Júlia Gádoros

Catechol‐O‐methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children

Methylphenidate is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD) but it is not effective in every case. Therefore, identifying genetic and/or biological markers predicting drug‐response is increasingly important. Here we present a case‐control study and pharmacogenetic association analyses in ADHD investigating three dopaminergic polymorphisms. Previous studies suggested variable number of tandem repeats (VNTR) in the dopamine D4 receptor (DRD4) and the dopamine transporter (DAT1) genes as genetic risk factors for ADHD and as possible markers of methylphenidate response. Our results did not indicate substantial involvement of these two VNTRs in ADHD, however, both the case‐control and the pharmacogenetic analyses showed significant role of the high activity Val‐allele of cathecol‐O‐methyltransferase (COMT) Val158Met polymorphism in our ADHD population. The Val‐allele was more frequent in the ADHD group (n = 173) compared to the healthy population (P = 0.016). The categorical analysis of 90 responders versus 32 non‐responders showed an association between the Val‐allele or Val/Val genotype and good methylphenidate response (P = 0.009 and P = 0.034, respectively). Analyzing symptom severity as a continuous trait, significant interaction of COMT genotype and methylphenidate was found on the Hyperactivity‐Impulsivity scale (P = 0.044). Symptom severity scores of all three genotype groups decreased following methylphenidate administration (P < 0.001), however Val/Val homozygote children had significantly less severe symptoms than those with Met/Met genotype after treatment (P = 0.015). This interaction might reflect the regulatory effect of COMT dominated prefrontal dopamine transmission on subcortical dopamine systems, which are the actual site of methylphenidate action.

Carboxylesterase 1 gene polymorphism and methylphenidate response in ADHD

Methylphenidate (MPH) is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD). Several pharmacogenetic studies suggested that catecholamine candidate genes influence individual MPH-responses, but these results are mostly contradictory. Genetic analyses of MPH metabolizing carboxylesterase 1 enzyme (CES1) have not been carried out, whereas, meta-analysis of CYP2D6 genetic variants has been already indicated significant pharmacogenetic differences in atomoxetine treatment. Here we present an association analysis of the CES1 Gly143Glu functional polymorphism in a Hungarian ADHD group (n = 173). The genotype frequencies were similar to that of the general population (5.8% vs 4.1% of Gly/Glu heterozygote). Pharmacogenetic analysis was conducted among 122 ADHD children treated with MPH. Neither the categorical analysis comparing 90 responders vs 32 non-responders, nor the dimensional analysis of Inattention and Hyperactivity-Impulsivity score reduction showed a significant main genotype effect. However, analyzing the daily dose, we observed an association with the rare 143Glu-variant: 5 patients in the responder group carrying the Glu-allele required lower doses of MPH for symptom reduction (0.410 +/- 0.127 vs 0.572 +/- 0.153 mg/kg, t(1,88) = 2.33, p = 0.022). This result warrants for further investigations of the CES1 gene in larger ADHD samples.

Dopaminergic candidate genes in tourette syndrome : Association between tic severity and 3' UTR polymorphism of the dopamine transporter gene

Multiple evidence suggests an involvement of the dopamine neurotransmitter system in Tourette syndrome (TS). Therefore, dopaminergic candidate genes are in the center of genetic association analyses of TS. In this study, 103 TS patients and their parents have been characterized for different dopamine‐related polymorphisms including the 48 bp variable number of tandem repeats (VNTR) of the dopamine D4 receptor (DRD4) gene, the 40 bp VNTR of the dopamine transporter (DAT1, SLC6A3) gene and the Val158Met polymorphism of the catechol‐O‐methyltransferase (COMT) gene. In addition, the 120 bp duplication and three single nucleotide polymorphisms (SNPs) were assessed in the promoter region of the DRD4 gene. The −616G allele and the 2‐G‐A‐C haplotype (i.e., the 2‐repeat form of the 120 bp sequence ∼ −616G ∼ −615A ∼ −521C combination) were preferentially transmitted, however, these results did not remain significant after correction for multiple testing. Case‐control analyses have also been carried out, resulting in negative findings. On the other hand, using a dimensional approach, the DAT1 40 bp VNTR showed an association with the peak tic‐severity as measured by the Yale Global Tic Severity Scale. Patients with at least one copy of the 9‐repeat allele had significantly more severe symptoms than individuals with the homozygous 10/10 genotype (P = 0.002). In summary, allele frequencies did not differ between cases and controls, but DAT1 genotype accounted for variations of tic severity within the TS group.

