Ágnes Vetró

Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. BDNF markers included the (GT)n microsatellite, Val66Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val66Met polymorphism demonstrated significant overtransmission of the val allele (χ2=7.12, d.f.=1, P=0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT)n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z=2.095, P=0.036). Significant haplotypes involved Val66Met and BDNF2 (P=0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val66Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.

Learning in Autism: Implicitly Superb

Background Although autistic people have shown impairments in various learning and memory tasks, recent studies have reported mixed findings concerning implicit learning in ASD. Implicit skill learning, with its unconscious and statistical properties, underlies not only motor but also cognitive and social skills, and it therefore plays an important role from infancy to old age. Methodology/Principal Findings We investigated probabilistic implicit sequence learning and its consolidation in Autism Spectrum Disorder (ASD). Three groups of children participated: thirteen with high-functioning ASD, 14 age-matched controls, and 13 IQ-matched controls. All were tested on the Alternating Serial Reaction Time Task (ASRT), making it possible to separate general skill learning from sequence-specific learning. The ASRT task was repeated after 16 hours. We found that control and ASD children showed similar sequence-specific and general skill learning in the learning phase. Consolidation of skill learning and sequence-specific learning were also intact in the ASD compared to the control groups. Conclusions/Significance These results suggest that autistic children can use the effects/results of implicit learning not only for a short period, but also for a longer stretch of time. Using these findings, therapists can design more effective educational and rehabilitation programs.

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.

Depression in children.

Purpose of review This summary of literature published during the past year focuses on research into factors that may contribute to development of childhood-onset depression and on appropriate assessment and treatment. Recent findings The recent literature suggests that investigating risk factors and gene–environment interactions could be fruitful in elucidating the aetiology of childhood-onset depression and could have implications for developing preventive (selective or targeted programmes) and therapeutic strategies. These strategies clearly should involve interventions to improve parent–child relationships and parenting style, especially in children at high risk early in their lives. Cognitive–behavioural therapy, interpersonal therapy and (in the case of severe depression) selective serotonin reuptake inhibitor medications (fluoxetine as the first-line option, with close monitoring for adverse effects during treatment) appear to be effective in the management of depression in children. However, recent reports on psychotherapies yield a less clear picture about their effectiveness in childhood depression than was previously indicated. Summary Controlled trial data and evidence-based guidelines for management of depressed children are limited with respect to pharmacological and psychotherapeutic options, especially in prepubertal and preschool children. Further research in this area is therefore warranted.

Association Study of the Estrogen Receptor Alpha Gene (ESR1) and Childhood-Onset Mood Disorders

Depressive disorders are heterogeneous psychiatric disorders involving deficits in cognitive, psychomotor, and emotional processing. Depressive disorders have a significant genetic component, with severe, recurrent and early‐onset forms demonstrating elevated heritability. In this study we genotyped eleven single nucleotide polymorphisms (SNPs) spanning the estrogen receptor alpha gene (ESR1) in a large family‐based childhood‐onset mood disorder (COMD) sample. None of the individual SNP or global haplotype analyses was significant in the entire COMD sample, but haplotype analysis of three SNPs in strong linkage disequilibrium (rs746432, rs2077647, and rs532010) uncovered an association with COMD, specifically in females. Our data are consistent with previous studies demonstrating a female‐specific association between ESR1 and neurobehavioral phenotypes. These results suggest the existence of sex‐specific etiological factors in depressive disorders, related to estrogen, with onset in childhood.

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.

Association study of neurotrophic tyrosine kinase receptor type 2 (NTRK2) and childhood-onset mood disorders.

Childhood‐onset mood disorders (COMD) are often familial, and twin studies of COMD provide compelling evidence that genetic factors are involved. Deficits in neural plasticity have been suggested to underlie the development of depression. The receptor tropomyosin related kinase B (TrkB) and its ligand, brain derived neurotrophic factor (BDNF), play essential roles in neural plasticity, and mRNA expression of both of these genes has been shown to be influenced by stress and chronic antidepressant treatment. In addition, TrkB knock‐out mice display inappropriate stress coping mechanisms. Having previously shown that BDNF is associated with COMD, in this study we investigated the gene encoding TrkB, neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) as a susceptibility factor in COMD. We tested for association of NTRK2 with COMD in two independent samples: (a) a case‐control sample matched on ethnicity and gender, consisting of 120 cases who met DSM III/IV criteria for major depressive or dysthymic disorder before age 14 or bipolar I/II before the age of 18, and controls, and (b) a family based control sample of 113 families collected in Hungary, identified by a proband between the age of 7 and 14 who met DSM IV criteria for major depressive disorder or bipolar I/II disorder. There was no evidence for an allelic or genotypic association of three polymorphisms of NTRK2 with COMD in the case‐control sample. Also, in the family based sample, using the transmission disequilibrium test (TDT), we did not identify any evidence of allelic association for each marker individually or when haplotypes were analyzed. Based on these results, using these three polymorphisms, we do not find support for NTRK2 as a susceptibility gene for COMD.

Association study of CREB1 and childhood-onset mood disorders

Several lines of evidence suggest that the cellular pathways involved in synaptic plasticity contribute to the risk of depression. These findings include the evidence that chronic antidepressant treatment upregulates the cAMP signal transduction cascade resulting in increased expression and function of the cAMP responsive element binding protein (CREB), a transcription factor that increases the expression of key growth factors involved in synaptogenesis and neurogenesis. Recently, linkage to CREB1 was reported for early‐onset depression in families recruited from the Pittsburgh area. This finding was significant only in female sibling pairs from those families. Two specific DNA variants, −656G/A and a C insertion/deletion in intron 8, were identified in CREB1 that co‐segregated with depression in two of the families. We sought to investigate the relationship of CREB1 to childhood‐onset mood disorders (COMD) using a sample of 195 nuclear families (225 affected children) collected in Hungary. We genotyped the two CREB1 DNA variants previously identified as linked to depression as well as three additional polymorphisms spanning the gene. In addition, we genotyped the −656G/A DNA change and the intron 8 polymorphism in a sample of 112 probands with mood disorders collected in the Pittsburgh area and matched controls, and examined the distribution of alleles. The −656A allele was not observed in our samples and there was no evidence for association of the intron 8 polymorphism in either the sample from Pittsburgh (χ2 = 0.061, 1 d.f., P = 0.803) or Hungary (χ2 = 0.040, 1 d.f., P = 0.842). We found no evidence for an association with the other three polymorphisms or with the haplotypes of these markers. Further, we found no sex‐specific relationship. Our results, therefore, do not support the previous evidence for this gene as a major factor contributing to depression.

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.