Search

BackgroundOur study examined whether the early-onset depression phenotype among young adults (probands) is associated with the metabolic syndrome (MetS) and its components, and if MetS characterizes unaffected but high-risk siblings of probands.MethodsWe studied three groups of young adults (Mage = 25 years, s.d. = 3.84 years): probands with histories of childhood onset depression – i.e. early-onset phenotype – (n = 293), their unaffected siblings (high-risk siblings, n = 273), and healthy controls (n = 171). Participants completed a full psychiatric interview, physical and laboratory assessments, and self-rating scales. MetS was defined using the criteria of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001).ResultsEarly-onset depression phenotype and being a high-risk sibling were associated with higher MetS composite scores relative to that of controls, but did not differ from one another. With regard to MetS components: Probands and siblings had similarly larger waist circumference and lower HDL than did controls, while siblings and controls had lower triglyceride levels than did probands but did not differ from one another. Groups did not differ on glucose levels and SBP.ConclusionsOur study extends the literature on the association between MetS and depression and underscores the importance of depression phenotypes: failure to account for the clinical heterogeneity of depression may partly underlie the inconsistent findings regarding its relation to MetS. The results also suggest that, in depression-prone populations, MetS may predate and possibly function as a risk factor for eventual depression.

Background: Both depression and anxiety (two of the most common internalizing psychopathologies among youths) are associated with difficulties in emotion regulation (ER). Little is known about whether anxiety as a comorbid condition has an effect on the habitual use of different ER strategies in youngsters with depression histories. We aimed 1) to compare ER in adolescents with histories of childhood onset major depressive disorder (MDD) with and without comorbid anxiety and 2) to examine whether certain ER response clusters (Cognitive, Social, and Behavioral/Physical) characterize comorbid children and adolescents. Methods: We analyzed data on 217 youth (11–18 years old) with depression history: 85 subjects with lifetime anxiety comorbidity (comorbid group) and 132 without lifetime anxiety (non-comorbid group). Psychiatric diagnosis was established by a comprehensive Diagnostic and Statistical Manual of Mental Disorders (DSM) IV-based diagnostic procedure. ER strategies were examined via the self-rated “Feelings and Me” Child version questionnaire (FAM-C). Results: The comorbid group used maladaptive ER strategies significantly more frequently than the non-comorbid youngsters. The Behavioral/Physical and Social ER skills, especially those reflecting social withdrawal and self-harm, were responsible for the higher maladaptive scores. Limitations: Because our study is a cross-sectional analysis, we have no information about the development or the onset of maladaptive ER strategies. Therefore, we were unable to examine whether maladaptive ER was a risk factor or a consequence of the internalizing psychopathology and comorbidity. Conclusions: Comorbid anxiety worsens the impaired use of ER strategies in depression-prone youths. Further longitudinal research is needed to explore the causal role of dysfunctional ER in the development of internalizing psychopathology.

Hyphae represent a hallmark structure of multicellular fungi with immense importance in their life cycle, including foraging for nutrients, reproduction, or virulence. Hypha morphogenesis has been the subject to intense interest, yet, the origins and genetic underpinning of the evolution of hyphae are hardly known. Using comparative genomics, we here show that the emergence of hyphae correlates with multiple types of genetic changes, including alterations of gene structure, gene family diversification as well as co-option and exaptation of ancient eukaryotic genes (e.g. phagocytosis-related genes). Half of the gene families involved in hypha morphogenesis have homologs in unicellular fungi and non-fungal eukaryotes and show little or no duplications coincident with the origin of multicellular hyphae. Considerable gene family diversification was observed only in transcriptional regulators and genes related to cell wall synthesis and modification. Despite losing 35-46% of their genes, yeasts retained significantly more multicellularity-related genes than expected by chance. We identified 414 gene families that evolved in a correlated fashion with hyphal multicellularity and may have contributed to its evolution. Contrary to most multicellular lineages, the origin of hyphae did not correlate with the expansion of gene families encoding kinases, receptors or adhesive proteins. Our analyses suggest that fungi took a unique route to multicellularity that involved limited gene family diversification and extensive co-option of ancient eukaryotic genes.

