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.     

BDNF Val66Met and childhood adversity on response to physical exercise and internet-based cognitive behavioural therapy in depressed Swedish adults

The genetic effect of Brain-derived neurotrophic factor (BDNF) on treatment response in depression is not consistent in the literature. Childhood adversity is a known risk factor for depression which has been reported to increase depression susceptibility by interacting with BDNF genetic variation. We aimed to explore whether the BDNF variation Val66Met and childhood adversity (CA) predicted the treatment response to a 12-week intervention with physical exercise (PE) or internet-based cognitive behavioural therapy (ICBT) when compared with treatment as usual (TAU). A prospective cohort study nested within a randomised control trial was conducted using data from 547 participants with mild to moderate depression. Depression severity at baseline and follow-up was measured using the Montgomery-Åsberg Depression Rating Scale. Met allele carriers without exposure to CA and current antidepressant use showed higher treatment response to PE than Val homozygotes. There was no evidence to support that BDNF Val66Met or CA alone predicted treatment response to PE and ICBT. The Met carriers had higher serum mature BDNF level. These data suggest that Met allele carriers benefit more from PE treatment but only if they are not exposed to early adversity.     

Sex-specific association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and plasma BDNF with attention-deficit/hyperactivity disorder in a drug-naïve Han Chinese sample

A functional polymorphism of the brain derived neurotrophic factor gene (BDNF) (Val66Met) has been suggested to be involved in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). It also has an impact on peripheral BDNF levels in psychiatric disorders. This study examined the association of Val66Met with plasma BDNF level of ADHD in Han Chinese children (170 medication – naïve ADHD patients and 155 unaffected controls, aged 6–16 years). The Val allele was showed a higher frequency in females with ADHD (n=84) than controls (P=0.029) from the case-control association study. The analysis of covariance (ANCOVA) indicated that the mean plasma BDNF levels of ADHD patients were significantly higher than that of controls (P=0.001). We performed both total sample and sex stratified analyses to investigate the effect of Val66Met genotype on the plasma BDNF levels, but only a trend of association was found in females with ADHD (n=84), with a tendency of lower plasma BDNF level in Val allele carriers than Met/Met genotype carriers (P=0.071). Our results suggested a sex-specific association between BDNF and ADHD. Furthermore, there was a possible sex-specific relationship between the BDNF Val66Met genotype and plasma BDNF levels. However, further studies are required to elucidate the role of BDNF in ADHD.     

Smoking and BDNF Val66Met polymorphism in male schizophrenia: A case-control study

Some recent studies show an association between a functional polymorphism of BDNF gene (Val66Met) and the susceptibility to nicotine dependence and we hypothesized that this polymorphism was associated with smoking in both schizophrenia patients and healthy controls. The BDNF Val66Met gene polymorphism was genotyped in 690 chronic male schizophrenia patients (smoker/nonsmoker = 522/169) and 628 male controls (smoker/nonsmoker = 322/306) using a case-control design. Nicotine dependence (ND) was assessed by the cigarettes smoked per day (CPD), the Heaviness of Smoking Index (HSI), and the Fagerstrom Test for ND (FTND). Patients also were rated on the Positive and Negative Syndrome Scale (PANSS). The results showed no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. In patient groups, however, the smokers with the Met allele had significantly higher HSI scores (Met/Met: 2.8 ± 1.7 vs. Met/Val: 2.2 ± 1.7 vs. Val/Val: 2.0 ± 1.6, p < 0.01) and a trend toward a significantly higher FTND score (p = 0.09) than those with the Val/Val genotype. In addition, the smokers showed significantly lower PANSS negative symptom and total scores, longer duration of illness and more hospitalizations (all p < 0.05). In the control group, the smokers with the Met allele started smoking significantly earlier than those with the Val/Val genotype (both p < 0.05). These results suggest that the BDNF Val66Met polymorphism may affect a smoker's response to nicotine in both schizophrenia and healthy controls from a Chinese Han population, but with differential effects in different aspects of smoking behaviors.     

