Dopamine Transporter Gene Polymorphism Research Articles

Genetic association of SLC6A3 (dopamine transporter) gene polymorphisms with personality disorders and substance abuse disorders: a systematic review and meta-analysis.

Personality disorders (PD) are characterized by socially dysfunctional behavioral patterns that affect patients and show higher incidence rates within families. Substance abuse disorders (SAD) are exemplified by extensive and prolonged use of substances, including alcohol, nicotine, or illegal drugs. Genetic predisposition for both PD and SAD has been reported to involve gene variants regulating dopaminergic pathways. Yet, discrepancy among reported results necessitates further elucidation of potential hereditary-related risk factors. Because both disorders impose a societal burden, knowledge on the impact of certain genetic backgrounds on these diseases could help develop evidence-based strategies for efficacious treatment approaches. In the present study a systematic review was performed, and the association between dopamine transporter gene polymorphism (SLC6A3), particularly rs28363170 entailing a 40-bp variable number tandem repeat, and PD as well as SAD was investigated recruiting meta-analysis approach. Initial literature search for PD yielded 1577, from which nine fulfilled eligibility criteria to be used in a meta-analysis including 729 cases and 2113 controls. From the 934 studies retrieved for SAD, only 29 articles with 5221 cases and 4822 controls were used for meta-analysis. A statistically significant association was seen between rs28363170 (for the 9-repeat allele) and PD in European populations according to the co-dominant mode of inheritance. For SAD no statistically significant correlation under any mode of inheritance was observed. There was no indication of time-trend phenomena. Our findings demonstrate the association of SLC6A3 gene polymorphism with PD, thus underling the need to understand neurobiological mechanisms inherent to the above disorders to guide treatment strategies under the perspective of personalized medicine.

Association of Dopamine Transporter Gene (DAT1) 40 bp 3' UTR VNTR Polymorphism (rs28363170) and Cannabis Use Disorder.

Cannabis remains the most widely used illicit drug among Nigerians, often associated with psychiatric disorders. Since genetic predisposition has been implicated in substance use disorders, we, therefore, aimed at finding out the relationship between dopamine transporter gene (DAT1) polymorphism and cannabis use disorder. We recruited 104 patients from a tertiary psychiatric facility in Lagos, Nigeria, who were diagnosed with cannabis use disorder according to ICD-10 and 96 non-smokers as a comparative group. The smokers were screened with Cannabis Use Disorder Identification Test (CUDIT), and cannabis dependence was assessed with the Severity of Dependence Scale (SDS). Genotyping was carried out for the 40 bp 3' UTR VNTR of the DAT1 (rs28363170). The frequencies of 9R/9R, 9R/10R, 10R/10R among non-smokers and smokers were 14 (14.3%), 25 (26.2%), 57 (59.5%) and 17 (16.3%), 54 (51.9%), 33 (31.7%) respectively. The genotype distribution was in Hardy Weinberg equilibrium (HWE) only in the smokers' population (χ² = 1.896, P = .166). Individuals with the 10R allele were almost twice as likely as the 9R carriers to smoke cannabis (OR = 1.915, 95% CI: 1.225-2.995). However, this polymorphism was not associated with the quantity of cannabis smoked, age at onset of smoking, CUDIT, and SDS scores. The DAT VNTR polymorphism was associated with cannabis smoking but not cannabis use disorder.

Smoking Genes: A Case-Control Study of Dopamine Transporter Gene (SLC6A3) and Dopamine Receptor Genes (DRD1, DRD2 and DRD3) Polymorphisms and Smoking Behaviour in a Malay Male Cohort.