Association between the 120-bp duplication of the dopamine D4 receptor gene and attention deficit hyperactivity disorder: Genetic and molecular analyses†

Abnormalities of the dopamine neurotransmission have been hypothesized to play an important role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Promoter variants of the dopamine D4 receptor gene (DRD4) have attracted particular interest due to their possible role in regulation of gene transcription. Here we describe the haplotype analysis of the 120 base pair duplication (120‐bp dup) and three SNPs (−616C/G, −615A/G, −521C/T) in the 5′ region of the DRD4 gene among children with ADHD. We observed a trend (χ2 = 14.905, df = 9, P = 0.093) in the four‐locus haplotype distribution between ADHD probands (N = 173) and controls (N = 284). The homozygote genotype of the 1‐repeat form of the 120‐bp dup (1–1) had a significantly higher frequency among ADHD children than in controls (8.1% vs. 3.2%, χ2 = 5.526, df = 1, P = 0.019, Odds Ratio = 2.71). In addition, a novel, 4‐repeat allele was identified among ADHD patients. This particular allele has been cloned to the luciferase expression vector and its transcriptional activity has been compared to the 1‐ and 2‐repeat allele. The number of repeats of the 120‐bp dup was found to have an effect on transcriptional activity in both neuroblastoma and retinoblastoma cell lines in a dose‐dependent manner (1‐repeat > 2‐repeat > 4‐repeat). These results suggest that the 1‐repeat form of the 120‐bp dup might be a risk factor of ADHD, especially in the homozygous form and/or in the context of certain haplotypes.

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and Childhood-Onset Mood Disorders

Background/Aims: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. Methods: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. Results: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. Conclusion: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

Attention-deficit hyperactivity disorder and suicidality in a treatment naïve sample of children and adolescents.

BACKGROUND The aim of the present study was to investigate the possible association between attention-deficit/hyperactivity disorder (ADHD) and suicidality. METHODS Using a structured interview (Mini International Neuropsychiatric Interview Kid), the authors examined 418 treatment naïve children/adolescents (aged: 3-18 years). Suicidality was defined by the M.I.N.I. Kid as having any current suicidal ideations and/or suicide attempts. RESULTS Two hundred and eleven children/adolescents fulfilled the DSM-IV diagnosis of ADHD and a further 105 showed symptoms of ADHD in subthreshold level. Multiple mediation analyses resulted in a moderated meditational model in which the relationship between symptoms of ADHD and current suicidality was fully mediated by the symptoms of comorbid conditions, but this was moderated by age. In children under 12 years, significant mediators were the symptoms of specific anxiety disorders, while in the adolescent group symptoms of major depressive episode and dysthymia and symptoms of substance abuse/dependence approved as significant mediators. LIMITATIONS As the study was cross-sectional, it did not reveal any causal relationship among the investigated factors. Furthermore, as the study population included a treatment naïve clinical sample, we can assume that adolescents, who and/or whose family seek for help at the first time in this age belonged to the less sever end of the spectrum. CONCLUSIONS ADHD symptoms are associated with an increased risk of suicidality in treatment naïve children/adolescents. The mechanisms of this relationship can be understood only when developmental factors are considered. Our findings suggest that clinicians should screen suicidality and comorbid symptoms routinely in patients with ADHD.

Association of the GABRD gene and childhood-onset mood disorders

The chromosome 1p36 region was previously indicated as a locus for susceptibility to recurrent major depressive disorder based on a linkage study in a sample of 497 sib pairs. We investigated the gamma‐aminobutyric acid A (GABAA) δ receptor subunit gene, GABRD, as a susceptibility gene to childhood‐onset mood disorders (COMD) because of substantial evidence implicating GABAergic dysfunction in mood disorders and the position of this gene near the 1p36 linkage region. Using a sample consisting of 645 Hungarian families with a child/adolescent proband diagnosed with a mood disorder with the onset of the first episode before age 15, we found some evidence for the association of two polymorphisms located within the gene, rs2376805 and rs2376803, as well as significant evidence for biased transmission of the haplotypes of these two markers (global χ2 test for haplotypes = 12.746, 3 df, P = 0.0052). Furthermore, significant evidence of association was only observed in male subjects (n = 438) when the results were analyzed by sex (χ2 = 9.000 1 df, P = 0.003 for rs2376805). This was in contrast with the previous linkage findings, as LOD scores exceeding 3 were only in female–female pairs in that study. These findings point to the GABRD gene as a susceptibility gene for COMD; however, this gene may not explain the previous linkage finding.

