Progress on the molecular basis of mental illness in children

September 14, 2000

Six articles in the current issue of Molecular Psychiatry, Nature Publishing Group (http://www.nature.com/mp) present a series of novel and highly interesting findings on the molecular basis of mental disorders in children. It is promising that such progress is now being made on the biology of childhood mental disorders, which have a profound impact on emotional growth, psychosocial development, and acquisition of professional skills. These six articles are accompanied by an independent editorial by Dr. David Collier, Institute of Psychiatry, University of London, that puts such work into perspective. ARTICLE: Elevated hypothalamic/midbrain serotonin transporter availability in depressive drug-naive children and adolescents

AUTHORS: M Dahlstrsm, A Ahonen, H Ebeling, P Torniainen, J HeikkilS, IK Moilanen
Department of Pediatrics, Clinic of Child Psychiatry, University of Oulu, FIN 220 Oulu, Finland
Department of Clinical Chemistry, Division of Nuclear Medicine, University of Oulu, FIN 220, Oulu, Finland

Cumulative data suggest depression in adulthood being connected to reduced availability of brain serotonin while the role of dopamine remains less specific. Prospective studies have shown a continuity of depressive episodes from childhood to adulthood. The object of this study was to examine whether alterations in brain serotonin and/or dopamine transporter levels are already present in depressive children and adolescents. The authors examined 41 drug-naive patients (aged 7-17) by (SPET) using [123I]b-CIT as a tracer for monoamine transporters. The series were divided into groups with depression present and no depression present. In this study, the depressive child and adolescent patients had significantly higher serotonin transporter availability (p<0.02) in the hypothalamic/midbrain area. Age did not correlate to the hypothalamic/midbrain serotonin transporter availability. No significant difference in dopamine transporter availability in striatum was found between the depressive and the non-depressive children and adolescents.

Citation source: Molecular Psychiatry 2000 Volume 5, pages 514-522.

For further information on this work, please contact Dr. Minna Dahlstrsm, Clinic of Child Psychiatry, Oulu University Hospital, 90220 Oulu, Finland. Tel: 358-40-5704754; FAX: 358-8-315-5240; E-mail: minna.dahlstrom@oulu.fi


ARTICLE: A family-based and case control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder

AUTHORS: J Holmes, A Payton, JH Barrett, T Hever, H Fitzpatrick, AL Trumper, R Harrington, P McGuffin, MJ Owen, WER Ollier, J Worthington, A Thapar
University Department of Child and Adolescent Psychiatry, Royal Manchester Children's Hospital, Manchester, M27 4HA, UK
ARC Epidemiology Unit, The University of Manchester, Manchester M13 9PL, UK Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK
Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, Wales, CF14 4XN, UK

Attention deficit hyperactivity disorder (ADHD) is a common childhood onset psychiatric condition, characterized by marked and pervasive inattention, overactivity and impulsiveness. ADHD is known to aggregate within families and evidence provided by twin and adoption research suggests a strong genetic component to ADHD. Positive associations with the 480bp allele of DAT1 and allele 7 of DRD4 have now been independently replicated, however other studies have failed to find support for these findings. The authors examined the previously reported DAT1 and DRD4 polymophisms in a well-characterized sample of 137 children with ADHD, using family-based and case control approaches. These results indicate no evidence of association with the DAT1 480bp allele, despite a sample size that has over 80% power to detect a previously reported effect size. For DRD4, they reported a significant increase in allele 7 amongst ADHD probands and their parents, compared to ethnically matched controls. Negative TDT results for DRD4 are discussed further.

Citation source: Molecular Psychiatry 2000 Volume 5, pages 523-530.

For further information on this work, please contact Dr. Anita Thapar, Child and Adolescent Psychiatry Section, Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, Wales CF4 4XN, United Kingdom. Tel: 44-29-2074-3241; FAX: 44-29-2074-7839; E-mail: thapar@cardiff.ac.uk ARTICLE: Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD)

AUTHORS: JT McCracken, SL Smalley, JJ McGough, L Crawford, M Del'Homme, R Cantor, A Liu, SF Nelson
Department of Psychiatry and Biobehavioral Sciences, UCLA Neuropsychiatric Institute, Mental Retardation Research Center, and the Department of Human Genetics, UCLA School of Medicine

Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder. Evidence from family studies suggests that risk for ADHD is partly inherited. Several studies have identified a link between a specific variant in a gene, which leads to a change in the protein structure of the dopamine 4 receptor gene (DRD4) with ADHD. However, several other types of gene changes within DRD4 have been identified that could also contribute to risk for ADHD. Recently, another common variant of the DRD4 gene has been described involving a repeated element which precedes the portion of the gene which determines the protein structure. In this report, the authors describe results of analysis of this new DRD4 gene variant in a large sample of children with ADHD and their parents. Results showed a significant excess number of the gene variant transmitted with ADHD from parents. These data add further support for the role of variations in the DRD4 gene as contributors to increased risk for ADHD.

Citation source: Molecular Psychiatry 2000 Volume 5 pages 531-536.