Dopamine receptor and dopamine transporter genes polymorphisms have been associated with cigarette smoking behaviour in different populations. The aim of this case–control study was to evaluate polymorphisms in the dopamine transporter gene (SLC6A3 (rs27072)) and the dopamine receptor genes (DRD1 (rs686), DRD2 (rs1800497) and DRD3 (rs7653787)) and their contribution to smoking behaviour in a Malay male population. We identified 476 participants over the age of 18 years comprising 238 smokers and 238 non-smokers. Information such as age, height, weight, body mass index, systolic and diastolic blood pressures, marital status, and smoking status of close family members were taken. For the genetic study, we genotyped four genes (SLC6A3 (rs27072), DRD1 (rs686), DRD2 (rs1800497) and DRD3 (rs7653787)) using the polymerase chain reaction–restriction fragment length polymorphism method and further confirmed our findings with sequencing. Dopamine receptor genes (DRD1, DRD2 and DRD3) were found to be associated with smoking behaviour in a Malay male population. The dopamine transporter gene (SLC6A3) did not show this association. Significant differences were observed between smokers’ and non-smokers’ age, systolic blood pressure, marital status and family members who smoke. Smoking behaviour is significantly influenced by genetic variations of DRD1, DRD2 and DRD3 in a Malay male population.

Association of dopamine transporter gene polymorphisms with the risk of Parkinson's Disease

Introduction: Parkinson's disease (PD) is a second most common neurodegenerative disease. Age, genetic and environmental factors play important role in PD pathogenesis. Current study is aimed to identify the functional dopamine transporter gene polymorphisms - SLC6A3, SLC6A4, and SLc18A2 involved in PD pathogenesis in south Indian population.

New Insights on the Effects of Methylphenidate in Attention Deficit Hyperactivity Disorder.

This narrative review describes an overview of the multiple effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD) and its potential neurobiological targets. It addressed the following aspects: 1) MPH effects on attention and executive functions in ADHD; 2) the relation between MPH efficacy and dopamine transporter gene (DAT) polymorphism; and 3) the role of MPH as an epigenetic modulator in ADHD. Literature analysis showed that MPH, the most commonly used psychostimulant in the therapy of ADHD, acts on multiple components of the disorder. Marked improvements in attentional and executive dysfunction have been observed in children with ADHD during treatment with MPH, as well as reductions in neurological soft signs. MPH efficacy may be influenced by polymorphisms in the DAT, and better responses to treatment were associated with the 10/10 genotype. Innovative lines of research have suggested that ADHD etiopathogenesis and its neuropsychological phenotypes also depend on the expression levels of human endogenous retrovirus (HERV). In particular, several studies have revealed that ADHD is associated with HERV-H over-expression and that MPH administration results in decreased expression levels of this retroviral family and a reduction in the main symptoms of the disorder. In conclusion, there is a confirmed role for MPH as an elective drug in the therapy of ADHD alone or in association with behavioral therapy. Its effectiveness can vary based on DAT polymorphisms and can act as a modulator of HERV-H gene expression, pointing to targets for a precision medicine approach.

Analysis of Polymorphic Variants of the Dopamine Transporter (DAT1) Gene Polymorphism and Personality Traits Among Athletes.

Personality traits, especially in sport are modulatory factors of athletes’ behavior – his/ her conscientiousness, the will to achieve an aim, perseverance and motivation of activity. Not only are biological predispositions related to anatomical or biochemical traits of success, but they are also largely determined by personality traits that result from genetic factors. In our research we joined tests of athlete’s personality in correlation with genotypes of the dopamine transporter (DAT1) gene polymorphism. The selection of this polymorphism was based on previous reports connecting the influence of dopamine with motivation and numerous arguments supporting its correlation with human behavior. We observed significant differences among polymorphisms DAT 9/9, 9/10, 10/10 in terms of proportion of particular genotypes between athletes and the control group. We also found significant differences in the NEO FFI sten scale for conscientiousness. We noticed that anxiety was related with genotypic variants of DAT1, specifically the 9/10 VNTR variant, which conditioned lower levels of anxiety in the group of tested athletes. By contrast, the lower sten value of agreeability was statistically significant for the group of athletes that were carriers of the 10/10 VNTR genotype. Heterozygous 9/10 VNTR among athletes showed lower levels of anxiety in comparison with the control group, whereas agreeability determined using the NEO FFI scale represented a lower value among athletes that had the 10/10 polymorphism. We may thus conclude that the presence of polymorphic variants of the dopamine transporter gene corresponds to athletes’ personality traits.

