Genetic epistasis between the brain-derived neurotrophic factor Val66Met polymorphism and the 5-HTT promoter polymorphism moderates the susceptibility to depressive disorders after childhood abuse

Background

Based on biological interactions between the serotonergic system and the brain-derived neurotrophic factor (BDNF), BDNF is a plausible candidate for a gene–gene–environment interaction moderating the interaction between the s/l- promoter polymorphism of the serotonin transporter (5-HTTLPR) and childhood abuse. We tested the hypothesis of a three-way interaction with respect to depressive symptoms.

Methods

2035 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and the Childhood Trauma Questionnaire. All subjects were genotyped for the BDNF Val66Met (rs6265) and the s/l 5-HTTLPR polymorphisms.

Results

Tobit regression analyses revealed a three-way-interaction between the three genotypes of 5-HTTLPR and the BDNF genotypes and overall childhood abuse for the BDI-II score (p = 0.02). Emotional abuse carried the main effect of the interaction (p = 0.008). The s/s genotype of the 5-HTTLPR exerted its negative impact on mental health after childhood abuse only in the presence of the BDNF Val/Val genotype but not in the presence of the BDNF Met allele. In contrast, the l allele of the 5-HTTLPR also emerged as a genetic risk factor for depression in carriers of one or two Met alleles.

Conclusions

Our results point to a gene–gene–environment interaction that relevantly impacts on the role of the s/s genotype of the 5-HTTLPR in childhood abuse: Depending on the BDNF background (Val/Val versus Met allele) the s/s genotype showed either protective or risk properties with regard to depressive symptoms.     

COMT Val158Met × SLC6A4 5-HTTLPR interaction impacts on gray matter volume of regions supporting emotion processing

There have been several reports on the association between the Val¹⁵⁸Met genetic polymorphism of the catechol-O-methyltransferase (COMT) gene, as well as the serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4), and frontolimbic region volumes, which have been suggested to underlie individual differences in emotion processing or susceptibility to emotional disorders. However, findings have been somewhat inconsistent. This study used diffeomorphic anatomic registration through exponentiated Lie algebra (DARTEL) whole-brain voxel-based morphometry to study the genetic effects of COMT Val¹⁵⁸Met and SLC6A4 5-HTTLPR, as well as their interaction, on the regional gray matter volumes of a sample of 91 healthy volunteers. An interaction of COMT Val¹⁵⁸Met × SLC6A4 5-HTTLPR genotypes with gray matter volume was found in bilateral parahippocampal gyrus, amygdala, hippocampus, vermis of cerebellum and right putamen/insula. In particular, the gray matter volume in these regions was smaller in individuals who were both COMT-Met and 5-HTTLPR-S carriers, or both COMT-Val and 5-HTTLPR-L homozygotes, as compared with individuals with intermediate combinations of alleles. The interaction of COMT Val¹⁵⁸Met and SLC6A4 5-HTTLPR adds to the understanding of individual differences in emotion processing.     

The catechol o‐methyltransferase (COMT) val158met polymorphism modulates the association of serious life events (SLE) and impulsive aggression in female patients with borderline personality disorder (BPD)

Wagner S, Baskaya Ö, Anicker NJ, Dahmen N, Lieb K, Tadi? A. The catechol o‐methyltransferase (COMT) val¹⁵⁸met polymorphism modulates the association of serious life events (SLE) and impulsive aggression in female patients with borderline personality disorder (BPD). Objective: We analyzed i) the effects of serious life events (SLE) on impulsive aggression, and ii) modulating effects of the COMT Val¹⁵⁸Met polymorphism on the association between SLEs and impulsive aggression in borderline personality disorder (BPD). Method: One hundred and twelve female BPD patients from Germany were included in this study. Impulsive aggression was assessed by the Buss‐Durkee‐Hostility Inventory (BDHI). Results: Childhood sexual abuse was associated with lower BDHI sum score (P = 0.003). In COMT Val¹⁵⁸Val carriers, but not in Val/Met and Met/Met carriers, childhood sexual abuse and the cumulative number of SLEs were associated with lower BDHI sum scores (P < 0.05). Conclusion: This study analyzing a specific gene × environment interaction in female BPD patients suggests an association between SLEs and impulsive aggression, as well as a modulating effect of the COMT Val¹⁵⁸Val genotype on the relation between SLEs and impulsive aggression.     