The association between brain-derived neurotrophic factor Val66Met variants and psychotic symptoms in posttraumatic stress disorder

Abstract

Objectives. Psychotic symptoms frequently occur in veterans with combat-related posttraumatic stress disorder (PTSD). Brain-derived neurotrophic factor (BDNF) plays a major role in neurodevelopment, neuro-regeneration, neurotransmission, learning, regulation of mood and stress responses. The Met allele of the functional polymorphism, BDNF Val66Met, is associated with psychotic disorders. This study intended to assess whether the Met allele is overrepresented in unrelated Caucasian male veterans with psychotic PTSD compared to veteran controls. Methods. The BDNF Val66Met variants were genotyped in 576 veterans: 206 veterans without PTSD and 370 veterans with PTSD subdivided into groups with or without psychotic features. Results. Veterans with psychotic PTSD were more frequently carriers of one or two Met alleles of the BDNF Val66Met polymorphism than veterans with PTSD without psychotic features and veterans without PTSD. Conclusions. The study shows that veterans with psychotic PTSD carried more Met alleles of the BDNF Val66Met than non-psychotic veterans with PTSD or veterans without PTSD. The results might add further support to the hypothesis that psychotic PTSD is a more severe subtype of PTSD.     

Association of the Val66Met polymorphism of the BDNF gene with primary cranial–cervical dystonia patients from South-west China

BackgroundThe etiology of primary dystonia remains unclear. Recent genetic studies suggest that the Val66Met polymorphism of the BDNF gene is a genetic modifier in cranial–cervical dystonia in Caucasians. However, the finding is not consistent.Patients and MethodsA total of 193 patients with primary cranial–cervical dystonia from the Department of Neurology, West China Hospital of Sichuan University was included. From the same region, 216 healthy individuals were recruited as a control group. The Val66Met SNP was identified by polymerase chain reaction-restriction fragment length polymorphism.ResultsIn the present study, cervical dystonia (59.59%) was the most common type of primary cranial–cervical dystonia. No significant difference was found in the genotype and minor allele frequencies between all patients and controls, between cervical dystonia patients and controls, and between craniocervical dystonia patients and controls. However, significant differences were found in the genotype and minor allele frequencies of Val66Met SNP between blepharospasm (BSP) patients and controls (P = 0.0080 and P = 0.0042, respectively), and between BSP patients and patients with craniocervical derived from BSP (P = 0.0010 and P = 0.0002, respectively).ConclusionMinor allele “A” of BDNF Val66Met SNP may increase the risk for developing BSP and may be a protective factor for preventing BSP progressing to craniocervical dystonia. More association studies involving a larger number of participants are needed to confirm the present findings.     

Lack of association between brain-derived neurotrophic factor Val66Met polymorphism and aggressive behavior in schizophrenia

We investigated the association of the Val66Met gene polymorphism in the Brain-Derived Neurotrophic Factor (BDNF) gene with aggressive behavior among Southern Han Chinese schizophrenia patients. We used polymerase chain reaction-restriction fragment length polymorphism to determine the genotypes and the Modified Overt Aggression Scale (MOAS) to measure aggressive behavior. No significant differences in genotype or allele distribution of Val66Met were identified between aggressive and non-aggressive schizophrenia patients.     

Food restriction leads to binge eating dependent upon the effect of the brain-derived neurotrophic factor Val66Met polymorphism

Brain-derived neurotrophic factor (BDNF) regulates food intake and energy metabolism. It has also been suggested that mutations in the human BDNF gene and its receptor TrkB account for disturbed eating and obesity. The Met-allele of the BDNF Val66Met polymorphism has been associated with eating disorders, but the underlying mechanism of its contribution is not known. We report herewith that the effect of BDNF Val66Met polymorphism on binge eating in adolescent girls is dependent on severe food restriction. The scores on EDI-2 Bulimia subscale were significantly higher in BDNF Met-allele carriers who made attempts to regulate their body weight by reducing their meal frequency or by starving. This finding may help to explain why some people develop binge eating in response to dieting and others do not.     

The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: A community twin-based study

PurposeTo test whether firstly, different parental rearing components were associated with different dimensions of psychiatric symptoms in adulthood, secondly BDNF-Val66Met polymorphism moderated this association and thirdly, this association was due to genetic confounding.MethodPerceived parental rearing according to Parental Bonding Instrument (PBI), psychiatric symptoms evaluated with the Brief Symptom Inventory (BSI) and the BDNF-Val66Met polymorphism were analyzed in a sample of 232 adult twins from the general population.ResultsIn the whole sample, paternal care was negatively associated with depression. Maternal overprotection was positively associated with paranoid ideation, obsession-compulsion and somatization. Gene-environment interaction effects were detected between the BDNF-Val66Met polymorphism and maternal care on phobic anxiety, paternal care on hostility, maternal overprotection on somatization and paternal overprotection also in somatization. In the subsample of MZ twins, intrapair differences in maternal care were associated with anxiety, paranoid ideation and somatization.ConclusionsMet carriers were, in general, more sensitive to the effects of parental rearing compared to Val/Val carriers in relation to anxiety and somatization. Contra-intuitively, our findings suggest that high rates of maternal care might be of risk for Met carriers regarding anxiety. Results from analyses controlling for genetic confounding were in line with this finding.     