Review of dopamine transporter gene polymorphisms in major depressive disorder

1.Introduction. Given the latest epidemiological data on depression and suicide, as well as the existence of some hypotheses that dopamine system dysfunction is involved in depression, it was necessary to review and summarize the latest studies in the literature. 2.Materials and methods. Using the PubMed database, 8 clinical studies on dopamine transporter gene and depression published before April 2018 were selected. 3.Results. In the selected studies, 3465 subjects were included, of which 2527 were patients diagnosed with major depressive disorder and 938 healthy subjects were included in the control groups. Half of the studies included also studied the polymorphisms of other genes (eg DRD2, SLC6A2, COMT, ABC1, CREB1 and others). 4.Discussions. The results of these studies are not sufficient to support the involvement of dopamine transporter gene polymorphisms in depression. Several multicenter studies involving several patient samples are needed to draw a clear conclusion.

Genes of dopamine receptors and transporter in patients with schizophrenia: associations with the clinical characteristics of the disorder

Genotyping of 28 polymorphisms of 5 dopamine receptor genes and 12 polymorphisms of dopamine transporter gene was performed in 475 schizophrenia patients and 135 healthy individuals. Associations of several polymorphisms of the DRD2, DRD3 and SLC6A3 genes were identified with leading symptoms and late debut of schizophrenia.

Association study between polymorphisms of dopamine transporter gene (SLC6A3), dopamine D1 receptor gene (DRD1), and autism

Introduction Autism is an etiologically and clinically heterogeneous group of disorders, collectively referred to as 'autism spectrum disorders'. Dopamine (DA) modulates a wide variety of processes, functions, and behaviors that are abnormal in individuals with autism spectrum disorders. The DA transporter gene SLC6A3 (solute carrier family 6, member 3) is a crucial regulator of DA homeostasis and neurotransmission. SLC6A3 gene has many polymorphisms which are associated with hangs in gene expression that may affect extracellular DA levels. The rs2550936 single-nucleotide polymorphism (SNP) at SLC6A3 gene decreased SLC6A3 expression or DA transporter availability. Also, the rs4532 SNP at dopamine D1 receptors (DRD1) is apparently a good candidate for affecting autism risk or modifying the classical symptoms of autism. Aim This study aimed to analyze the association between rs2550936 SNP at SLC6A3 gene and rs4532 SNP at the DRD1 gene and autism and their association with various demographical and clinical data of autistic children. Patients and methods This study included 50 autistic patients (36 males and 14 females) and 50 age-matched and sex-matched nonautistic controls for comparison. All patients were subjected to history taking, physical examination, language assessment, intelligence quotient, and childhood autism rating scale as well as analysis of SLC6A3 gene rs2550936 SNP and DRD1 gene rs4532 SNP using PCR–restriction fragment length polymorphism (RFLP), which was done for both patients and nonautistic controls. Results There has been a statistically significant relationship between the age of mother and different genotypes of SLC6A3 gene in autistic patients (P = 0.030). DRD1 rs4532 A/G and A/A genotype frequencies were significantly higher in autistic patients (52%) compared with nonautistic controls (40%) (P = 0.043). Conclusion DRD1 rs4532 polymorphism might be a risk factor increasing autism susceptibility as well as the association of the patient age with its different genotypes. There was a significant difference in the mother's age at conception and different genotypes of the SLC6A3 gene in autistic patients.

Study of the link between dopamine transporter gene polymorphisms and response to paroxetin and escitalopram in patients with lifelong premature ejaculation.