Attention-deficit/hyperactivity disorder phenotype is influenced by a functional catechol-O-methyltransferase variant

The catechol-O-methyltransferase gene (COMT) plays a crucial role in the metabolism of catecholamines in the frontal cortex. A single nucleotide polymorphism (Val¹⁵⁸Met SNP, rs4680) leads to either methionine (Met) or valine (Val) at codon 158, resulting in a three- to fourfold reduction in COMT activity. The aim of the present study was to assess the COMT Val¹⁵⁸Met SNP as a risk factor for attention-deficit/hyperactivity disorder (ADHD), ADHD symptom severity and co-morbid conduct disorder (CD) in 166 children with ADHD. The main finding of the present study is that the Met allele of the COMT Val¹⁵⁸Met SNP was associated with ADHD and increased ADHD symptom severity. No association with co-morbid CD was observed. In addition, ADHD symptom severity and early adverse familial environment were positive predictors of lifetime CD. These findings support previous results implicating COMT in ADHD symptom severity and early adverse familial environment as risk factors for co-morbid CD, emphasizing the need for early intervention to prevent aggressive and maladaptive behavior progressing into CD, reducing the overall severity of the disease burden in children with ADHD.     

Association between Novelty Seeking of opiate-dependent patients and the catechol-O-methyltransferase ValMet polymorphism

Background

Candidate genes of the dopaminergic system have been reported as key elements in shaping human temperament. Catechol-O-methyltransferase (COMT) plays a vital role in dopamine inactivation, and the Val¹⁵⁸Met single nucleotide polymorphism (rs4680) in its gene has been recently associated with the Novelty Seeking (NS) temperament scale of the Temperament and Character Inventory in studies of healthy adults, as well as methamphetamine abusers.

Method

Our goal was to examine the association between temperament dimensions of the Temperament and Character Inventory and the COMT Val¹⁵⁸Met variation in a Hungarian sample of 117 heroin-dependent patients and 124 nondependent controls.

Results

Case-control analysis did not show any significant difference in allele or genotype distributions. However, dimensional approach revealed an association between the COMT Val¹⁵⁸Met and NS (P = .01): both controls and opiate users with Met/Met genotypes showed higher NS scores compared to those with the Val allele. The NS scores are also significantly higher among opiate users; however, no interaction was found between group status and COMT genotype.

Conclusion

Association of the COMT polymorphism and NS temperament scale has been shown for heroin-dependent patients and controls regardless of group status.     

Association between Antipsychotics-Induced Restless Legs Syndrome and Tyrosine Hydroxylase Gene Polymorphism

Objective

Restless legs syndrome (RLS) has been reported to be more prevalent in schizophrenic patients who take antipsychotics. The cause of RLS is unknown but associated with dopaminergic deficiency. Tyrosine hydroxylase (TH) is the enzyme responsible for catalyzing the conversion of L-tyrosine to DOPA. The purpose of this study is to determine whether the TH gene Val81Met polymorphism is associated with antipsychotic-induced RLS.

Methods

One hundred ninety Korean schizophrenic patients were evaluated by the diagnostic criteria of the International RLS Study Group (IRLSSG). The genotyping was performed by PCR-based methods.

Results

Of the one hundred ninety schizophrenic patients, 44 (23.2%) were found to have RLS. Although there were no significant associations between TH genotypes or allele frequencies and RLS, when separate analyses were performed by sex (male or female), we detected significant differences in the frequencies of the genotype (χ²=6.15, p=0.046) and allele (χ²=4.67, p=0.031) of the TH gene Val81Met polymorphism between those with and without RLS in the female patients.