For further information on this work, please contact Dr. James T. McCracken, UCLA Neuropsychiatric Institute & Hospital, Child & Adolescent Psychiatry, 48-270 NPI, 760 Westwood Plaza, Los Angeles, CA 90024-1759. Tel: 310-825-0470; Fax: 310-206-4446; Email: jmccracken@mednet.ucla.edu ARTICLE: Evidence for the serotonin HTR2A and HTR1B receptor genes as a susceptibility factor in attention deficit hyperactivity disorder (ADHD)

AUTHORS: JF Quist, CL Barr, R Schachar, W Roberts, M Malone, R Tannock, VS Basile, J Beitchman, JL Kennedy
Neurogenetics Section, Clarke Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
Department of Psychiatry, The Toronto Western Hospital, Toronto, Ontario, Canada
The Hospital for Sick Children, Toronto, Ontario, Canada

Mounting evidence from animal and human studies suggests a role for serotonin in mediating behavior symptomatic of ADHD and it is recognized that serotonin neurotransmission functionally regulates dopamine activity, modulated in part by the serotonin 2A receptors (5-HT2A). Defects in the serotonin 2A receptor gene, therefore, may indirectly modify dopamine function leading to behavioral change. Using a family based association approach, the present study assesses for non-random transmission of alleles from parents to ADHD children at the T102C and His452Tyr polymorphisms within the serotonin 2A gene. Results indicate preferential transmission of the 452Tyr allele to the affected child that may be important given that this variant has been shown to alter the functionality of the receptor. This result suggests that the HTR2A gene may be a risk factor for ADHD, providing evidence for the involvement of at least one other neurotransmitter system in the neurobiology of ADHD.

Citation source: Molecular Psychiatry 2000 Volume 5 pages 537-541.

For further information on this work, please contact Dr. James L. Kennedy, Neurogenetics Section, Centre for Addiction and Mental Health, Clarke Division, 250 College Street, R-31, Toronto, Ontario, Canada M5T 1R8. Tel: 416-979-4987; Fax: 416-979-4666; Email: james_kennedy@camh.net ARTICLE: Association of a functional polymorphism of the serotonin transporter gene with anxiety-related temperament and behavior problems in children: A longitudinal study from infancy to the mid-teens

AUTHORS: AF Jorm, M Prior, A Sanson, D Smart, Y Zhang, S Easteal
Centre for Mental Health Research and the John Curtin School of Medical Research, Australian National University, Canberra 0200, Australia
Department of Psychology, Royal Children's Hospital/University of Melbourne, Parkville, Victoria 3052, Australia

A functional polymorphism in the regulatory region of the serotonin transporter gene has been reported to the associated with anxiety-related traits. Because allelic associations may be specific to particular stages of development, the authors attempted to replicate this finding in a study involving 660 children who have been studied over time from age 4-8 months to 15-16 years. These children have been assessed for temperament, behavior problems and symptoms of anxiety and depression. Some associations with anxiety-related measures were found to emerge at adolescence, but these were opposite in direction with earlier work. Nevertheless, the study illustrates the value of a developmental perspective in association studies.

Citation source: Molecular Psychiatry 2000 Volume 5 pages 542-545.

For further information on this work, please contact Dr. Anthony Jorm, NHMRC Psychiatric Epidemiology Research Centre, Australian National University Canberra, ACT 0200, Australia. Tel: 61-2-6249-2741; FAX: 61-2-6249-0733; E-mail: anthony.jorm@anu.edu.au ARTICLE: Attention Deficit Hyperactivity Disorder and the Gene for the Dopamine D5 Receptor

AUTHORS: CL Barr, KG Wigg, Y Feng, G Zai, M Malone, W Roberts, R Schachar, R Tannock, and JL Kennedy
Department of Psychiatry, The Toronto Western Hospital, Toronto, Ontario, Canada
Department of Psychiatry, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
Psychiatry Research and Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada
Neurogenetics Section, Clarke Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

A recent study has suggested a possible association of a polymorphism near the dopamine D5 receptor gene (DRD5) and attention-deficit hyperactivity disorder. The polymorphism studied was a (CA)n repeat located in the cosmid containing the D5 receptor gene and the allele that was reported to be associated with attention-deficit hyperactivity disorder (ADHD) was the 148 bp allele. In this study the authors sought to replicate this finding in a sample of 92 families ascertained through a child with ADHD. The authors observed a trend for this allele to be transmitted to the ADHD children, but this was not significant. The authors did observe biased transmission of two other alleles, the 136 bp allele and the 146 bp allele. For these two alleles the bias was for these two alleles not to be transmitted to the ADHD children. The number of informative transmissions for these two alleles was small therefore it would be premature to make any conclusions from our study concerning the role of DRD5 in ADHD.

Citation source: Molecular Psychiatry 2000 Volume 5 pages 546-551.

For further information on this work, please contact Dr. Cathy Barr, The Department of Psychiatry, The Toronto Western Hospital, Room MP14-302, 399 Bathurst Street, Toronto, Ontario, M5T 1S8, Canada. Tel: 416-603-5800 ext. 2744; Fax: 416-603-5126; email: cbarr@uhnres.utoronto.ca
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For independent commentary on all these articles, please refer to the guest editorial by Dr. David Collier titled " Mission: not impossible? Candidate gene studies in child psychiatric disorders," which can be provided upon request. Head of Molecular Genetics Section, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, SE5 8AF. Tel: 44-020-7848-0631; Fax: 44-020-7848-0051; E-mail: sphadco@iop.kcl.ac.uk

Citation source: Molecular Psychiatry 2000 Volume 5 pages 457-460.

Molecular Psychiatry is published by the Nature Publishing Group. http://www.nature.com/mp

Editor: Julio Licinio, M.D.; phone: +1 310 206-6207; FAX: +1 310 825-6407; e-mail: licinio@ucla.edu Editorial assistant: Ms. Ava Martin; phone: +1 310 206-6739; FAX: +1 310 825-6407; e-mail: molecularpsychiatry@mednet.ucla.edu For a copy of these articles, please contact Ms. Martin.

PLEASE CITE MOLECULAR PSYCHIATRY AS THE SOURCE OF THIS MATERIAL.




Molecular Psychiatry

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