We evaluated the role of dopamine (DA) transporter gene polymorphism in lifelong premature ejaculation (LPE) and its role in determining the response to paroxetine and escitalopram. Eighty consecutive patients and controls were recruited. Sixty of them suffered from LPE. They were divided into two equal groups. One group received paroxetine 20 mg daily for 3 months and the other one received ecistalopram 20 mg daily for 3 months. Their wives were instructed to measure the intra-vaginal ejaculation latency time using stopwatch. Five milliliters of blood was withdrawn from patients and controls for PCR analysis. The present study revealed that the mean ages of the patients and controls were 41.42 and 36.4 years, respectively. The majority of the patients were of (10R/10R) genotypes of the DA transporter gene polymorphism, whereas the controls were of (6R/6R) genotypes and this revealed statistically significant result (P-value=0.001). Both paroxitine and escitalopram significantly delayed ejaculation in the responders (P-values=0.001 and 0.001, respectively). The study revealed significant association between such response and DA transporter gene polymorphism (P-values of fold increase and log FI were 0.019 and 0.010, respectively). To the best of our knowledge, this is the first report to demonstrate a highly significant association between such response and DA transporter gene polymorphism in patients with LPE.

Evaluation of VNTR polymorphisms of dopamine transporter gene and the risk of bipolar disorder in Zahedan, southeast Iran.

The exact role of dopamine transporter gene (DAT1) in the pathogenesis of bipolar disorder type 1 (BD) is not understood. In the present study, we aimed to evaluate the possible association between 30, 40 and 63 bp variable number tandem repeat (VNTR) polymorphisms of DAT1 gene and the risk of type 1 (BD) in a sample of Iranian population. This case-control study was performed on 152 BD patients and 153 psychiatrically healthy subjects. Genotyping of the variant was done by polymerase chain reaction method. Totally, the findings did not support an association between DAT1 VNTR polymorphisms and the risk of BD in a sample of southeast Iranian population.

Dopamine transporter gene polymorphism in children with ADHD: A pilot study in Indonesian samples.

Several studies showed that DAT1 polymorphism closed related with ADHD although the results were not consistently found. Studies in China, South Korea, Japan revealed that 10-repeat allele gave a risk for ADHD. Based on that understanding, this study tried to identify whether the similar polymorphism of DAT1 was also apparent in Indonesian children with ADHD. This was a case - control study. Case was 50 Indonesian origin children with ADHD and without any other mental disorders and metal retardation. Control is Indonesian origin children without ADHD, other mental disorders and mental retardation. ADHD diagnosis was taken after doing the psychiatric interview and observation based on the DSM-IV TR diagnostic criteria for ADHD at the Child and Adolescent Psychiatry Out-patient Clinic, Dr. Cipto Mangunkusumo National Referral Hospital - Faculty of Medicine Universitas Indonesia. DNA isolation, DNA purity and concentration were measured. PCR was done by using a primer based on Homo sapiens solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3), RefSeq Gene on chromosome 5 with accession number NG_015885.1. To identify the serial of repeated allele, we used the sequencing technique. There were 47 children with ADHD and 48 children without ADHD that involved in the final analysis. The mean of age amongst ADHD group was 9.18 (2.42) and 8.10 (2.46) years old in non-ADHD group. The 10-repeated allele of DAT1 was the highest proportion in both. This finding was apparently similar with other studies on DAT1 polymorphism across Asian.

Study of the Dopamine Transporter Gene (DAT1) Polymorphism and Serotonin Transporter Promoter Gene in Patients with Lifelong Premature Ejaculation and Its Relation to the Response to SSRIs = دراسة جين ناقل الدوبامين وجين ناقل سيروتونن المحفز في المرضى الذين يعانون من سرعة القذف وعلاقته بالاستجابة لمانع إعادة امتصاص سيروتونن الانتقائي

Background: Dopamine and serotonin transporter genes play an important role in the control of the mechanism of ejaculation. Objectives: Evaluation of the role of serotonin transporter gene promoter and dopamine transporter gene polymorphisms in lifelong premature ejaculation and their role in determining the response to paroxetin and escitalopram. Patients and Methods: Eighty consecutive patients and controls were recruited. Forty of them suffered lifelong premature ejaculation. They were divided into two equal groups: One group received paroxetine (20 mg daily)for 1 month, and the other one received ecistalopram (20 mg daily) for 1 month. Their wives were instructed to measure the intravaginal ejaculation latency time using stopwatch. Five ml blood was withdrawn from patients and controls for PCR. Results: The present study revealed that the majority of the patients were SL and SS genotypes of the serotonin transporter gene promoter polymorphism. Also, this study revealed that the majority of the patients were (10R/10R) genotypes of the dopamine transporter gene polymorphism. Both of paroxitine and escitalopram significantly delayed ejaculation in the responders. Conclusion: The study revealed significant association between such response and dopamine transporter gene polymorphism. The present study augmented the significant effect of both paroxetine and escitalopram in delaying ejaculation in the responders.