Conclusion

These findings suggest that the TH gene Val81Met SNP might be associated with antipsychotic-induced RLS in female schizophrenic patients.     

Kynurenine pathway is altered in BDNF Val66Met knock-in mice: Effect of physical exercise

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been correlated with increased predisposition to develop cognitive and psychiatric disorders, and with a reduced response to some therapeutic treatments. However, the mechanisms underlying these impairments are currently not completely understood. Remarkably, kynurenine pathway alterations have also been implicated in cognitive and psychiatric disorders. Moreover, recent evidence suggests that physical exercise may promote beneficial effects by controlling kynurenine metabolism in the muscle.The aim of the present study was to assess whether the kynurenine pathway was differentially regulated in sedentary and exercising wild-type (BDNF^Val/Val) and homozygous knock-in BDNF Val66Met (BDNF^Met/Met) mice. We found that plasma and hippocampal levels of kynurenic acid and the hippocampal mRNA levels of IDO1 and KAT2 protein levels were increased in BDNF^Met/Met mice and were not modulated by physical exercise. On the contrary, KAT1 protein levels in the gastrocnemius muscle were reduced, whereas MCP1 mRNA in the gastrocnemius muscle and GFAP protein in the hippocampus were increased in BDNF^Met/Met mice compared to BDNF^Val/Val mice, and reduced by physical exercise. Physical exercise increased plasmatic kynurenine levels only in BDNF^Met/Met mice, and protein levels of KAT1 and KAT4 in the gastrocnemius muscle and hippocampus respectively, regardless of the genotype. Finally, we found that physical exercise was able to enhance the hippocampal-dependent memory only in the BDNF^Val/Val mice. Overall our results showing an overactivation of the kynurenine pathway in the BDNF^Met/Met mice may suggest a possible mechanism underlying the cognitive deficits reported in the BDNF Val66Met carriers.     

Impact of COMT Val158Met‐polymorphism on appetitive conditioning and amygdala/prefrontal effective connectivity

Appetitive conditioning is an important mechanism for the development, maintenance, and treatment of psychiatric disorders like substance abuse. Therefore, it is important to identify genetic variations, which impact appetitive conditioning. It has been suggested that the Val¹⁵⁸Met‐polymorphism in the Catechol‐O‐Methyl‐Transferase (COMT) is associated with the alteration of neural processes of appetitive conditioning due to the central role of the dopaminergic system in reward processing. However, no study has so far investigated the relationship between variations in the COMT Val¹⁵⁸Met‐polymorphism and appetitive conditioning. In this fMRI study, an appetitive conditioning paradigm was applied, in which one neutral stimulus (CS+) predicted appetitive stimuli (UCS) while a second neutral stimulus (CS?) was never paired with the UCS. As a main result, we observed a significant association between the COMT Val¹⁵⁸Met‐genotype and appetitive conditioning: skin conductance responses (SCRs) revealed a significant difference between CS+ and CS? in Val/Val‐allele carriers but not in the other genotype groups. Val/Val‐allele carriers showed increased hemodynamic responses in the amygdala compared with the Met/Met‐allele group in the contrast CS+ > CS?. In addition, psychophysiological‐interaction analysis revealed increased effective amygdala/ventromedial prefrontal cortex connectivity in Met/Met‐allele carriers. The increased amygdala activity points to facilitated appetitive conditioning in Val/Val‐allele carriers while the amygdala/prefrontal connectivity results could be regarded as a marker for altered emotion regulation during conditioning, which potentially impacts appetitive learning sensitivity. The SCRs finding indicates a stronger conditioned response in the Val/Val‐allele group and dovetails with the neural differences between the groups. These findings contribute to the current research on COMT in emotional processing. Hum Brain Mapp 36:1093–1101, 2015. © 2014 Wiley Periodicals, Inc.     