The purpose of this study was to test developmentally informed hypotheses about regulatory responses to sadness that attenuate versus exacerbate it (adaptive versus maladaptive mood repair responses, respectively) across late childhood, early adolescence, and mid-adolescence. In a multi-site study in Hungary, clinic-based, 7- to 14-year-olds with Diagnostic and Statistical Manual of Mental Disorders' (4th ed., text rev.) depressive disorders (N = 697; 55% male) and age/sex matched (at 1:2) nondepressed, school-based controls (N = 1,394) reported on their usual responses to sadness/dysphoria; parental reports were obtained separately. Adaptive and maladaptive response repertoire scores were compared across ages within and across subject groups, and by informant, controlling for confounds. Contrary to Hypothesis 1, older (vs. younger) youths in both groups reported fewer adaptive regulatory responses. Maladaptive response repertoires were unrelated to age among controls but significantly increased with age among depressed youths, particularly the girls. Partially supporting Hypothesis 2, subject groups differed in age-related trajectories of mood repair repertories, but not as expected (e.g., younger depressed children reported larger adaptive response repertoires than did controls). Parental reports revealed no developmental changes in offspring's mood repair repertories. Parent-offspring reports were most discordant for younger (vs. older) offspring, tended to converge around age 11, and were consistently and significantly larger in the depressed sample. Self-reported adaptive mood repair repertories appear to have been laid down by late childhood and then undergo "trimming" across ages 7-14 years. The extensive maladaptive mood repair response repertoires of depressed youths, which increased with age, distinguish them primarily from controls. Therefore, reducing maladaptive regulatory responses to sadness should be a priority when treating depressed youths.

Background Adversity during early development has been shown to have enduring negative physiological consequences. In turn, atypical physiological functioning has been associated with maladaptive processing of negative affect, including its regulation. The present study therefore explored whether exposure to adverse life events in childhood predicted maladaptive (less flexible) parasympathetic nervous system functioning during the processing of negative affect among adolescents with depression histories. Methods An initially clinic-referred, pediatric sample (N = 189) was assessed at two time points. At Time 1, when subjects were 10.17 years old (SD = 1.42), on average, and were depressed, parents reported on adverse life events the offspring experienced up to that point. At Time 2, when subjects were 17.18 years old (SD = 1.28), and were remitted from depression, parents again reported on adverse life events in their offspring's lives for the interim period. At time 2, subjects' parasympathetic nervous system functioning (quantified as respiratory sinus arrhythmia) also was assessed at rest, during sad mood induction, and during instructed mood repair. Results Extent of adverse life events experienced by T1 (but not events occurring between T1 and T2) predicted less flexible RSA functioning 7 years later during the processing of negative affect. Adolescents with more extensive early life adversities exhibited less vagal withdrawal following negative mood induction and tended to show less physiological recovery following mood repair. Conclusions Early adversities appear to be associated with less flexible physiological regulatory control during negative affect experience, when measured later in development. Stress-related autonomic dysfunction in vulnerable youths may contribute to the unfavorable clinical prognosis associated with juvenile-onset depression.

Although hedonic capacity is diminished during clinical depression, it is unclear whether that deficit constitutes a risk factor or persists after depression episodes remit. To examine these issues, adolescents with current/past major depression (probands; n = 218), never-depressed biological siblings of probands ( n = 207), and emotionally well controls ( n = 183) were exposed to several positively valenced probes. Across baseline and hedonic probe conditions, controls consistently reported higher levels of positive affect than high-risk siblings, and siblings reported higher levels of positive affect than probands (remitted and depressed probands’ reports were similar). Extent of positive affect across the protocol predicted adolescents’ self-reports of social support network and parental reports of offspring’s use of various adaptive mood repair responses in daily life. Attenuated hedonic responding among youths remitted from depression offers partial support for anhedonia as a trait, whereas its presence among never-depressed high-risk siblings argues for anhedonia as a potential diathesis for clinical depression.

Summary Background Oxytocin (OXT) and prolactin (PRL) are neuropeptide hormones that interact with the serotonin system and are involved in the stress response and social affiliation. In human studies, serum OXT and PRL levels have been associated with depression and related phenotypes. Our purpose was to determine if single nucleotide polymorphisms (SNPs) at the loci for OXT , PRL and their receptors, OXTR and PRLR , were associated with childhood-onset mood disorders (COMD). Methods Using 678 families in a family-based association design, we genotyped 16 SNPs at OXT , PRL , OXTR and PRLR to test for association with COMD. Results No significant associations were found for SNPs in the OXTR , PRL , or PRLR genes. Two of three SNPs 3′ of the OXT gene were associated with COMD ( p ≤ 0.02), significant after spectral decomposition, but were not significant after additionally correcting for the number of genes tested. Supplementary analyses of parent-of-origin and proband sex effects for OXT SNPs by Fisher's Exact test were not significant after Bonferroni correction. Conclusions We have examined 16 OXT and PRL system gene variants, with no evidence of statistically significant association after correction for multiple tests.

