Sex-dependent complex association of TPH2 with multiple dimensions of ADHD.

BACKGROUND: Tryptophan hydroxylase 2 (TPH2) is a key enzyme in the biosynthesis of serotonin in the brain. This study aims to investigate the role of a functional variant in TPH2 (rs17110747) in the pathophysiology of ADHD. This variant has been implicated in mood disorders in recent meta-analysis. This study uses a comprehensive approach that combines association testing and pharmaco-dynamic evaluation of behaviour, in a large sample of children with ADHD (n = 570). METHODS: The association between various ADHD relevant traits and rs17110747 was analyzed using family-based association tests (FBAT). Children were assessed by parents, teachers and research staff under three experimental conditions (EC): baseline, placebo, and methylphenidate using a double-blind placebo-controlled crossover trial. OUTCOMES: FBAT analysis conducted in a sample stratified based on sex of the proband, showed that there was a highly significant overtransmission of the G allele from parents to affected girls. In addition, significant association with several behavioral and cognitive dimensions of ADHD was observed only when the proband was female. Further, girls with the G/G genotype (rs17110747) had greater response to placebo when evaluated by parents. INTERPRETATION: These results suggest that there may be a complex association of TPH2 in the etiology of ADHD, with a sex-specific effect.

Organophosphate Agent Induces ADHD-Like Behaviors via Inhibition of Brain Endocannabinoid-Hydrolyzing Enzyme(s) in Adolescent Male Rats.

Anticholinergic organophosphate (OP) agents act on the diverse serine hydrolases, thereby revealing unexpected biological effects. Epidemiological studies indicate a relationship between the OP exposure and development of attention-deficit/hyperactivity disorder (ADHD)-like symptoms, whereas no plausible mechanism for the OP-induced ADHD has been established. The present investigation employs ethyl octylphosphonofluoridate (EOPF) as an OP-probe, which is an extremely potent inhibitor of endocannabinoid (EC, anandamide and 2-arachidonoylglycerol)-hydrolyzing enzymes: that is, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). An ex vivo experiment shows that EOPF treatment decreases FAAH and MAGL activities and conversely increases EC levels in the rat brain. Subsequently, EOPF (treated intraperitoneally once at 0, 1, 2, or 3 mg/kg) clearly induces ADHD-like behaviors (in elevated plus-maze test) in both Wistar and spontaneously hypertensive rats. The EOPF-induced behaviors are reduced by a concomitant administration of cannabinoid receptor inverse agonist SLV-319. Accordingly, the EC system is a feasible target for OP-caused ADHD-like behaviors in adolescent rats.

Methylenetetrahydrofolate reductase and psychiatric diseases.

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for the critical process of one-carbon metabolism involving folate and homocysteine metabolisms. It is known that some polymorphism of MTHFR would result in reduction of MTHFR enzyme activity as well as DNA methylation process, later shown to have significant impacts in various psychiatric diseases. However, it is unclear whether the polymorphism of MTHFR could be an independent or an add-on risk factor for specific psychiatric symptoms, such as anxiety, depression, positive, or negative symptoms of schizophrenia, or acts as risk factor for specific psychiatric disorders, such as schizophrenia, major depression, autisms, and bipolar disorders. It is also understudied on whether folate supplements could be an effective treatment for psychiatric patients with defect MTHFR activity. In this review, we not only gathered the most recent discoveries on MTHFR polymorphism and related DNA methylation in various psychiatric disorders, but also highlighted the potential relationships between MTHFR activity and implication of folate-related function in specific mental diseases.

Salivary cortisol and alpha-amylase diurnal profiles and stress reactivity in children with Attention Deficit Hyperactivity Disorder.