Suicide ideators and attempters with schizophrenia--the role of 5-HTTLPR, rs25531, and 5-HTT VNTR Intron 2 variants

AimTo examine the role of 5-HTTLPR, rs25531 and 5-HTT VNTR Intron 2 variants in subjects with psychotic disorders manifesting suicide ideation and behaviour.MethodsThe study included 519 subsequently hospitalized subjects who were genotyped for 5-HTTLPR, rs25531 and 5-HTT VNTR In2 variants. Clinical assessments included structured psychiatric interview, sociodemographic characteristics, suicide ideation and behaviour (SIBQ), severity of psychopathology (PANSS) and depression (CDSS).ResultsThree subgroups were identified: suicide attempters (N = 161), suicide ideators (N = 174) and subjects who never reported suicide ideation or behaviour (comparative group, N = 184). Major findings: 1) Suicide attempters scored highest on the CDSS, while no differences between the three clinical subgroups were detected in the PANSS scores; 2) Suicide attempters were more frequently the carriers of L_A allele, while subjects in the comparative group were more frequently the carriers of low expression 5-HTTLPR/5-HTT rs25531 haplotype SL_G; 3) No difference was found between the three clinical groups in the 5-HTT VNTR In2 variants; 4) Subjects with 5-HTTLPR/5-HTT rs25531 intermediate expression haplotype (L_AL_G, SL_A) scored higher on the PANSS general psychopathology subscale; 5) There was no association between suicide attempt or ideation and 5-HTTLPR/In2 or 5-HTTLPR/rs25531/In2 haplotype distribution.ConclusionThe suicide ideators, attempters and controls did not differ significantly in 5-HTTLPR or 5-HTT VNTR In 2 variants, but 5-HTTLPR/5-HTT rs25531 haplotype might be a useful genetic marker in distinguishing these three clinical groups.     

COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life

Objective: A functional polymorphism in the catechol‐o‐methyltransferase gene (COMT Val¹⁵⁸Met) may moderate the psychosis‐inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted. Method: The experience sampling technique was used to collect data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25). Results: Carriers of the COMT Val¹⁵⁸Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure, conditional on prior evidence of psychometric psychosis liability. Conclusion: The findings confirm that in people with psychometric evidence of psychosis liability, COMT Val¹⁵⁸Met genotype moderates the association between cannabis and psychotic phenomena in the flow of daily life.     

No evidence of association betweenCatechol-O-Methyltransferase (COMT) Val158Met genotype and performance on neuropsychological tasks in children with ADHD: A case-control study

Background  

Several studies have suggested an association between the functionalVal ¹⁵⁸ Met polymorphism in theCatechol-O-Methyltransferase (COMT) gene and neurocognitive performance. Two studies showed that subjects with the low activityMet allele performed better on the Wisconsin Card Sorting Test (WCST) and another study found an effect on processing speed and attention.     

The 5-HTTLPR Polymorphism modulates the association of serious life events (SLE) and impulsivity in patients with Borderline Personality Disorder

Background

Impulsivity belongs to the key features of Borderline Personality Disorder (BPD). It has been linked to altered serotoninergic neurotransmission and, genetically, to an over-representation of the short (S) allele of the serotonin transporter promoter-linked polymorphic region polymorphism (5-HTTLPR). On the other hand, serious life events (SLE) are of major importance in the development of BPD. However, the inter-relations between SLEs, impulsivity, and 5-HTTLPR are not understood.

Method

159 BPD patients from Germany were included in this study. Impulsivity was assessed by the Barratt Impulsiveness Scale (BIS). We analysed (1) the effects of SLEs on impulsivity; and (2) modulating effects of the 5-HTTLPR polymorphism on the effects of SLEs on impulsivity.

Results

Regression analyses confirmed a decreasing effect of childhood sexual abuse, the cumulative SLE-related reactions and the impairment by SLEs on BIS sum score. Regarding BIS sum score, all SLEs except for rape were associated with a decrease of impulsivity in SS/SL carriers and an increase of BIS sum score in LL carriers.

