Additive effect of three noradrenergic genes (ADRA2A, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects (original) (raw)
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Clinical and Molecular Genetics of ADHD and Tourette Syndrome: Two Related Polygenic Disorders
Annals of The New York Academy of Sciences, 2006
Abstract: ADHD is a polygenic disorder due to the additive effect of genes affecting dopamine, norepinephrine, serotonin, GABA, and other neurotransmitters. Some of the specific loci involved are dopamine genes—DRD2, DRD4, DRD5, and the dopamine transporter; norepinephrine (NE) and epinephrine (EPI) genes—dopamine b-hydroxylase, ADRA2A, ADRA2C, PNMT, norepinephrine transporter, MAOA, COMT; serotonin genes—TDO2, HTR1A, HTR1DA, serotonin transporter; GABA genes—GABRB3; androgen receptor and other genes. This model is consistent with all of the present knowledge about ADHD including (a) the increased frequency of ADHD in the relatives of ADHD probands, (b) the presence of a wide spectrum of comorbid behaviors (depression, anxiety, learning, conduct, oppositional-defiant, conduct and substance abuse disorders) in ADHD probands and their relatives on both parental sides, (c) the close relationship to Tourette syndrome (TS), (d) the failure to find the genes for TS using linkage analysis, (e) the brain imaging studies showing hypometabolism of the frontal lobes, (f) the relationship between dopamine D2 receptor density and regional blood flow, (g) the correlation between tics and dopamine D2 receptor density in TS, (h) the motor hyperactivity of dopamine transporter and dopamine D3 receptor gene knockout mice, (i) the LeMoal and Shaywitz dopamine deficiency animal models of ADHD, (j) the NE models of ADHD, (k) the failure to explain ADHD on the basis of any single neurotransmitter defect, (l) the response of ADHD to dopamine and a2-adrenergic agonists, (m) the small percentage of the variance of specific behaviors accounted for by each gene, and numerous other aspects of ADHD. The implications of the polygenic model for the understanding, diagnosis and treatment of ADHD and TS, as well as other psychiatric disorders, are reviewed.
Clinical Genetics, 2001
The present study is based on the proposal that complex disorders resulting from the effects of multiple genes are best investigated by simultaneously examining multiple candidate genes in the same group of subjects. We have examined the effect of 20 genes for dopamine, serotonin, and noradrenergic metabolism on a quantitative score for attention deficit hyperactivity disorder (ADHD) in 336 unrelated Caucasian subjects. The genotypes of each gene were assigned a score from 0 to 2, based on results from the literature or studies in an independent set of subjects (literature-based scoring), or results based on analysis of variance for the sample (optimized gene scoring). Multivariate linear regression analysis with backward elimination was used to determine which genes contributed most to the phenotype for both coding methods. For optimized gene scoring, three dopamine genes contributed to 2.3% of the variance, p=0.052; three serotonin genes contributed to 3%, p=0.015; and six adrenergic genes contributed to 6.9%, p=0.0006. For all genes combined, 12 genes contributed to 11.6% of the variance, p=0.0001. These results indicate that the adrenergic genes play a greater role in ADHD than either the dopaminergic or serotonergic genes combined. The results using literature-based gene scoring were similar. An examination of two additional comorbid phenotypes, conduct disorder and oppositional defiant disorder (ODD), indicated they shared genes with ADHD. For ODD different genotypes of the same genes were often used. These results support the value of the simultaneous examination of multiple candidate genes.
The genetics of ADHD: A literature review of 2005
Current Psychiatry Reports, 2006
Investigations into the genetic basis of attention-deficit/ hyperactivity disorder (ADHD) continue to yield compelling results as candidate gene studies reveal more information about this elusive disorder. Family, twin, and adoption studies further the notion that ADHD is a highly heritable disorder with direct genetic and environmental influence. The year 2005 saw many ADHD candidate gene studies, with most focused on the catecholaminergic candidates. Although many genes were studied in 2005, a large portion of findings has been supportive of the roles of dopaminergic genes’ relationship to clinical phenotypes and drug response. These studies often require replication. Clinical implications continue to be speculative, as larger sample sizes are needed to validate findings to the general population. Further understanding of endophenotypes and the impact of comorbidities also is necessary for proper clinical intervention. Forthwith, we provide a summary of ADHD genetic studies published in 2005.