The chromosome 13q region has been linked to bipolar disorder in a number of genome scans as well as focused linkage studies. Previously we identified linkage to the 13q32 region in a genome scan of 146 affected sibling pair families from Hungary with juvenile-onset mood disorders. Within this region are the overlapping genes G72/G30, with G72 now officially named as D-amino-acid oxidase activator (DAOA). This locus has been associated with panic disorder, schizophrenia, and bipolar disorder. In this study, we tested for association to 11 markers in these genes and mood disorders in a sample of 646 nuclear families identified with a proband with onset of a mood disorder before 14.9 years of age. We identified evidence for association to three markers within the gene (rs2391191, rs3918341, rs1935062), two of which had been associated with bipolar disorder in previous studies. When corrected for the number of markers tested, the results were no longer significant, however the prior evidence for association of this gene in multiple studies points to this gene as a potential contributor to juvenile-onset mood disorders. © 2008 Wiley-Liss, Inc.

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.

Genome scans have revealed significant evidence for linkage of depression to chromosome 15q25.3-q26.2. The gene for neurotrophic tyrosine kinase receptor 3 (NTRK3), the receptor for neurotrophin-3 (trkC) and a key gene in neurotrophin signaling, is located within this region and, given evidence for synaptic plasticity as a mechanism in mood disorders, was considered a prime candidate. The authors investigated NTRK3 as a susceptibility gene for childhood-onset mood disorders.The study sample consisted of 603 families with 723 affected children and adolescents diagnosed with a mood disorder with onset of the first episode by age 15. The authors genotyped 18 polymorphic markers across the NTRK3 gene in this sample and tested for association.Results identified significant evidence for association for five of the markers using the transmission disequilibrium test. Four of the five markers were located in a region of strong linkage disequilibrium and were highly correlated. Haplotype results provided significant evidence for association to haplotypes composed of markers located in two haplotype blocks.The results for NTRK3 as well as the authors' previous finding for association to brain-derived neurotrophic factor in this sample support synaptic plasticity as a mechanism contributing to mood disorders that begin during childhood and adolescence and specifically implicate the NTRK3 gene as a contributing factor in the 15q-linked region.

We investigated the relationship of the gene for the X-linked orphan G protein-coupled receptor (GPR50) to childhood-onset mood disorders in a sample of 384 families with 468 affected children and adolescents collected in Hungary. Our choice of this gene for study was based on a previous report of an association of GPR50 with bipolar disorder and major depressive disorder. A significant association with the deletion allele of an insertion/deletion polymorphism (Delta502-505) located in exon 2 had been reported in a sample of 226 patients with major depressive disorder and 264 patients with bipolar disorder. The association was more significant in females compared with males in those samples. We used for this study a polymorphism in complete linkage disequilibrium with the Delta502-505 polymorphism, Thr532Ala (rs561077), and two additional polymorphisms, Val606Ile (rs13440581) and an intronic polymorphism (rs2072621). We found no evidence for an association for the markers analyzed individually, nor for haplotypes of these markers. Further, we found no evidence of association when the results were analyzed in girls only (n=215). We, therefore, failed to replicate the previous association of this gene with mood disorders.

Study Objectives: To examine sleep disturbance (insomnia and hypersomnia) and associated clinical profiles among depressed children and adolescents in terms of illness history, depressive severity, depressive phenomenology, and psychiatric comorbid disorders. Design: Clinical profiles from standardized clinical evaluations were compared. Setting: Twenty-three mental health facilities in Hungary between April 2000 and December 2004. Patients and Measurements: Five hundred fifty-three children with a current episode of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition major depressive disorder: 55% were boys, mean age was 11.7 years (SD = 2.0, range = 7.3-14.9), and 94% were Caucasian. Sleep and depressive symptoms were assessed with the Interview Schedule for Children and Adolescents-Diagnostic Version. Interventions: N/A. Results: Of the total sample, 72.7% had sleep disturbance: 53.5% had insomnia alone, 9.0% had hypersomnia alone, and 10.1% had both disturbances. Depressed girls were more likely to have sleep disturbance than boys (77.0% vs 69.2%, p