Brain‐derived neurotrophic factor gene polymorphism predicts interindividual variation in the sleep electroencephalogram

Previous studies have suggested that brain‐derived neurotrophic factor (BDNF) participates in the homeostatic regulation of sleep. The objective of this study was to investigate the influence of the Val66Met functional polymorphism of the BDNF gene on sleep and sleep EEG parameters in a large population‐based sample. In total 337 individuals participating in the São Paulo Epidemiologic Sleep Study were selected for analysis. None of the participants had indications of a sleep disorder, as measured by full‐night polysomnography and questionnaire. Spectral analysis of the EEG was carried out in all individuals using fast Fourier transformation of the oscillatory signals for each EEG electrode. Sleep and sleep EEG parameters in individuals with the Val/Val genotype were compared with those in Met carriers (Val/Met and Met/Met genotypes). After correction for multiple comparisons and for potential confounding factors, Met carriers showed decreased spectral power in the alpha band in stage one and decreased theta power in stages two and three of nonrapid‐eye‐movement sleep, at the central recording electrode. No significant influence on sleep macrostructure was observed among the genotype groups. Thus, the Val66Met polymorphism seems to modulate the electrical activity of the brain, predicting interindividual variation of sleep EEG parameters. Further studies of this and other polymorphic variants in potential candidate genes will help the characterization of the molecular basis of sleep. © 2014 Wiley Periodicals, Inc.     

The BDNF Val66Met polymorphism is an independent risk factor for high lethality in suicide attempts of depressed patients

Some authors have reported an association of BDNF Val66Met polymorphism with suicidal behavior and/or clinical aspects of suicidal attempts. We evaluated, here, the impact of BDNF Val66Met polymorphism on the clinical characteristics of suicide attempts. The study was conducted on a cohort of 120 consecutive patients who were admitted to the Emergency Hospital of Porto Alegre, Brazil, due to a suicide attempt. Variables of univariate analyses were included in a logistic regression model to test whether the risk factors had independent effect. In univariate analyses, sex, BDNF genotype, intent and method of suicide attempt were all risk factors for high lethality in suicide attempts. After logistic regression analysis, male sex (O.R. = 3.03; 95% C.I = 1.34–6.84; 0.008) and the presence of BDNF 66Met allele (O.R. = 2.62; 95% C.I = 1.04–6.57; 0.04) were significantly and independently associated with the high lethality in suicide attempts. The present study showed that BDNF 66Met allele is an independent predictor of high lethality in suicide attempts of depressed patients. This finding is important because it might allow earlier identification of patients at high risk for suicide, perhaps providing better tools for clinical care of these patients in the future.     

Val66Met polymorphism association with serum BDNF and inflammatory biomarkers in major depression

Objectives: Current evidence supports participation of neurotrophic and inflammatory factors in the pathogenesis of major depressive disorder (MDD). Some studies reported an association between the Val66Met polymorphism (rs6265) of brain-derived neurotrophic factor (BDNF) gene with MDD and peripheral BDNF levels. However, no previous studies have examined the association of this polymorphism with inflammation. The present study assessed the association of the Val66Met polymorphism with serum levels of BDNF and inflammatory markers among depressed outpatients.

Methods: All participants (n?=?73) met DSM-IV criteria for a unipolar depressive episode. The serum levels of BDNF and inflammatory biomarkers (IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ) were compared between individuals presenting with at least one Met allele (Met-carriers) and those homozygous for the Val allele.

Results: In our sample (84.9% female, mean age 52.4?±?10.3 years), 24.7% (n?=?18) were Met-carriers. After Bonferroni correction, the Met allele was significantly associated with higher BDNF and lower TNF-α. These associations persisted after adjusting for potential confounders.

Conclusions: The pattern of low BDNF and high inflammation in MDD may be influenced by the Val66Met polymorphism. The association of a polymorphism in the BDNF gene with inflammatory markers in addition to BDNF levels suggests an interaction between these systems.     

Allelic differences in the brain-derived neurotrophic factor Val66Met polymorphism in late-life depression.