There is growing evidence for dysregulation of the stress system in individuals with Attention Deficit Hyperactivity Disorder (ADHD). The stress system includes neuroanatomical and functional components that function in concert to maintain homeostasis and its main effectors are the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic/adrenomedullary nervous system (SNS). As stress system activity demonstrates a distinct circadian variation, we aimed to describe simultaneously, diurnal rhythms of both the HPA axis and the SNS in children with ADHD and a comparison group. Moreover, we attempted to investigate stress responses to a physical stressor, venipuncture, in both groups. Sixty-two prepubertal children with ADHD combined (ADHD-C) or inattentive (ADHD-I) type and 40 typically developing children provided saliva samples at six specific time points during a day, as well as before and 10 min after a scheduled morning venipuncture. Salivary cortisol and α- amylase were selected as reliable noninvasive biomarkers for HPA axis and SNS function and were measured in the samples obtained. Results revealed that children with ADHD-C had lower mean cortisol values both 30 min after awakening and at 18:00 h than controls (p = 0.002 and p = 0.018 respectively), as well as lower mean Cortisol Awakening Response (CAR) and Area Under the Curve for "wake to bed" period (AUCi) values of cortisol (p = 0.004 and p = 0.001, respectively). Also, mean CAR and cortisol AUCi were lower in children with ADHD-I than the control group (p = 0.034 and p = 0.038 respectively). Alpha-amylase measurements showed an increase over time (p < 0.001), which was similar in all three groups. Interestingly, α-amylase changes over time were correlated with the corresponding cortisol changes (p < 0.001). Venipuncture, elicited a significant increase only in α-amylase levels and more so in the control group (p = 0.003). These findings suggest a partial hypofunction of the stress system in children with ADHD.

Mice lacking cyclin-dependent kinase-like 5 manifest autistic and ADHD-like behaviors.

Neurodevelopmental disorders frequently share common clinical features and appear high rate of comorbidity, such as those present in patients with attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). While characterizing behavioral phenotypes in the mouse model of cyclin-dependent kinase-like 5 (CDKL5) disorder, a neurodevelopmental disorder caused by mutations in the X-linked gene encoding CDKL5, we found that these mice manifested behavioral phenotypes mimicking multiple key features of ASD, such as impaired social interaction and communication, as well as increased stereotypic digging behaviors. These mice also displayed hyper-locomotion, increased aggressiveness and impulsivity, plus deficits in motor and associative learning, resembling primary symptoms of ADHD. Through brain region-specific biochemical analysis, we uncovered that loss of CDKL5 disrupts dopamine synthesis and the expression of social communication-related key genes, such as forkhead-box P2 and mu-opioid receptor, in the corticostriatal circuit. Together, our findings support that CDKL5 plays a role in the comorbid features of autism and ADHD, and mice lacking CDKL5 may serve as an animal model to study the molecular and circuit mechanisms underlying autism-ADHD comorbidity.

Interactions Between Early Trauma and Catechol-O-Methyltransferase Genes on Inhibitory Deficits in Children With ADHD.

OBJECTIVE: To investigate the interaction between childhood trauma exposure with the catechol-O-methyltransferase (COMT) and dopamine receptor D4 (DRD4) polymorphisms in relation to neuropsychological measures in children with ADHD. METHOD: A cross-sectional examination of early traumatic experiences and the continuous performance test (CPT) were performed in 55 children with ADHD. Participants were also genotyped for the DRD4 exon III 48-bp variable number of tandem repeats (VNTR) polymorphism and the COMT Val158-Met (rs4680) polymorphism. RESULTS: There was significant interaction between the effects of the COMT genotype and trauma in commission errors. In participants with ADHD carrying the COMT Val/Val genotype, the group exposed to trauma showed significantly higher commission errors than the non-traumatized group. However, for the participants with other genotypes, no significant differences were found. CONCLUSION: This study suggests that there exists a genetic influence on the association between childhood trauma and the severity of inhibitory deficits in children with ADHD.

Case report: Cytochrome P450 implications for comorbid ADHD and OCD pharmacotherapy.

TOPIC: This case report details the treatment of an early adolescent already receiving treatment for attention-deficit hyperactivity disorder who presents with recurrent obsessive-compulsive disorder. Potential atomoxetine (Strattera) and fluoxetine (Prozac) interactions via Cytochrome P450 (CYP450) pathways are examined and alternate therapies are recommended. PURPOSE: Provide a discussion of psychopharmacogenomics, especially in the case of combining medications, CYP450 enzymes, and clinical implications in the context of the burgeoning field of precision medicine. The following questions are addressed: 1) What are the recommendations for pharmacogenetics testing? 2) How should pharmacogenetics inform medication selection? 3) What impact should CYP450 knowledge have on medication dosing? SOURCES: Peer-reviewed journals, U.S. Health and Human Services, National Institutes of Health, National Medical Library, and the Clinical Pharmacology database. CONCLUSIONS: Genetic testing as a prescriptive tool is not indicated for all medications; however, potential drug-drug interactions, narrow therapeutic drug index, and side effect toxicity contribute to the need for testing. An understanding of CYP450 metabolism and drug interaction as well as metabolism phenotypes should inform prescribing and dosing psychotropic medications.