OBJECTIVE: To examine various forms of suicidality specified in DSM-IV and their clinical characteristics in a large sample of children and adolescents with major depressive disorder (MDD). METHOD: Subjects included 553 children and adolescents (aged 7.0-14.9 years) recruited between April 2000 and December 2004 from 23 mental health facilities in Hungary. Subjects received standardized clinical evaluations and best-estimate consensus DSM-IV diagnoses of MDD. All subjects were in a current episode of MDD at their assessment date. RESULTS: Approximately 68% of the sample had recurrent thoughts of death, 48% had suicidal ideation, 30% had suicide plan, and 12% had attempted suicide. Compared with nonsuicidal peers, suicidal children and adolescents were more severely depressed, had more depressive symptoms, and more likely had comorbid disorders. However, depressed children and adolescents with various forms of suicidality were very similar in clinical characteristics. Feelings of worthlessness, depressed mood, psychomotor agitation, and comorbid separation anxiety and conduct disorders were independent correlates of at least 1 form of suicidality. Only feelings of worthlessness was related to all 4 suicidal behaviors, after adjustment for other depressive symptoms, comorbid disorders, and demographics. CONCLUSION: Clinical characteristics differ between nonsuicidal and suicidal children and adolescents but are very similar across various forms of suicidality. Feelings of worthlessness may play a central role in the development of suicidal behavior. Interventions toward the enhancement of self-esteem and amelioration of underlying psychopathology may be crucial for the prevention of suicide attempts in depressed children and adolescents. Language: en

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.

Background: Genome-wide association studies (GWAS) of bladder cancer risk recently identified several signals on chromosome 20p12.2 marked by single nucleotide polymorphisms (SNPs) rs6104690, rs62185668 and rs6108803 (Figueroa et al, HMG, 2015). Interestingly, associations of SNPs rs62185668 and rs6108803 were significantly stronger for the risk of muscle-invasive (stages T2-T4) compared to non-muscle-invasive (stages Ta and T1) bladder cancer, suggesting that detailed analysis of these signals could further our understanding of aggressive bladder cancer. Methods: We used data from The Cancer Genome Atlas (TCGA) bladder cancer set (n = 412) and an independent RNA-seq dataset for 12 bladder tissues. qRT-PCR analysis was performed with custom TaqMan assays in an additional set of 40 tumor and 40 adjacent normal bladder tissue samples. RNAscope in situ hybridization analysis with custom probes was used to evaluate mRNA expression in bladder tissue microarrays that included 7 pairs of normal-tumor bladder tissues. Results: At a distance of more than 300 and 800 Kb, JAG1 and BTD3 are the closest genes to the GWAS signals in the 20p12.2 region. Analysis of TCGA data did not show significant association of JAG1 and BTD3 expression with genotypes of 20p12.2 GWAS markers analyzed through TCGA-genotyped proxies SNPs rs6040291 and rs6074214. Using RNA-seq data in an independent set of 12 bladder tissue samples, we discovered a novel putative gene in the 20p12.2 region. Cloning of this gene from bladder tumor tissue and annotation by several methods showed two alternative splicing forms, designated as major and minor transcripts. Expression of the major transcript in bladder tumors was significantly increased with the rs6104690-A allele (P = 0.014), which is associated with increased risk of bladder cancer. SNPs with stronger association with muscle-invasive bladder cancer (rs62185668 and rs6108803) showed weaker or non-significant associations with expression of this novel transcript (P = 0.037 and P = 0.42, respectively). This transcript might be protein-coding as it is predicted to have several open reading frames for short peptides, or it may be a long non-coding RNA (lncRNA). RNAscope analysis in bladder tumors showed nuclear expression of the major transcript. Functional analysis of this novel gene in relation to bladder cancer is underway. Conclusions: A novel gene might be related to the GWAS signals within the 20p12.2 region and the risk of bladder cancer. Citation Format: Rouf Banday, Wusheng Yan, Candace D. Middlebrooks, Eniko Kiss, Ludmila Prokunina-Olsson. Analysis of a novel gene in relation to bladder cancer GWAS signals within the 20p12.2 region. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2563.

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 (GABA(A)) delta 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 chi(2) 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 (chi(2) = 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.

Mother-child agreement and influencing factors were studied in depressed and non-depressed children.We hypothesized that age and gender of the child and maternal depression influenced mother-child agreement; parents of depressed children underestimated the quality of life of their children; agreement was better in older and non-depressed children.We studied depressed children with Major Depressive Disorder (n = 354, mean age = 11.69 +/- 2.05 years), and non-depressed school-age children (n = 1695, mean age = 10.34 +/- 2.19 years). Psychiatric diagnosis was obtained by a semi-structured interview; depressive symptoms and quality of life were measured by self-reported questionnaires.Mother-child agreement about depressive symptoms increased as children got older. Mother-son reports showed significant difference, mother-daughter reports were similar. Depressed mothers reported more serious symptoms for their children. Depressed children's parent rated lower quality of life than children for themselves. Agreement was influenced by depression of the child and only marginally by age.Age and psychiatric illness of the examined person influences agreement, which finding may well be important in practice.

