity disorder and their unaffected siblings. , 2004, Journal of the American Academy of Child and Adolescent Psychiatry.

[19]  B. J. Casey,et al.  Evidence for a mechanistic model of cognitive control , 2001, Clinical Neuroscience Research.

[20]  D. Weinberger,et al.  Genetic variability of human brain size and cortical gyral patterns. , 1997, Brain : a journal of neurology.

[21]  S. Faraone,et al.  Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. , 2001, The American journal of psychiatry.

[22]  L. Leamy Morphometric studies in inbred and hybrid house mice. VI. A genetical analysis of brain and body size , 1985, Behavior genetics.

[23]  J. Swanson,et al.  Evidence of positive selection acting at the human dopamine receptor D4 gene locus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  P. Schwartzkroin,et al.  Genetic and phenotypic variation in weight of brain and spinal cord between inbred strains of mice. , 1973, Brain research.

[25]  M. Owen,et al.  Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD. , 2004, The American journal of psychiatry.

[26]  Douglas W. Jones,et al.  Genotype Influences In Vivo Dopamine Transporter Availability in Human Striatum , 2000, Neuropsychopharmacology.

[27]  M. Botvinick,et al.  Conflict monitoring and cognitive control. , 2001, Psychological review.

[28]  B. J. Casey,et al.  Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[29]  E H Cook,et al.  Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations , 2000, Molecular Psychiatry.

[30]  J. Rapoport,et al.  Anatomic brain abnormalities in monozygotic twins discordant for attention deficit hyperactivity disorder. , 2003, The American journal of psychiatry.

[31]  F. Castellanos,et al.  Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes , 2002, Nature Reviews Neuroscience.

[32]  M I Posner,et al.  Attention deficit/hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  N. Mather PERFORMANCE OF LEARNING DISABLED SUBJECTS AND GIFTED SUBJECTS ON THE WOODCOCK-JOHNSON PSYCHO-EDUCATIONAL BATTERY AND THE WECHSLER INTELLIGENCE SCALE FOR CHILDREN--REVISED (WISC-R). , 1984 .

[34]  Manzar Ashtari,et al.  Caudate nuclei volumes in schizophrenic patients treated with typical antipsychotics or clozapine , 1995, The Lancet.

[35]  Sarah Durston,et al.  A review of the biological bases of ADHD: what have we learned from imaging studies? , 2003, Mental retardation and developmental disabilities research reviews.

[36]  R. Kahn,et al.  Automated Separation of Gray and White Matter from MR Images of the Human Brain , 2001, NeuroImage.

[37]  R. S. Kahn,et al.  Automatic Segmentation of the Ventricular System from MR Images of the Human Brain , 2001, NeuroImage.

[38]  D. Comings,et al.  Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. , 1999, Journal of the American Academy of Child and Adolescent Psychiatry.

[39]  C. Tamminga,et al.  D2-Family receptor distribution in human postmortem tissue: an autoradiographic study , 1995, Neuroreport.

[40]  Cynthia G. Wible,et al.  Caudate, putamen, and globus pallidus volume in schizophrenia: A quantitative MRI study , 1995, Psychiatry Research: Neuroimaging.

[41]  R. Ebstein,et al.  The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA) , 2002, Molecular Psychiatry.

[42]  B. Finlay,et al.  Linked regularities in the development and evolution of mammalian brains. , 1995, Science.

[43]  M. Posner,et al.  Mapping the genetic variation of executive attention onto brain activity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[44]  D. Shaffer,et al.  NIMH Diagnostic Interview Schedule for Children Version IV (NIMH DISC-IV): description, differences from previous versions, and reliability of some common diagnoses. , 2000, Journal of the American Academy of Child and Adolescent Psychiatry.

[45]  M. Johnston,et al.  Neurobiology of Rett syndrome: a genetic disorder of synapse development , 2001, Brain and Development.

[46]  L. Rohde,et al.  Attention-deficit hyperactivity disorder: a study of association with both the dopamine transporter gene and the dopamine D4 receptor gene. , 2001, American journal of medical genetics.

[47]  N J Cox,et al.  Association of attention-deficit disorder and the dopamine transporter gene. , 1995, American journal of human genetics.

[48]  M. Posner,et al.  Assessing the molecular genetics of attention networks , 2002, BMC Neuroscience.

[49]  A. Paterson,et al.  Dopamine D4 Receptor Gene: Novelty or Nonsense? , 1999, Neuropsychopharmacology.

[50]  N. Volkow,et al.  Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. , 1998, The American journal of psychiatry.

[51]  J. Lusher,et al.  Dopamine D4 receptor gene (DRD4) is associated with Novelty Seeking (NS) and substance abuse: the saga continues . . . , 2001, Molecular Psychiatry.

[52]  A. Kluger,et al.  A meta-analysis of the association between DRD4 polymorphism and novelty seeking , 2002, Molecular Psychiatry.

[53]  R. Kerwin,et al.  Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain. , 1998, Brain research. Molecular brain research.

[54]  J. Cheverud,et al.  Heritability and association of cortical petalias in rhesus macaques (Macaca mulatta). , 1990, Brain, behavior and evolution.

[55]  J S Fowler,et al.  Mechanism of action of methylphenidate: Insights from PET imaging studies , 2002, Journal of attention disorders.

[56]  T. Achenbach Integrative Guide for the 1991 CBCL/4-18, Ysr, and Trf Profiles , 1991 .

[57]  Daniel R Weinberger,et al.  Imaging genomics. , 2003, British medical bulletin.

[58]  R. Kahn,et al.  Quantitative genetic modeling of variation in human brain morphology. , 2001, Cerebral cortex.

[59]  R. Kahn,et al.  The Effect of Clozapine on Caudate Nucleus Volume in Schizophrenic Patients Previously Treated with Typical Antipsychotics , 2001, Neuropsychopharmacology.

[60]  T. Braver,et al.  A theory of cognitive control, aging cognition, and neuromodulation , 2002, Neuroscience & Biobehavioral Reviews.

[61]  L. Krubitzer,et al.  Nature versus nurture revisited: an old idea with a new twist , 2003, Progress in Neurobiology.