The Association between Major Depressive Disorder in Childhood and Risk Factors for Cardiovascular Disease in Adolescence

Objective Depression in adults is associated with risk factors for cardiovascular disease (CVD). It is unclear, however, when the association between clinical depression and cardiac risk factors develops or how early in life this association can be detected. Methods In an ongoing study of pediatric depression, we compared CVD risk factors including smoking, obesity, physical activity level, sedentary behavior, and parental history of CVD across three samples of adolescents: probands with established histories of childhood-onset major depressive disorder (n = 210), never-depressed siblings of probands (n = 195), and controls with no history of any major psychiatric disorder (n = 161). Results When assessed during adolescence, 85% of the probands were not in a major depressive episode. Nevertheless, at that assessment, probands had a higher prevalence of regular smoking (odds ratio [OR] = 12.54, 95% confidence interval [CI] = 4.36–36.12) and were less physically active than controls (OR = 0.59, CI = 0.43–0.81) and siblings (OR = 0.70, CI = 0.52–0.94) and had a higher rate of obesity than did controls (OR = 3.67, CI = 1.42–9.52). Parents of probands reported high rates of CVD (significantly higher than did parents of controls), including myocardial infarction and CVD-related hospitalization (ORs = 1.62–4.36, CIs = 1.03–15.40). Differences in CVD risk factors between probands and controls were independent of parental CVD. Conclusions Major depression in childhood is associated with an unfavorable CVD risk profile in adolescence, and risks for pediatric depression and CVD may coincide in families. Effective prevention and treatment of childhood depression may be a means to reduce the incidence of adult CVD.

Further genetic evidence implicates the vasopressin system in childhood‐onset mood disorders

Studies in both animals and humans advocate a role for the vasopressin (AVP) system in the aetiology of depressive symptoms. Attention has particularly focused on the role of AVP in the overactivation of the hypothalamic‐pituitary‐adrenal (HPA)‐axis in mood disorders. Elevated AVP plasma levels have been found in mood disorder patients, which are often positively correlated with the severity of symptoms. We recently reported an association between childhood‐onset mood disorders (COMD) and polymorphisms in the receptor responsible for the AVP‐mediated activation of the HPA‐axis (AVPR1B). As genetic variation in the vasopressinergic system could provide a mechanism to explain the endocrine alterations observed in mood disorders, we investigated other genes in this system. The gene encoding AVP is the strongest candidate, particularly as genetic variation in this gene in rodents is associated with anxiety‐related behaviours. Six single‐nucleotide polymorphisms (SNPs) were genotyped across the AVP gene in a sample comprised of 586 Hungarian nuclear families ascertained through affected probands with a diagnosis of COMD. In addition, AVP coding and putative regulatory regions were screened for mutations using denaturing high‐performance liquid chromatography. One SNP, 3′ to the AVP, gene reached significance (P = 0.03), as did the overtransmission of a five‐marker haplotype with a frequency of 22% (P = 0.0001). The subsequent mutation screen failed to identify any putative functional polymorphisms. The outcome of this study, combined with our previous association between COMD and AVPR1B, implicates genetic variation in vasopressinergic genes in mediating vulnerability to COMD.

Age and sex analyses of somatic complaints and symptom presentation of childhood depression in a Hungarian clinical sample

OBJECTIVE To determine whether the symptom presentation of major depressive disorder (MDD) in a large clinical sample of youngsters is influenced by age, sex, and the interaction of age and sex. METHOD The sample included 559 children (mean age = 11.69 years; range, 7-14 years; 247 girls) with MDD recruited from 23 mental health facilities across Hungary. Psychiatric evaluations were conducted via the semistructured Interview Schedule for Children and Adolescents-Diagnostic Version (ISCA-D). Final DSM-IV diagnoses were rendered via the best-estimate diagnostic procedure. Evaluations were conducted between April 2000 and May 2005. RESULTS Six depression symptoms increased with age: depressed mood (odds ratio [OR] = 1.10, P < .05), hypersomnia (OR = 1.17, P < .05), psychomotor retardation (OR = 1.11 P < .05), fatigue (OR = 1.13, P < .01), thoughts of death (OR = 1.11, P < .05), and suicidal ideation (OR = 1.18, P < .01), while psychomotor agitation decreased with age (OR = 0.91, P < .05). Boys were less likely to evidence anhedonia (OR = 0.67, P < .05), insomnia (OR = 0.68, P < .05), and hypersomnia (OR = 0.56, P < .05) but more likely to have psychomotor agitation (OR = 1.59, P < .01). There were no age-by-sex interactions. Rates of somatic complaints did not decrease with age (OR = 1.01, P > .05). CONCLUSIONS The symptom presentation of MDD becomes somewhat more neurovegetative as children get older. However, girls display more affective and atypical symptoms across all age groups. Somatic complaints were common regardless of age and should be considered an associated feature of depression in children and adolescents.