The authors summarize their experiences in research organization accumulated during 13 years. At first they outline preliminary studies which are prerequisites of high prestige international grants. Then they describe the huge administrative apparatus dedicated - besides skilled professionals - for the construction and organization of the research, the management, continuous checking and evaluation of data in such a multisite study. Finally, they report on the scientific results obtained after 13 years of hard work.

Recent evidence supports a pathological link between heart disease and depressive symptoms, suggesting that depression is both etiologic and prognostic to heart disease. Thus, biological molecules which are at the interface between heart and mind are plausible candidate genes for depressive disorders. To investigate this line of enquiry we have investigated two genes, Endothelin 1 (EDN1) and Angiotensin-converting enzyme (ACE) in a family-based sample with childhood-onset mood disorders (COMDs). EDN1 is highly expressed in endothelium where it acts as a potent vasoconstrictor, and is also expressed in the brain where it exhibits neurotransmitter characteristics. ACE acts as a potent vasopressor, and interacts with the hypothalamic-pituitary-adrenocortical (HPA) system, which is often dysregulated in mood disorders. Furthermore, ACE has recently been found to be associated with major depression. Polymorphisms were selected to best capture the genetic variation at the two loci, and to replicate previous associations. The markers were genotyped across EDN1 and ACE in a sample comprised of 382 Hungarian nuclear families ascertained through affected probands diagnosed with a mood disorders before the age of 15. We found no evidence of association between either of these genes and COMD. Consequently, we were unable to support our hypothesis that these two genes, which are involved in both vascular and brain functions are contributing to the susceptibility to mood disorders of children/adolescents.

GRIN1 rs4880210 139,143,515 50 G T 0.122 0.878 76 70 0.247 0.619 rs28489906 139,158,220 Intron 2 G A 0.470 0.530 171 170 0.003 0.957 rs6293 139,171,059 Exon 6 A G 0.692 0.303 166 157 0.251 0.616 rs10747050 139,175,697 Intron 11 A G 0.951 0.049 24 33 1.427 0.232 GRIN2A rs1071504 10,187,517 50 C T 0.279 0.721 138 144 0.128 0.721 rs2302711 10,183,199 Intron 2 C T 0.282 0.718 141 140 0.004 0.952 rs1070503 10,172,675 Intron 3 C T 0.866 0.134 67 79 0.987 0.320 rs727605 9,863,065 Intron 5 G A 0.694 0.306 161 133 2.671 0.102 rs8049651 9,851,167 Exon 6 G A 0.726 0.274 153 125 2.825 0.093 rs1014531 9,763,295 Exon 14, 30UTR G A 0.617 0.383 184 163 1.272 0.260 G A 0.797 0.203 117 109 0.283 0.594 rs2284416 13,810,481 Intron 2 T G 0.464 0.536 174 189 0.620 0.431 rs2268115 13,760,992 Intron 3 T G 0.561 0.439 169 170 0.003 0.957 rs2284407 13,733,473 Intron 3 G T 0.582 0.418 186 176 0.276 0.599 rs2268097 13,644,099 Intron 9 A G 0.583 0.417 170 174 0.047 0.829 rs890 13,606,575 Exon 13, 30UTR G T 0.452 0.548 183 172 0.341 0.559

Purpose: An important question in child psychiatry is the agreement between parents and children. We studied mother–child concordance about the quality of life of children (QoL). We hypothesized that mothers of depressed children rate lower QoL than children for themselves while mothers of non-depressed children rate better QoL; that inter-informant agreement is higher in the non-depressed sample; and finally that agreement increases with age of the child. Methods: QoL of depressed children (N = 248, mean age 11.45 years, SD 2.02) were compared to that of non-depressed children (N = 1695, mean age 10.34 years, SD 2.19). QoL was examined by a 7 item questionnaire (ILK). Results: Mothers of depressed children rated lower QoL than their children while mothers of nondepressed children rated higher QoL than their children. Agreement was low in both samples but higher in the controls. Inter-informant agreement was only influenced by depression. Conclusions: Our results show that mothers relate more serious negative effects to childhood depression than their children and rate less problems for their non-depressed children compared to self-reports. Mother–child agreement is negatively influenced by depression which further stresses the importance of obtaining reports from the child and at least one parent in order to understand the subjective experiences caused by the illness.

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.

The serotonin system has been implicated in neuropsychiatric disorders, including mood disorders.We investigated polymorphisms in two serotonin-receptor genes, HTR1B and HTR2A, and the serotonin transporter (SLC6A4) in two independent samples of patients with childhood-onset mood disorders (COMD): 203 patients from Pittsburgh, USA with matched controls and 448 small families from Hungary.Case-control and family-based analyses showed no association between COMD and any of the studied polymorphisms (all P values0.05). Haplotype analysis of SLC6A4 was also negative in both samples.Overall, the examination of genetic variants at the HTR1B, HTR2A, and SLC6A4 loci indicated no association between the selected polymorphisms and COMD.