Gene-Environment Correlation Between the Dopamine Transporter Gene (DAT1) Polymorphism and Childhood Experiences of Abuse.

In the present study, we investigated the possible gene-environment correlation between the dopamine transporter gene (DAT1) polymorphism and childhood experiences of abuse and neglect. Genetic information was obtained from 1,442 male and 2,178 female twins and their siblings drawn from a Finnish population-based sample. The Childhood Trauma Questionnaire was used to measure the childhood experiences of abuse and neglect. In men, the DAT1 polymorphism was associated with having experienced sexual abuse in childhood, such that men with the 9R9R genotype reported less sexual abuse experiences than men with the 9R10R or the 10R10R genotypes. In women, there was an association between the DAT1 polymorphism and childhood experiences of emotional abuse, such that women with the 9R9R genotype reported less emotional abuse experiences than women with the 9R10R or 10R10R genotypes. No other associations between the DAT1 polymorphism and childhood experiences of abuse and neglect were found. In sum, the results suggested that some genetic components might predispose children to experience childhood abuse and neglect. Possible reasons for this association were discussed.

COMT genotype affects brain white matter pathways in attention-deficit/hyperactivity disorder.

Increased dopamine availability may be associated with impaired structural maturation of brain white matter connectivity. This study aimed to derive a comprehensive, whole-brain characterization of large-scale axonal connectivity differences in attention-deficit/hyperactivity disorder (ADHD) associated with catechol-O-methyltransferase gene (COMT) Val158Met polymorphism. Using diffusion tensor imaging, whole-brain tractography, and an imaging connectomics approach, we characterized altered white matter connectivity in youth with ADHD who were COMT Val-homozygous (N = 29) compared with those who were Met-carriers (N = 29). Additionally, we examined whether dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4) polymorphisms were associated with white matter differences. Level of attention was assessed using the continuous performance test before and after an 8-week open-label trial of methylphenidate (MPH). A network of white matter connections linking 18 different brain regions was significantly weakened in youth with ADHD who were COMT Met-carriers compared to those who were Val-homozygous (P < 0.05, family-wise error-corrected). A measure of white matter integrity, fractional anisotropy, was correlated with impaired pretreatment performance in continuous performance test omission errors and response time variability, as well as with improvement in continuous performance test response time variability after MPH treatment. Altered white matter connectivity was exclusively based on COMT genotypes, and was not evident in DAT1 or DRD4. We demonstrated that white matter connectivity in youth with ADHD is associated with COMT Val158Met genotypes. The present findings suggest that different layers of dopamine-related genes and interindividual variability in the genetic polymorphisms should be taken into account when investigating the human connectome.

Association between amygdala reactivity and a dopamine transporter gene polymorphism.

Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3′ untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli. Amygdala reactivity was examined by comparing regional cerebral blood flow, measured with positron emission tomography and [15O]water, during exposure to angry and neutral faces, respectively, in a Swedish sample comprising 32 patients with social anxiety disorder and 17 healthy volunteers. In a separate US sample, comprising 85 healthy volunteers studied with blood oxygen level-dependent functional magnetic resonance imaging, amygdala reactivity was assessed by comparing the activity during exposure to threatening faces and neutral geometric shapes, respectively. In both the Swedish and the US sample, 9-repeat carriers displayed higher amygdala reactivity than 10-repeat homozygotes. The results suggest that this polymorphism contributes to individual variability in amygdala reactivity.

Association of dopamine gene variants, emotion dysregulation and ADHD in autism spectrum disorder.