Conclusions

This study analyzing a specific gene x environment interaction in BPD patients suggests an interaction between SLEs and the 5-HTTLPR S/L polymorphism in the development of impulsivity in BPD patients. Clinical and research implications are discussed.     

CACNA1C SNP rs1006737 associates with bipolar I disorder independent of the Bcl-2 SNP rs956572 variant and its associated effect on intracellular calcium homeostasis

Objectives. Intracellular calcium (Ca²⁺) dyshomeostasis (ICDH) has been implicated in bipolar disorder (BD) pathophysiology. We previously showed that SNP rs956572 in the B-cell CLL/lymphoma 2 (Bcl-2) gene associates with elevated B lymphoblast (BLCL) intracellular Ca²⁺ concentrations ([Ca²⁺]_B) differentially in BD-I. Genome-wide association studies strongly support the association between BD and the SNP rs1006737, located within the L-type voltage-dependent Ca²⁺ channel α1C subunit gene (CACNA1C). Here we investigated whether this CACNA1C variant also associates with ICDH and interacts with SNP rs956572 on [Ca²⁺]_B in BD-I. Methods. CACNA1C SNP rs1006737 was genotyped in 150 BD-I, 65 BD-II, 30 major depressive disorder patients, and 70 healthy subjects with available BLCL [Ca²⁺]_B and Bcl-2 SNP rs956572 genotype measures. Results. SNP rs1006737 was significantly associated with BD-I. The [Ca²⁺]_B was significantly higher in BD-I rs1006737 A compared with healthy A allele carriers and also in healthy GG compared with A allele carriers. There was no significant interaction between SNP rs1006737 and SNP rs956572 on [Ca²⁺]_B. Conclusions. Our study further supports the association of SNP rs1006737 with BD-I and suggests that CACNA1C SNP rs1006737 and Bcl-2 SNP rs956572, or specific causal variants in LD with these proxies, act independently to increase risk and ICDH in BD-I.     

COMT Val158Met polymorphism is related with interpersonal problem solving in schizophrenia

ObjectiveThe aim of this study was to investigate associations between COMT Val¹⁵⁸Met polymorphism, and interpersonal problem solving capacity and cognitive functions in schizophrenia.MethodsCOMT Val¹⁵⁸Met polymorphism was studied with ARMS-PCR method in 99 outpatients with schizophrenia. Brief Psychiatric Rating Scale was used to assess symptom severity. The Assessment of Interpersonal Problem Solving Skills (AIPSS) was used to evaluate problem solving capacity. Continuous Performance Test (CPT) and Wisconsin Card Sorting Test (WCST), were used to measure cognition.ResultsPatients with Met/Met genotype had higher AIPSS subscores for detecting the problem, than those with Val/Val at baseline (p = 0.02). Met allele was also found to be related with higher AIPSS-receiving skills (p = 0.04). Val allele was found to be related with more commission errors in CPT (p = 0.03). There was no relation between Val¹⁵⁸Met polymorphism and WCST and clinical measurements.ConclusionOur findings suggest that Val allele might be related to poor performance on detecting the interpersonal problems, and attention in schizophrenia.     

Executive attention in schizophrenic males and the impact of COMT Val108/158Met genotype on performance on the attention network test

Background: Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val^108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val^108/158Met on executive attention, using ANT. Methods: We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val^108/158Met genotype on executive attention as assessed by the ANT. Results: Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Conclusions: Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val^108/158Met on cognitive performance.     

Association of the functional serotonin transporter haplotype with familial form of obsessive compulsive disorder in Iranian patients

Objective: Several polymorphisms have been reported in the 5-HTTLPR of the serotonin transporter gene (SLC6A4). Family-based evidences for the association of 5-HTTLPR polymorphisms with OCD were previously reported but results were controversial. The present study investigated the possible correlation of SLC6A4 polymorphisms (5-HTTLPR, rs25532, rs25531) in Iranian OCD patients considering gender, age of onset, family history of psychiatric disorders, obsessive and compulsive subtypes and severities.