The study of the quality of life in various strata of society is a very important task. No quality of life research has been done on the Hungarian child population until now. In the present study, we assessed the life quality in a sample of elementary school-aged children by asking both the parents and the children themselves.Data were collected from 2,620 children and their parents (mean age: 10.45 years, sd: 2.2 years) by administering the Invertar Lebensqualität Kindern und Jugendlichen (ILK) questionnaire. Reliability and validity data of the questionnaire were examined separately for the child, adolescent, and parent versions.Internal consistency was adequate in all three versions, Cronbach alpha was above 0.6. Test-retest reliability (ICC) ranged between 0.67 and 0.75. Discriminant validity was measured in a non-depressed sample versus a population showing symptoms of clinical depression s. Based on the ILK questionnaire, the two samples were clearly different in their quality of life. Satisfaction with school and psychic well-being worsens with increasing age in the average paediatric population. Relations with family members pose problems in 13-15 year-olds, while peer relations cause difficulty to 6-9 year-olds. Most often parents underestimate the troubles of their children.The ILK questionnaire is well suited for both comprehensive and detailed examinations of quality of life in Hungarian child populations. It shows adequate reliability and validity. Further research is needed to identify factors influencing the quality of life of Hungarian youngsters and to improve therapeutic options.

Few Hungarian studies have been published about the relationship between individual life events and childhood and adolescent onset depression. In the present study we examined the significance of life events that might be risk factors of childhood depressive symptoms.We collected data in 9 elementary schools in two regions of Hungary. 2,652 pupils were examined. Life events were collected from the parents through a self-report questionnaire. Depressive symptoms were measured by the shortened version of the Child Depression Inventory (CDI).Of the 20 life events that were examined, the following showed a significant relationship with the average depressive-symptom scores: illness of family members--especially that of a sibling, divorce, frequent quarrel among family members, teasing, financial problems and moving apartments. In boys, serious illness of the father, frequent quarrel among family members and teasing; in girls, divorce of parents, frequent quarrel among family members, psychiatric illness of a sibling, financial problems, moving apartments and teasing increased the risk of depression.The experience of a number of life events can significantly increase the risk of childhood and adolescent depression.

Adolescence is a risk period for both affective disorders and unhealthy behaviours. The association between depression and smoking and drinking problems is well established in the literature on adult and adolescent patients. Smoking at a young age increases the risk of substance abuse in later life, which in turn further increases the functional impairment caused by psychiatric illness. In our study, we investigated the frequency of smoking, alcohol consumption and substance use and their association to psychiatric diagnoses in a child population suffering from depression.The study was carried out on 267 children at risk for depression. Psychiatric diagnosis was set up based on a semi-structured interview, while information on the severity of depressive symptoms and unhealthy behaviours was collected through self-report questionnaires.Mean age of the sample was 12.4 years (sd: 2.6 years), a major depressive disorder was present in 51%. Smoking and alcohol drinking rates were increased in the sample, 19.9% and 24%, respectively. MDD and comorbid anxiety disorders in general increased the risk of alcohol consumption (OR=2.81 and OR=2.61, respectively), while comorbid behavioural disorders enhanced the likelihood of smoking (OR=3.72). More specifically, generalized anxiety disorder, social phobia and conduct disorder had the highest importance of the comorbid diagnoses identified in the study.Early screening for smoking and alcohol drinking is very important in child and adolescent populations suffering from depressive symptoms. Comorbid psychiatric illnesses, such as anxiety and conduct disorder, increase the risk of unhealthy behaviours. Early preventive measures might positively influence later quality of life.