The aim of the present study was to evaluate the association of dopaminergic gene variants with emotion dysregulation (EMD) and attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorder (ASD). Three dopamine transporter gene (SLC6A3/DAT1) polymorphisms (intron8 5/6 VNTR, 3'-UTR 9/10 VNTR, rs27072 in the 3'-UTR) and one dopamine D2 receptor gene (DRD2) variant (rs2283265) were selected for genotyping based on à priori evidence of regulatory activity or, in the case of DAT1 9/10 VNTR, commonly reported associations with ADHD. A sample of 110 children with ASD was assessed with a rigorously validated DSM-IV-referenced rating scale. Global EMD severity (parents' ratings) was associated with DAT1 intron8 (ηp(2)=.063) and rs2283265 (ηp(2)=.044). Findings for DAT1 intron8 were also significant for two EMD subscales, generalized anxiety (ηp(2)=.065) and depression (ηp(2)=.059), and for DRD2 rs2283265, depression (ηp(2)=.053). DRD2 rs2283265 was associated with teachers' global ratings of ADHD (ηp(2)=.052). DAT1 intron8 was associated with parent-rated hyperactivity (ηp(2)=.045) and both DAT1 9/10 VNTR (ηp(2)=.105) and DRD2 rs2283265 (ηp(2)=.069) were associated with teacher-rated inattention. These findings suggest that dopaminergic gene polymorphisms may modulate EMD and ADHD symptoms in children with ASD but require replication with larger independent samples.

Genetics of preparation and response control in ADHD: the role of DRD4 and DAT1

Difficulties with performance and brain activity related to attentional orienting (Cue-P3), cognitive or response preparation (Cue-CNV) and inhibitory response control (Nogo-P3) during tasks tapping executive functions are familial in ADHD and may represent endophenotypes. The aim of this study was to clarify the impact of dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) gene polymorphisms on these processes in ADHD and control children. Behavioural and electrophysiological parameters from cued continuous performance tests with low and high attentional load were assessed in boys with ADHD combined type (N=94) and controls without family history of ADHD (N=31). Both groups were split for the presence of at least one DRD4 7-repeat allele and the DAT1 10-6 haplotype. Children with ADHD showed diminished performance and lower Cue-P3, CNV and Nogo-P3 amplitudes. Children with DRD4 7R showed similar performance problems and lower Cue-P3 and CNV, but Nogo-P3 was not reduced. Children with the DAT1 10-6 haplotype had no difficulties with performance or Cue-P3 and CNV, but contrary to expectations increased Nogo-P3. There were no Genotype by ADHD interactions. This study detected specific effects of DRD4 7R on performance and brain activity related to attentional orienting and response preparation, while DAT1 10-6 was associated with elevated brain activity related to inhibitory response control, which potentially compensates increased impulsivity. As these genotype effects were additive to the impact of ADHD, the current results indicate that DRD4 and DAT1 polymorphisms are functionally relevant risk factors for ADHD and presumably other disorders sharing these endophenotypes.

Association between gene variants and response to buprenorphine maintenance treatment

A variety of studies were addressed to differentiate responders and non-responders to substitution treatment among heroin dependent patients, without conclusive findings. In particular, preliminary pharmacogenetic findings have been reported to predict treatment effectiveness in mental health and substance use disorders. Aim of the present study was to investigate the possible association of buprenorphine (BUP) treatment outcome with gene variants that may affect kappa-opioid receptors and dopamine system function. One hundred and seven heroin addicts (West European, Caucasians) who underwent buprenorphine maintenance treatment were genotyped and classified into two groups (A and B) on the basis of treatment outcome. Non-responders to buprenorphine (group B) have been identified taking into account early drop out, continuous use of heroin, severe behavioral or psychiatric problems, misbehavior and diversion during the 6 months treatment period. No difference was evidenced between responders and non-responders to BUP in the frequency of kappa opioid receptor (OPRK1) 36G>T SNP. The frequency of dopamine transporter (DAT) gene polymorphism (SLC6A3/DAT1), allele 10, was evidently much higher in “non-responder” than in “responder” individuals (64.9% vs. 55.93%) whereas the frequency of the category of other alleles (6, 7 and 11) was higher in responder than in non-responder individuals (11.02% vs. 2.13% respectively). On one hand, the hypothesis that possible gene-related changes in kappa-opioid receptor could consistently affect buprenorphine pharmacological action and clinical effectiveness was not confirmed in our study, at least in relation to the single nucleotide polymorphism 36G>T. On the other hand, the possibility that gene-related dopamine changes could have reduced BUP effectiveness and impaired maintenance treatment outcome was cautiously supported by our findings. DAT1 gene variants such as allele 10, previously reported in association with personality and behavioral problems, would have influenced the effects of BUP-induced dopamine release, modulated through mu and kappa opioid receptors, and probably the related reinforcing capacity of the drug.