Methods: The included OCD patients fulfilled the criteria for DSM-IV-TR whom Y-BOCS score was more than 9. Blood samples (184 cases and 192 controls) were genotyped by means of PCR-RFLP.

Results: Mean of Y-BOCS scores of included patients was 20.1?±?0.69. Rs25532?CC genotype showed significant association with OCD in men and were detected more in the patients reported positive family history of psychiatric disorders but the other single loci (5-HTTLPR and rs25531) did not associate with OCD. Haplotype analysis showed significant association of 14-A variant with OCD and revealed the association of 14-A/14-A genotype with familial form of OCD.

Conclusions: The findings of this study showed the association of SLC6A4 variants with familial form of OCD and proposed stratified analyses in the genetic studies facilitate identification of genetic risk factors for this heterogeneous disorder.     

Association of the serotonin transporter promoter region polymorphism with biased attention for negative word stimuli

Background: Biased attention for emotional stimuli reflects vulnerability or resilience to emotional disorders. The current study examines whether the 5‐HTTLPR polymorphism is associated with attentional biases for negative word stimuli. Methods: Unmedicated, young adults with low current depression and anxiety symptoms (N=106) were genotyped for the 5‐HTTLPR, including the single nucleotide polymorphism (SNP) rs25531 in the long allele of the 5‐HTTLPR. Participants then completed a standard dot‐probe task that measured attentional bias toward anxiety, dysphoric, and self‐esteem words. Results: The L_AL_A allele group demonstrated an attentional bias away from negative word stimuli. This attentional bias was absent among the S/L_G carriers. Conclusions: These findings replicate previous work and suggest that 5‐HTTLPR L_A homozygotes possess a protective attentional bias that may decrease susceptibility to depression and anxiety. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

The serotonin transporter gene polymorphism (5-HTTLPR) and affective symptoms among women diagnosed with borderline personality disorder

Gene variants of the serotonin transporter have been associated with vulnerability to affective disorders. In particular, the presence of one or two copies of the short (s) allele of the 5-HTTLPR polymorphism has been associated with reduced serotonin transporter expression and function, and vulnerability to affective disorders. To test for an association between variants of the serotonin transporter gene polymorphism (5-HTTLPR) and relevant clinical features of borderline personality disorder (BPD), a psychiatric disorder with symptoms characteristic for serotonin dysfunction, 77 women with BPD were genotyped in the 5-HTTLPR polymorphism. They rated their subjective experience of borderline-specific, depressive, anxious and obsessive-compulsive symptoms, and were interviewed about lifetime incidence of suicide attempts and self-harming acts. Carriers of two s alleles of the 5-HTTLPR reported more symptoms of borderline, depression, anxiety and obsessive-compulsive behaviours, but not of suicidal and self-injury behaviour, compared to carriers of a long (l) allele. This indicates that the 5-HTTLPR ss homozygous genotype might influence serotonin function affecting susceptibility to both borderline-specific, depressive, anxious and obsessive-compulsive symptoms in BPD, and leading to a more severe symptomatology related to these clinical features. Further, this suggests that 5-HTT gene variants may not be as influential on suicidal and self-injury behaviour in BPD.     

No evidence for preferential transmission of common valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor gene (BDNF) in ADHD

Summary Attention deficit/hyperactivity disorder (ADHD) is a highly heritable common neurodevelopmental disorder with onset in childhood. A coding SNP (rs6265, Val66Met) of the brain-derived neurotrophic factor gene (BDNF) has recently been associated with ADHD. More specifically, paternal over-transmission of the common Val66 allele to affected children had been observed. We aimed to confirm these findings in a large, sufficiently powered, and well characterized German ADHD family sample. The Val66Met polymorphism of BDNF was genotyped in 294 families comprising one or more affected sibs (468 children). Contrary to previous reports, we did not observe over-transmission of the common Val66 allele, from either parent to affected children. We did not find support for an involvement of the Val66 allele of the Val66Met polymorphism of BDNF in the pathogenesis of ADHD in our sample. First two authors contributed equally.