CPI-17 is a cytosolic protein of 17 kDa that becomes a potent inhibitor of certain type 1 protein serine/threonine phosphatases, including smooth muscle myosin light-chain phosphatase (MLCP), when phosphorylated at Thr38. Several protein kinases are capable of phosphorylating CPI-17 at this site in vitro; however, in intact tissue, compelling evidence only exists for phosphorylation by protein kinase C (PKC). Agonist-induced activation of heterotrimeric G proteins of the Gq/11 family via seven-transmembrane domain-containing, G protein-coupled receptors results in phospholipase Cbeta-mediated hydrolysis of membrane phosphatidylinositol 4,5-bisphosphate to generate inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DAG). IP3 triggers Ca2+ release from the sarcoplasmic reticulum. DAG and Ca2+ together activate classical isoforms of PKC, and DAG activates novel PKC isoforms without a requirement for Ca2+. Activated PKC phosphorylates CPI-17 at Thr38, enhancing its potency of inhibition of MLCP approx 1000-fold. The myosin light-chain kinase (MLCK):MLCP activity ratio is thereby increased at the prevailing cytosolic free-Ca2+ concentration ([Ca2+]i), resulting in an increase in phosphorylation of the 20-kDa light chains of myosin II (LC20) catalyzed by Ca2+- and calmodulin-dependent MLCK and contraction of the smooth muscle. Physiologically, this mechanism can account for some instances of Ca2+ sensitization of smooth muscle contraction (i.e., an increase in force in response to agonist stimulation without a change in [Ca2+]i).

Genome-wide association studies (GWAS) have identified a number of single nucleotide polymorphisms (SNPs) associated with bladder cancer risk. Here, we explored the bladder cancer GWAS signal SNP rs798766 (C/T), which is located in the intron of TACC3 upstream of FGFR3 at 4p16.3 locus. This region represents a high linkage disequilibrium (LD) block and includes two more genes, TMEM129 and SLBP. Several SNPs in r2 = 1 with rs798766 are located within coding and non-coding regions of these genes; however, the coding SNPs are synonymous. Previously, genetic association of this GWAS marker has been shown by eQTL analysis with FGFR3 and TACC3 mRNA expression in adipose tissue. However, genetic association for all four genes and their several alternatively spliced isoforms remains largely unexplored in primary bladder normal and tumor tissue. We used genotype and RNA-seq data from The Cancer Genome Atlas (TCGA), bladder cancer data set (n = 242). Within the 1000 Kb region surrounding rs798766 we imputed genotypes of 13,529 SNPs in the TCGA data set based on the 1000 Genomes reference panel. Next, we performed eQTL analysis of FGFR3, TACC3, SLBP and TMEM129 both at gene level and at individual isoform level with genotypes of GWAS and several other markers. For validation, we used an independent panel of 42 bladder tumor and 42 adjacent normal tissue samples, using TaqMan expression assays. Expression was analyzed by general linear regression based on an additive genetic model, adjusting for age, sex and race. At the gene level in the TCGA data, we found significant association with TACC3 expression (p = 1.9 × 10−2unadj and p = 3.5 × 10−2 adj). The association was stronger for expression of an alternatively spliced isoform of TMEM129, designated TMEM129β, (p = 4.57×10−4unadj and p = 3.5 × 10−3adj). Computational annotation revealed that SNP rs2236786, r2 = 1 with GWAS marker, is located within a cassette exon that is an intron for isoform TMEM129β. Further analysis revealed that rs2236786 alleles affect a binding motif for alternative splicing factors SF2ASF, hnRNPF and CUG-BP. The functional exploration of this finding is underway. In conclusion, we suggest that the molecular phenotype of the 4p16.3 bladder cancer GWAS signal could be associated with differential expression of more than one gene (FGFR3, TACC3, SLBP and TMEM129) and their alternatively spliced isoforms. We present the first evidence for possible association of alternative splicing of TMEM129 and bladder cancer GWAS signal. Note: This abstract was not presented at the meeting. Citation Format: A. Rouf Banday, Ashley Paquin, Candace Middlebrooks, Eniko Kiss, Ludmila Prokunina-Olsson. An alternatively spliced isoform of TMEM129 shows association with bladder cancer GWAS marker rs798766. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4617. doi:10.1158/1538-7445.AM2015-4617

Background Psychiatric assessments of children typically involve two informants, the child and the parent. Understanding discordance in their reports has been of interest to clinicians and researchers. We examine differences between mothers' and children's report of children's depressive symptom severity, and factors that may influence their reports and level of agreement. We hypothesized that agreement between mother and child would improve if (1) the mother is depressed, due to improved recall of mood congruent symptoms, (2) the child is older, due to better social-cognitive and communication skills, and (3) the child is a female. Methods Subjects were 354 children (158 girls; mean age 11.69 years, SD: 2.05 years) with Major Depressive Disorder. Depressive symptoms were evaluated by a semi-structured interview separately with the mother and the child. Agreement on symptom severity was based on concordance of the presence and extent of symptoms. Results Maternal reports were significantly higher than their son's but not daughters'. Girls, particularly with increasing age, reported higher levels of symptoms; however mothers' reports were not affected by child sex or age. Maternal depression predicted more severe symptom reports for both children and mothers. Agreement between the mother and the child increased as children got older. Limitations The same clinician interviewed the mother and the child, which might inflate rates of agreement. However, this method mirrors clinical evaluation. Conclusion During a clinical interview one must consider the age and sex of the child and the depressive state of the mother in assimilating information about the child.