Monoamine oxidase B gene variants associated with attention deficit hyperactivity disorder in the Indo-Caucasoid population from West Bengal.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention, excessive motor activity and impulsivity detected mostly during childhood. These traits are known to be controlled by monoamine neurotransmitters, chiefly dopamine, serotonin and norepinephrine. Monoamine oxidase A (MAOA) and B (MAOB), two isoenzymes bound to the outer membrane of mitochondria, are involved in the degradation of monoamines and were explored for association with ADHD in different ethnic groups. In the present study, few exonic as well as intronic MAOB variants were analyzed in ADHD probands (N = 150) and ethnically matched controls (N = 150) recruited following the Diagnostic and Statistical Manual for Mental Disorders-4(th) edition (DSM-IV). Appropriate scales were used for measuring the behavioural attributes. Gene variants were analyzed by amplification of target sites followed by DNA sequencing and data obtained were analyzed by population based statistical methods. RESULTS: Out of 34 variants present in the analyzed sites, only seven functional variants, rs4824562, rs56220155, rs2283728, rs2283727, rs3027441, rs6324 and rs3027440, were found to be polymorphic. rs2283728 'C' (P = 3.45e-006) and rs3027440 'T' (P = 0.02) alleles showed higher frequencies in ADHD probands as compared to controls. rs56220155 'A' (P = 0.04) allele and 'GA' (P = 0.04) genotype showed higher frequencies in the male and female ADHD probands respectively as compared to sex-matched controls. Analysis of pairwise linkage disequilibrium revealed striking differences between probands and controls. Haplotype analysis revealed significantly higher occurrence of different haplotypes in the ADHD probands while some haplotypes were detected in the controls only. Higher scores for conduct problems were found to be associated with rs56220155 'A' (P = 0.05) allele in the male ADHD probands. Multifactor dimensionality reduction analysis showed independent as well as interactive effects of polymorphic variants which were more robust in the male probands. CONCLUSIONS: Since all the polymorphic variants analyzed were functional, it may be inferred that MAOB gene variants are contributing to the etiology of ADHD in the Indo-Caucasoid population from eastern India which merits further in depth analysis.

Monoamine oxidase A polymorphism moderates stability of attention problems and susceptibility to life stress during adolescence.

Attention problems affect a substantial number of children and adolescents and are predictive of academic underachievement and lower global adaptive functioning. Considerable variability has been observed with regard to the individual development of attention problems over time. In particular, the period of adolescence is characterized by substantial maturation of executive functioning including attentional processing, with the influence of genetic and environmental factors on individual trajectories not yet well understood. In the present investigation, we evaluated whether the monoamine oxidase A functional promoter polymorphism, MAOA-LPR, plays a role in determining continuity of parent-rated attention problems during adolescence. At the same time, a potential effect of severe life events (SLEs) was taken into account. A multi-group path analysis was used in a sample of 234 adolescents (149 males, 85 females) who took part in an epidemiological cohort study at the ages of 11 and 15 years. Attention problems during early adolescence were found to be a strong predictor of attention problems in middle adolescence. However, in carriers of the MAOA-LPR low-activity variant (MAOA-L), stability was found to be significantly higher than in carriers of the high-activity variant (MAOA-H). Additionally, only in MAOA-L carriers did SLEs during adolescence significantly impact on attention problems at the age of 15 years, implying a possible gene × environment interaction. To conclude, we found evidence that attention problems during adolescence in carriers of the MAOA-L allele are particularly stable and malleable to life stressors. The present results underline the usefulness of applying a more dynamic GxE perspective.

Family-based association study of the arsenite methyltransferase gene (AS3MT, rs11191454) in Korean children with attention-deficit hyperactivity disorder.