OBJECTIVE: The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with cognitive and neuroimaging changes. The authors examined the relationship between this polymorphism and depression in an elderly sample, hypothesizing that the Met66 allele would be associated with late-life depression. METHODS: A total of 245 elderly depressed white subjects and 94 elderly comparison white subjects completed clinical assessments and provided a blood sample for genotyping. Subjects were dichotomized as either homozygous for the Val66 allele or Met66 allele carriers. Gene frequencies were compared between groups, with separate analyses examining for differences in gene frequencies based on age of depression onset, family history, and depression history. Logistic regression models examined the relationship between genotype and depression after controlling for age, sex, and race. RESULTS: Depressed subjects were more likely to be Met66 allele carriers than were comparison subjects (38.8% versus 24.4%; chi(2) = 6.13, 1 df, p = 0.0133). This relationship remained significant after controlling for covariates (Wald chi(2) = 5.10, 1 df, p = 0.024; odds ratio: 1.92, 95% confidence interval: 1.09-3.38). There were no significant relationships between genotype and age of onset, number of episodes, or family history of depression. CONCLUSION: Met66 allele carriers have almost double the odds of having geriatric depression than do Val66 allele homozygotes. This polymorphism was unrelated to other clinical characteristics of depression in later life.     

The risk for major depression conferred by childhood maltreatment is multiplied by BDNF and SERT genetic vulnerability: a replication study

BackgroundThere is limited evidence for a moderating role of both serotonin transporter (SERT) and brain-derived neurotrophic factor (BDNF) genes on the risk for major depression (MD) developing after childhood maltreatment. However, research on this topic remains inconclusive, and there is a lack of data from longitudinal studies with large and representative population samples. Our study aimed to clarify whether, in the presence of previous childhood maltreatment, individuals carrying low functional alleles for both SERT 5-HTTLPR and BDNF Val66Met polymorphisms had a higher risk for MD.MethodsWe explored 2- and 3-way gene (SERT and BDNF) × environment (childhood maltreatment) interactions in a large sample of Spanish adults who were followed up over a 3-year period and assessed in person for both DSM-IV MD and exposure to childhood maltreatment.ResultsOur study included 2679 participants. Those with both the 5-HTTLPR s allele and the BDNF Met allele showed the highest risk of MD if they had previously experienced emotional (z = 2.08, p = 0.037), sexual (z = 2.19, p = 0.029) or any kind of childhood abuse (z = 2.37, p = 0.018). These 3-way interactions remained significant regardless of whether the 5-HTTLPR triallelic or the 5-HTTLPR biallelic polymorphisms were included in the analyses.LimitationsRetrospective assessment of childhood maltreatment may have resulted in a moderate degree of recall bias.ConclusionOur results confirm that the risk of depression conferred by childhood maltreatment is modified by variation at both SERT and BDNF genes.     

Interaction of the DRD3 and BDNF gene variants in subtyped bipolar disorder

Objectives

Bipolar disorder is a severe mental disorder with prominent genetic etiologic factors. Dopaminergic dysfunction has been implicated in the pathogenesis of bipolar disorder, which suggests that the dopamine D3 receptor gene (DRD3) is a strong candidate gene. The brain-derived neurotrophic factor (BDNF) gene has been implicated in the etiology of bipolar disorder. We examined the association between the BDNF Val66Met and DRD3 Ser9Gly polymorphisms with two subtypes of bipolar disorder: bipolar-I and -II. Because BDNF regulates DRD3 expression (1), we also examined possible interactions between these genes.

Methods

We recruited 964 participants: 268 with bipolar-I, 436 with bipolar-II, and 260 healthy controls. The genotypes of the BDNF Val66Met and DRD3 Ser9Gly polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis.

Results

Logistic regression analysis showed a significant main effect for the Val/Val genotype of the BDNF Val66Met polymorphism (P = 0.020), which predicted bipolar-II patients. Significant interaction effects for the BDNF Val66Met Val/Val genotype and both DRD3 Ser9Gly Ser/Ser and Ser/Gly genotypes were found only in bipolar-II patients (P = 0.027 and 0.006, respectively).

Conclusion

We provide initial evidence that the BDNF Val66Met and DRD3 Ser9Gly genotypes interact only in bipolar-II disorder and that bipolar-I and bipolar-II may be genetically distinct.     

