Li D, Sham PC, Owen MJ, He L. Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 15: 2276-2284

Bio-X Life Science Research Center, Shanghai Jiao Tong University, Hao Ran Building, 1954 Hua Shan Road, Shanghai 200030, China.
Human Molecular Genetics (Impact Factor: 6.39). 08/2006; 15(14):2276-84. DOI: 10.1093/hmg/ddl152
Source: PubMed


Molecular genetic investigations of attention deficit hyperactivity disorder (ADHD) have found associations with a variable number of tandem repeat (VNTR) situated in the 3'-untranslated region of dopamine transporter gene (DAT1), a VNTR in exon 3 of dopamine receptor 4 gene (DRD4) and a microsatellite polymorphism located at 18.5 kb from the 5' end of dopamine receptor 5 gene (DRD5). A number of independent studies have attempted to replicate these findings but the results have been mixed, possibly reflecting inadequate statistical power and the use of different populations and methodologies. In an attempt to clarify this inconsistency, we have combined all the published studies of European and Asian populations up to October 2005 in a meta-analysis to give a comprehensive picture of the role of the three dopamine-related genes using multiple research methods and models. The DRD4 7-repeat (OR=1.34, 95% CI 1.23-1.45, P= 2 x 10(-12)) and 5-repeat (OR=1.68, 95% CI 1.17-2.41, P=0.005) alleles as well as the DRD5 148-bp allele (OR=1.34, 95% CI 1.21-1.49, P= 8 x 10(-8)) confer increased risk of ADHD, whereas the DRD4 4-repeat (OR=0.90, 95% CI 0.84-0.97, P=0.004) and DRD5 136-bp (OR=0.57, 95% CI 0.34-0.96, P=0.022) alleles have protective effects. In contrast, we found no compelling evidence for association with the 480-bp allele of DAT (OR=1.04, 95% CI 0.98-1.11, P=0.20). No significant publication bias was detected in current studies. In conclusion, there is a statistically significant association between ADHD and dopamine system genes, especially DRD4 and DRD5. These findings strongly implicate the involvement of brain dopamine systems in the pathogenesis of ADHD.

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    • "In this receptor densities and DA binding affinities (Asghari et al., 1995;Schoots & Van Tol, 2003) and, as a result, likely undersupply the postsynaptic cell with DA. Ample evidence supports the association of the 7R with ADHD symptoms (Li et al., 2006;Thapar et al., 2013;Wu et al., 2012). Other DRD4 mutations, however, produced null results in a meta-analysis on ADHD candidate genes (Wu et al., 2012). "
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    ABSTRACT: Objective: The ADHD-obesity link has been suggested to result from a shared underlying basis of suboptimal dopamine (DA); however, this theory conflicts evidence that an amplified DA signal increases the risk for overeating and weight gain. A model was tested in which ADHD symptoms, predicted by hypodopaminergic functioning in the prefrontal cortex, in combination with an enhanced appetitive drive, predict hedonic eating and, in turn, higher body mass index (BMI). Method: DRD2 and DRD4 markers were genotyped. The model was tested using structural equation modeling in a nonclinical sample (N = 421 adults). Results: The model was a good fit to the data. Controlling for education, all parameter estimates were significant, except for the DRD4-ADHD symptom pathway. The significant indirect effect indicates that overeating mediated the ADHD symptoms-BMI association. Conclusion: Results support the hypothesis that overeating and elevated DA in the ventral striatum-representative of a greater reward response-contribute to the ADHD symptom-obesity relationship.
    Full-text · Article · Jan 2016 · Journal of Attention Disorders
    • "For example, the long 7R variant of the DRD4 VNTR polymorphism is robustly associated with the increased risk of attention deficit hyperactivity disorder (ADHD) in children (Li et al., 2006). Other studies have evidenced that the DRD4 7R allele might be associated with higher rates of aggression and violent behavior not only in adults (Boutwell & Beaver, 2008) but also in children and adolescents (Farbiash, Berger, Atzaba-Poria, & Auerbach, 2014). "
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    ABSTRACT: Purpose The dopamine receptor 4 gene variable number of tandem repeats (DRD4 VNTR) polymorphism is associated either with an increased risk of ADHD, or with a higher incidence rate of violent criminal behavior and aggression in the human populations. However, it cannot be excluded that the risk variants of the DRD4 VNTR polymorphism, the 7-repeat and 5-repeat (7R and 5R) alleles might be associated with the increased occurrence of violent behavior in adults with no history of ADHD. Methods This study was to examine the prevalence of the certain risk variants of the DRD4 VNTR polymorphism in the men convicted of violent crimes, with no history of ADHD (n = 161). Results The prevalence of the 5R and 7R DRD4 VNTR alleles was higher in the men convicted of violent crimes, with no history of ADHD than in the general Russian Caucasian population (Novosibirsk city, n = 425). Conclusions This is the first evidence that both 7R and 5R, the ADHD-linked DRD4 VNTR alleles are directly associated with the incidence of violent behavior in the men with no history of ADHD. Results support the hypothesis that proactive aggression might be a genetically-based, separate feature of personality that is independent of ADHD.
    No preview · Article · Nov 2015 · Journal of Criminal Justice
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    • "Epidemiological studies have reported that ADHD affects about 10% of children and 5% of adults in the United States alone [1] [2] [3]. While the exact etiology of ADHD is still unknown, a number of studies suggested that ADHD may have a genetic basis showing an increasing evidence of polymorphisms in genes involved in dopamine neurotransmission [4] [5] [6] [7] [8] [9]. On the other hand, prenatal environmental factors such as smoking, diet, stress, and environmental toxins are also thought to be associated with ADHD-related behaviors in offspring [10] [11] [12] [13]. "
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    ABSTRACT: In recent years, the average consumption of sugar in humans from all ages has remarkably increased, exceeding the recommended limit. Pregnancy is a critical time for the global development of offsprings who are vulnerable to the deleterious effects of environmental factors. In this study, we investigated whether high sucrose consumption during pregnancy could affect the attention-deficit hyperactivity disorder (ADHD)-like neurobehavioral outcomes in offspring mice. Pregnant mice were randomly grouped and orally administered with either water as control (Con) or 30% wt/vol sucrose diluted in water at 6 (Suc6) or 9 (Suc9) g/kg dosage per day from gestational days 6 to 15. After the weaning period, offspring mice underwent a series of behavioral testing for locomotor activity, attention, and impulsivity. Although there is no obvious difference in gross development of offspring mice such as weight gain, high sucrose-exposed offspring mice showed a significantly increased locomotor activity. Moreover, these mice exhibited a dose-dependent decrease in attention and increase in impulsivity. In the striatum, a significantly increased dopamine transporter (DAT) mRNA expression was found in the Suc9 group along with dose-dependent decreases in the Drd1, Drd2 and Drd4 dopamine receptor subtypes. Furthermore, synaptosomal DAT protein expression was increased about twofold in the Suc9 group. Prenatal fructose exposure also induced hyperactive behavior in offspring mice suggesting the essential role of fructose in the dysregulated neurobehavioral development. These findings suggest prenatal sucrose consumption as a new risk factor for ADHD, which may need further attention and investigation in humans.
    Full-text · Article · Aug 2015 · The Journal of Nutritional Biochemistry
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