Molecular genetics of attention-deficit/hyperactivity disorder: an overview

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Abstract

As heritability is high in attention-deficit/hyperactivity disorder (ADHD), genetic factors must play a significant role in the development and course of this disorder. In recent years a large number of studies on different candidate genes for ADHD have been published, most have focused on genes involved in the dopaminergic neurotransmission system, such as DRD4, DRD5, DAT1/SLC6A3, DBH, DDC. Genes associated with the noradrenergic (such as NET1/SLC6A2, ADRA2A, ADRA2C) and serotonergic systems (such as 5-HTT/SLC6A4, HTR1B, HTR2A, TPH2) have also received considerable interest. Additional candidate genes related to neurotransmission and neuronal plasticity that have been studied less intensively include SNAP25, CHRNA4, NMDA, BDNF, NGF, NTF3, NTF4/5, GDNF. This review article provides an overview of these candidate gene studies, and summarizes findings from recently published genome-wide association studies (GWAS). GWAS is a relatively new tool that enables the identification of new ADHD genes in a hypothesis-free manner. Although these latter studies could be improved and need to be replicated they are starting to implicate processes like neuronal migration and cell adhesion and cell division as potentially important in the aetiology of ADHD and have suggested several new directions for future ADHD genetics studies.

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Structural variation of chromosomes in autism spectrum disorder.

Christian Marshall, Abdul Noor, John Vincent … (2008)

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.

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Molecular genetics of attention-deficit/hyperactivity disorder.

Stephen V. Faraone, Roy H Perlis, Alysa E Doyle … (2005)

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.

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The future of genetic studies of complex human diseases.

N Risch, K Merikangas (1996)

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Author and article information

Contributors

: +49-621-17034501 , +49-6421-17034505 , Tobias.Banaschewski@zi-mannheim.de

Journal

Journal ID (nlm-ta): Eur Child Adolesc Psychiatry

Title: European Child & Adolescent Psychiatry

Publisher: Springer-Verlag (Berlin/Heidelberg )

ISSN (Print): 1018-8827

ISSN (Electronic): 1435-165X

Publication date (Electronic): 10 February 2010

Publication date PMC-release: 10 February 2010

Publication date (Print): March 2010

Volume: 19

Issue: 3

Pages: 237-257

Affiliations

[1 ]Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Postbox 122120, 68072 Mannheim, Germany

[2 ]Department of Child and Adolescent Psychiatry and Psychotherapy, Philipps-University of Marburg, Hans-Sachs-Str. 6, 35039 Marburg, Germany

[3 ]Department of Child and Adolescent Psychiatry, University Duisburg-Essen, Virchowstr. 174, 45147 Essen, Germany

[4 ]Department of Human Genetics, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands

[5 ]Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands

[6 ]Division of Medical Sciences, Centre for Neuroscience (Psychiatry and Behaviour), University of Dundee, Dundee, DD1 9SY Scotland, UK