Human BDNF rs6265 polymorphism as a mediator for the generalization of contextual anxiety

The Met allele of the human brain-derived neurotrophic factor (BDNF) gene might be a risk factor for anxiety disorders and is associated with reduced hippocampal volume. Notably, hippocampus plays a crucial role in contextual learning and generalization. The role of the BDNF gene variation in human context-conditioning and generalization is still unknown. We investigated 33 carriers of the Met allele (18 females) and 32 homozygous carriers of the Val allele (15 females) with a virtual-reality context-conditioning paradigm. Electric stimulations (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but never in another virtual office (CTX-). During generalization, participants revisited CTX+ and CTX- and a generalization office (G-CTX), which was a mix of the other two. Rating data indicated successful conditioning (more negative valence, higher arousal, anxiety and contingency ratings for CTX+ than CTX-), and generalization of conditioned anxiety by comparable ratings for G-CTX and CTX+. The startle data indicated discriminative learning for Met allele carriers, but not for Val homozygotes. Moreover, a trend effect suggests that startle responses of only the Met carriers were slightly potentiated in G-CTX versus CTX-. In sum, the BDNF polymorphism did not affect contextual learning and its generalization on a verbal level. However, the physiological data suggest that Met carriers are characterized by fast discriminative contextual learning and a tendency to generalize anxiety responses to ambiguous contexts. We propose that such learning may be related to reduced hippocampal functionality and the basis for the risk of Met carriers to develop anxiety disorders.     

A common polymorphism in the brain-derived neurotrophic factor gene in patients with adult-onset primary focal and segmental dystonia

Brain-derived neurotrophic factor (BDNF) modulates neuroplasticity. A functional polymorphism [Val66Met (G196A)] in BDNF has been reported to modify cortical plasticity in humans. Physiologic investigations have revealed that dystonia might be a consequence of the pathologic plasticity of the sensorimotor cortex. We aimed to investigate the role of the Val66Met polymorphism in a cohort of Serbian patients with adult-onset primary focal and segmental dystonia (PTD). One hundred and forty-nine patients with primary adult-onset PTD, 194 patients with Parkinson’s disease (PD), and 366 healthy control subjects were recruited for the study. Patients with PTD and PD, as well as healthy controls had a similar distribution of genotypes and allele frequencies. There was no any significant difference in the allelic distribution at the Val66Met SNP of the BDNF gene among patients with adult-onset PTD, PD, and healthy volunteers from the same geographic areas. In addition, the presence of the Met allele did not influence the clinical characteristics of PTD patients. Patients with the Met variant did not differ by age at onset, number of affected regions, and efficacy of a sensory trick. Met66Met is not associated with an increased risk of dystonia.     

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.     

BDNF Val66Met,stress, and positive mothering: Differential susceptibility model of adolescent trait anxiety

Etiological research has indicated the gene–environment interaction (G × E) on adolescent anxiety. This study aimed to examine how the BDNF Val66Met polymorphism interacted with stressful life events and positive mothering to influence youth trait anxiety. The study sample included 780 community adolescents of Chinese Han ethnicity (M = 13.6, 51.3% females). Participants’ trait anxiety, exposure to stressful life events, and mother's warmth-reasoning were assessed by self-reported questionnaires. We found that BDNF Val66Met polymorphism significantly moderated the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. The influences were significantly greater in adolescents carrying one or two Val allele than those with Met/Met genotype. Moreover, the G × E interactions were more consistent with the differential susceptibility than the diathesis–stress model. Adolescents carrying Val allele who were more susceptible to adversity were also more likely to benefit from supportive experiences. These findings provide novel evidence for the role of BDNF Val66Met as a genetic susceptibility modulating the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. We speculate that BDNF Val66Met may moderate anxious youths’ responses to mindfulness-based stress reduction program and family-based treatment targeting the enhancement of positive parenting.     

Association of COMT and PRODH gene variants with intelligence quotient (IQ) and executive functions in 22q11.2DS subjects

The 22q11.2 deletion syndrome (22q11.2DS) carries the highest genetic risk factor for the development of schizophrenia. We investigated the association of genetic variants in two schizophrenia candidate genes with executive function (EF) and IQ in 22q11.2DS individuals.Ninety two individuals with 22q11.2 deletion were studied for the genetic association between COMT and PRODH variants and EF and IQ. Subjects were divided into children (under 12 years old), adolescents (between 12 and 18 years old) and adults (older than 18 years), and genotyped for the COMT Val158Met (rs4680) and PRODH Arg185Trp (rs4819756) polymorphisms. The participants underwent psychiatric evaluation and EF assessment. Our main finding is a significant influence of the COMT Val158Met polymorphism on both IQ and EF performance. Specifically, 22q11.2DS subjects with Met allele displayed higher IQ scores in all age groups compared to Val carriers, reaching significance in both adolescents and adults. The Met allele carriers performed better than Val carriers in EF tasks, being statistically significant in the adult group. PRODH Arg185Trp variant did not affect IQ or EF in our 22q11.2DS cohort. In conclusion, functional COMT variant, but not PRODH, affects IQ and EF in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood. Future studies should monitor the cognitive performance of the same individuals from childhood to old age.