Relationship between attention deficit hyperactivity disorder and alcohol dependence: a genetic view.

Dear Editor, Attention deficit hyperactivity disorder (ADHD), is a common, highly heritable childhood-onset psychiatric disorder affecting 2% – 6% of children worldwide. The recent paper examines the effects of child and adult ADHD symptoms in adults among male students on adult addiction acknowledgment and alcoholism potential (1). This article is an original study which provides that adult ADHD and child ADHD predict addiction acknowledgment while child ADHD and impulsivity predict alcohol potential. These findings add new evidence about prediction of adolescent and adult drug abuse and use by early ADHD. However, the biological mechanism of the relationship between ADHD and substance problems is still unclear. One of the important mechanisms is genetic correlation due to shared genetic loci. First, it has been shown that both ADHD and alcohol dependence have strong genetics components. Twin and adoption studies have indicated that ADHD has high heritability in the range of 75% – 91% (2), while family, twin, and adoption studies have revealed that genetic and environmental factors and their interactions contribute to the development of alcohol dependence, with a heritability of more than 50% (3). Second, ADHD has been found to be highly comorbid with nicotine dependence and alcohol dependence. Segregation analysis has provided multigenerational evidence of cosegregation among ADHD, nicotine dependence, and alcohol dependence, while linkage analysis has suggested several regions on human chromosomes with pleiotropic effects on ADHD and alcohol dependence (4). For example, significant linkages at 4q13.1 - 13.2 and 5q31 - 33 for ADHD has been implicated in alcohol dependence and nicotine dependence (4). Third, genetic association studies have suggested several genes which are responsible for both ADHD and alcohol dependence. For example, it has been reported associations between the dopamine transporter (DAT) gene polymorphisms and human disorders including ADHD and alcohol dependence (5). The variants of the dopamine D2 receptor gene (DRD2) has been found to be associated with alcoholism, drug dependency, obesity, smoking, pathological gambling, ADHD, Tourette syndrome, as well as other related compulsive behaviors (6). The tachykinin receptor 1 (TACR1) gene has been reported to be associated with bipolar disorder and alcoholism as well as ADHD (2). However, parts of the associations are not strong and the results are not always consistent due to biologic mechanisms (genetic heterogeneity, gene-gene interactions and gene-environment interactions etc.) and spurious mechanisms (inadequacies of genomic markers, type 1 error, limited sample sizes and power, cohort and age effects, and bias etc.). In addition, some other genes, such as the nicotinic receptor CHRNA5-A3-B4 subunit genes, do not contribute to the common genetic predisposition of ADHD and alcohol dependence (2, 7). In short, the current results not only support previous studies about the relationship between ADHD and alcohol and drug dependence but also provide further evidence on prediction of future substance dependence in adulthood through early ADHD (1). However, the sample size for the current study is relative small; therefore the results need further investigation using large sample and confirmation in other populations. In addition, further genetic and epigenetic study to identify the disease-causing variants including gene-environment interactions in ADHD and alcohol dependence would have promise for understanding the pathogenesis of these comorbity psychiatric disorders, predicting the risks and developing potential treatments for ADHD and alcohol dependence.