We examined the association between the selected polymorphisms in two candidate genes, the arsenite methyltransferase gene (AS3MT, rs11191454) and the inter-α-trypsin inhibitors heavy chain-3 gene (ITIH3, rs2535629), and attention-deficit hyperactivity disorder (ADHD) in a Korean population. A total of 238 patients with ADHD, along with both of their biological parents, were recruited. The children were administered intelligence quotient tests, whereas their parents completed the Child Behavior Checklist. In the transmission disequilibrium test on 181 trios, we found overtransmission of the A allele at the AS3MT rs11191454 polymorphism in children with ADHD (χ²=8.81, P=0.003). However, there was no preferential transmission at the ITIH3 rs52535629 polymorphism (χ²=0.14, P=0.707). Our results provide preliminary evidence for the overtransmission of the A allele at the AS3MT rs11191454 polymorphism in ADHD.

Association between monoamine oxidase gene polymorphisms and attention deficit hyperactivity disorder in Korean children.

Attention deficit hyperactivity disorder (ADHD) is a common disorder of the school-age population. ADHD is familial and genetic studies estimate heritability at 80-90%. The aim of the present study was to investigate the association between the genetic type and alleles for the monoamine oxidase (MAO) gene in Korean children with ADHD. The sample consisted of 180 ADHD children and 159 control children. We diagnosed ADHD according to DSM-IV. ADHD symptoms were evaluated with Conners' Parent Rating Scales and Dupaul Parent ADHD Rating Scales. Blood samples were taken from the 339 subjects, DNA was extracted from blood lymphocytes, and polymerase chain reaction was performed for MAO polymorphism. Allele and genotype frequencies were compared using the chi-square test. We compared the allele and genotype frequencies of MAO gene polymorphism in the ADHD and control groups. This study showed that there was a significant correlation among the frequencies of the rs5906883 (odds ratio [OR]=1.47, 95% confidence interval [CI]=1.08-2.00, p=0.014) and the rs3027407 (OR=1.41, 95% CI=1.03-1.91, p=0.029) alleles of MAO, but the final conclusions are not definite. Follow-up studies with larger patient or pure subgroups are expected. These results suggested that MAO might be related to ADHD symptoms.

Catechol-O-methyltransferase Val158-Met polymorphism and a response of hyperactive-impulsive symptoms to methylphenidate: A replication study from South Korea.

We investigated the association between the catechol-O-methyltransferase (COMT) Val(158)-Met (rs4680) genotype and both subjective and objective treatment responses to methylphenidate in Korean children with attention-deficit/hyperactivity disorder (ADHD). We enrolled 120 medication-naïve children with ADHD in an open-label, 8-week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical Global Impression Scale and the ADHD Rating Scale-IV (ADHD-RS), and completed the Continuous Performance Test (CPT) before and after treatment. We found a significant association between the COMT Val/Val genotype and a good response, in terms of hyperactive-impulsive scores on the ADHD-RS (odds ratio (OR) = 2.61; p = 0.044) and response-time variability on the CPT (OR = 2.66; p = 0.028). The association of the COMT Val/Val genotype with a good response, in terms of response time variability, was significant in both the sub-sample of combined-type (OR = 3.45; p = 0.026) and sub-sample of inattentive-type (OR = 5.52; p = 0.029); but the association with a good response in terms of hyperactive-impulsive scores was not significant in sub-sample analyses. Although the reported nominally significant associations did not stay significant after correcting for multiple testing, our results support previous findings about the possible involvement of the COMT (Val(158)-Met) polymorphism in the treatment response to methylphenidate in children with ADHD.

Potential contribution of monoamine oxidase a gene variants in ADHD and behavioral co-morbidities: scenario in eastern Indian probands.

Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed behavioral disorder in children with a high frequency of co-morbid conditions like conduct disorder (CD) and oppositional defiant disorder (ODD). These traits are controlled by neurotransmitters like dopamine, serotonin and norepinephrine. Monoamine oxidase A (MAOA), a mitochondrial enzyme involved in the degradation of amines, has been reported to be associated with aggression, impulsivity, depression, and mood changes. We hypothesized that MAOA can have a potential role in ADHD associated CD/ODD and analyzed 24 markers in a group of Indo-Caucasoid subjects. ADHD probands and controls (N = 150 each) matched for ethnicity and gender were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV. Appropriate scales were used for measuring CD and ODD traits. Markers were genotyped by PCR-based methods and data obtained analyzed using the Cocaphase program under UNPHASED. Only eight markers were found to be polymorphic. rs6323 "G" allele showed higher frequencies in ADHD (P = 0.0023), ADHD + CD (P = 0.03) and ADHD + ODD (P = 0.01) as compared to controls. Haplotype analysis revealed statistically significant difference for three haplotypes in ADHD cases (P < 0.02). Statistically significant differences were also noticed for haplotypes in ADHD + CD and ADHD + ODD cases (P < 0.01). LD analysis showed significant variation in different groups. Multidimensionality reduction analysis showed independent as well as interactive effects of markers. Genotypes showed correlation with behavioral problems in ADHD and ADHD + CD. We interpret that MAOA gene variants may contribute to the etiology of ADHD as well as associated co-morbid CD and ODD in this ethnic group.

Aberrant CaMKII activity in the medial prefrontal cortex is associated with cognitive dysfunction in ADHD model rats.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurobehavioral disorder accompanied by cognitive and learning deficits, which is prevalent among boys. Juvenile male stroke-prone spontaneously hypertensive rats (SHRSP) exhibit ADHD-like behaviors including cognitive deficits and represent one animal model of ADHD. Here, we define a mechanism underlying cognitive dysfunction observed in SHRSP. Acute methylphenidate (MPH: 1mg/kg, p.o.) administration to SHRSP significantly improved not only inattention in a Y-maze task but also cognitive dysfunction in a novel object recognition test. Interestingly, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity, which is essential for memory and learning acquisition, was excessively elevated in the medial prefrontal cortex (mPFC) but not in the hippocampal CA1 region of SHRSP compared with Wistar-Kyoto (WKY) rats. We also confirmed that elevated CaMKII autophosphorylation in the mPFC causes increased phosphorylation of the CaMKII substrate α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid-type glutamate receptor subunit 1 (GluR1) (Ser-831). Ca(2+)-dependent phosphorylation levels of factors such as extracellular signal-regulated kinase (ERK) and protein kinase C (PKC) were unchanged in the SHRSP mPFC. Also, protein levels of the dopamine D2 receptor (D2R) but not the dopamine D1 receptor (D1R) were increased in the SHRSP mPFC. Acute MPH (1mg/kg, p.o.) administration attenuated aberrant CaMKII activity and increased GluR1 phosphorylation observed in SHRSP. Taken together, we propose that cognitive impairment in SHRSP is associated with aberrant CaMKII activity in the mPFC.

Role of COMT in ADHD: a systematic meta-analysis.

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable childhood-onset psychiatric disorder with significant genetic contribution. Considerable evidence has implicated involvement of dopaminergic system and the prefrontal cortex (PFC) in the pathomechanism of ADHD. The catechol-O-methyltransferase (COMT) gene is of particular interest for ADHD as its crucial role in the degradation of dopamine in the PFC. We summarized the reported findings investigating associations between COMT gene and ADHD and performed a meta-analysis of previous studies to assess the overall magnitude and significance of the association.

Catecholaminergic gene variants: contribution in ADHD and associated comorbid attributes in the eastern Indian probands.

Contribution of genes in attention deficit hyperactivity disorder (ADHD) has been explored in various populations, and several genes were speculated to contribute small but additive effects. We have assessed variants in four genes, DDC (rs3837091 and rs3735273), DRD2 (rs1800496, rs1801028, and rs1799732), DRD4 (rs4646984 and rs4646983), and COMT (rs165599 and rs740603) in Indian ADHD subjects with comorbid attributes. Cases were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV-TR after obtaining informed written consent. DNA isolated from peripheral blood leukocytes of ADHD probands (N = 170), their parents (N = 310), and ethnically matched controls (n = 180) was used for genotyping followed by population- and family-based analyses by the UNPHASED program. DRD4 sites showed significant difference in allelic frequencies by case-control analysis, while DDC and COMT exhibited bias in familial transmission (P < 0.05). rs3837091 "AGAG," rs3735273 "A," rs1799732 "C," rs740603 "G," rs165599 "G" and single repeat alleles of rs4646984/rs4646983 showed positive correlation with co-morbid characteristics (P < 0.05). Multi dimensionality reduction analysis of case-control data revealed significant interactive effects of all four genes (P < 0.001), while family-based data showed interaction between DDC and DRD2 (P = 0.04). This first study on these gene variants in Indo-Caucasoid ADHD probands and associated co-morbid conditions indicates altered dopaminergic neurotransmission in ADHD.

Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with ADHD in myelomeningocele patients.

The objective of this study was to examine the relation between the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and behaviors related to attention- deficit/hyperactivity disorder (ADHD) in individuals with myelomeningocele. The rationale for the study was twofold: folate metabolizing genes, (e.g. MTHFR), are important not only in the etiology of neural tube defects but are also critical to cognitive function; and individuals with myelomeningocele have an elevated incidence of ADHD. Here, we tested 478 individuals with myelomeningocele for attention-deficit hyperactivity disorder behavior using the Swanson Nolan Achenbach Pelham-IV ADHD rating scale. Myelomeningocele participants in this group for whom DNAs were available were genotyped for seven single nucleotide polymorphisms (SNPs) in the MTHFR gene. The SNPs were evaluated for an association with manifestation of the ADHD phenotype in children with myelomeningocele. The data show that 28.7% of myelomeningocele participants exhibit rating scale elevations consistent with ADHD; of these 70.1% had scores consistent with the predominantly inattentive subtype. In addition, we also show a positive association between the SNP rs4846049 in the 3'-untranslated region of the MTHFR gene and the attention-deficit hyperactivity disorder phenotype in myelomeningocele participants. These results lend further support to the finding that behavior related to ADHD is more prevalent in patients with myelomeningocele than in the general population. These data also indicate the potential importance of the MTHFR gene in the etiology of the ADHD phenotype.

Association study between the dopamine-related candidate gene polymorphisms and ADHD among Saudi Arabia population via PCR technique.

Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders characterized by inattention, hyperactivity and impulsivity. In Saudi Arabia the prevalence of combined ADHD is 16.4 %. ADHD etiology is not clear and not completely understood. There are several evidences for involvement of dopaminergic, serotonergic and noradrenergic neurotransmitter systems in the pathogenesis of ADHD. Monoamine Oxidase A (MAOA) is involved in the degradation of all three of these neurotransmitters. Dopamine Transporter 1 (DAT1) plays an important role in controlling blood levels of dopamine. The aim of the present study is to investigate the association between ADHD and polymorphisms of MAOA 30 bp-promoter VNTR and DAT1 40 bp 3' UTRVNTR in Saudi population. PCR technique was employed to detect polymorphisms of MAOA and DAT1 genes in a sample of 120 ADHD subjects and 160 controls. Alleles and genotypes frequencies for both of MAOA and DAT1 polymorphisms were compared among ADHD subjects against controls. Association between ADHD and alleles as well as genotypes for each studied polymorphisms was tested by odds ratio (OR) test and the magnitude of this association was estimated by 95 % confidence interval (95 % CI). A significant association was found between two MAOA genotypes 3/4 and 3/2 with ADHD (P < 0.01, OR = 3, 4.9) as a risk effect. No significant association was found with MAOA alleles. Among DAT1 polymorphisms two alleles (7 and 11 repeats) (P < 0.01, OR = 2.5 and 3.3) as well as two genotypes (11/11 and 11/7) (P < 0.01, OR = 4, 3) showed significant association with ADHD as a risk effect. On the contrary, 9 and 10 repeats revealed significant association as a protective effect as well as 10/10 and 10/9 genotypes. These findings support the hypothesis that some of the MAOA and DAT1 polymorphisms have a causative role in the development of ADHD in the Saudi population. Another polymorphism did not give rise to support this hypothesis. This is the first report investigated the association between MAOA and DAT1 polymorphism at molecular level in Saudi Arabia population as well as Arab world. Therefore further studies are needed to generalize obtained results at Saudi Arabia.