Few Hungarian studies have been published about the prevalence of depressive symptoms and their risk factors in childhood. In the present study, we examined the prevalence of depressive symptoms and the importance of stressful life events as risk factors of depression in children.We collected data in 9 elementary schools in two regions of Hungary. The data of 2652 students were analysed. Depressive symptoms were measured by the shortened version of the Child Depression Inventory (CDI) and life events were collected from the parents through self-report questionnaire.The mean depressive score of the sample by the CDI was 3.61. 14.9% of the students had a score of 7 or higher, which implies an increased risk of clinical depression. Of the 29 life events which were examined, children experienced 2.35 on average. We found significant positive correlation between depressive symptoms and stressful life events. This effect of life events was not diminished significantly by the age and sex of the child.Based on our results we can conclude that the risk of depression increases in parallel with the number of stressful life events experienced by the child.

Adolescence is a high-risk period with regard to the development of both affective disorders and unhealthy behaviors. The association between depression and smoking and drinking in adulthood and adolescence has been well established. Smoking in a young age increases the risk of substance abuse later in life, which in turn further increases the functional impairment caused by psychiatric illnesses. In our study, we investigated the frequency of smoking, alcohol consumption and substance abuse and their association with psychiatric disorders in a child population affected by depression.The study was carried out on 267 children at risk for depression. Psychiatric diagnosis was assessed by a semi-structured interview, while information on severity of depressive symptoms and on unhealthy behaviors was collected through self-report questionnaires.Mean age of the sample was 12.4 years (SD: 2.6 years) and a major depressive disorder (MDD) was present in 51%. The prevalence of smoking and drinking behaviors was increased in the sample, 19.9% and 24%, respectively. MDD and comorbid anxiety disorders increased the risk of alcohol consumption (OR=2.81 and OR=2.61), while comorbid behavioral disorders enhanced the likelihood of smoking (OR=3.72). Of the various comorbid disorders, generalized anxiety disorder, social phobia and conduct disorder was shown to have notable effects.Early screening for smoking and drinking behavior is very important in child and adolescent populations affected by depression. Anxiety and behavioral disturbances associated with depression increase the risk of unhealthy behaviors. Taking preventive measures as early as possible might significantly influence quality of life later as an adult.

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.

Background and aims:According to the literature psychiatric illnesses decrease the quality of life (QL) of children and adolescents. There is no data, however, about the differential effect of psychiatric comorbidity on QL. We hypothesized that 1. any comorbidity would decrease the QL of depressed children and 2. attention deficit-hiperactivity disorder (ADHD) would have a more negative effect on the QL of depressed children than other illnesses.Methods:The sample consisted of 483 children diagnosed with major depression (MDD) (247 boys, mean age: 11.88 years, sd: 2,47). We compared 3 groups: 1. MDD without comorbidity (N=147), 2. MDD with comorbidity (no ADHD) (N=249), 3. MDD with ADHD with/without other comorbidity (N=87). Diagnoses were determined by semi-structured interview, quality of life was measured by self-report and parental report. Groups were compared by ANOVA, post hoc comparisons were done in cases of significant differences.Results:The MDD with ADHD group differed from the others in gender distribution, younger age at onset of depression, more frequent hospitalization and/or outpatient treatment. Child reported QL was not different among the groups. Parent reported QL was the highest in the MDD without comorbidity group, somewhat decreased in the MDD with comorbidity group and lowest in the MDD and ADHD group.Conclusions:ADHD worsens the course of MDD in children and adolescents. Quality of life of depressed children decreases further by additional comorbidity, but ADHD has the most negative effect in parents' opinion. It is important to ask both parent and child in examining QL of children.

Disturbances in stress hormones have been implicated in mood disorders, in particular in the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Arginine vasopressin (AVP) plays a crucial role in modulating the HPA axis under stress and does so through a G protein-coupled receptor, vasopressin V1b receptor (AVPR1b).To determine if genetic variation in AVPR1B could be contributing to vulnerability to mood disorders.We genotyped single nucleotide polymorphisms (SNPs) across the AVPR1B gene in a family-based sample with childhood-onset mood disorders. Six SNPs were genotyped; 2 were novel nonsynonymous polymorphisms, and the other 4 were constituents of a haplotype that was previously shown to be protective against depression.Twenty-three mental health facilities in Hungary.The sample was composed of 382 Hungarian nuclear families ascertained through affected probands with a diagnosis of childhood-onset mood disorder.Association with childhood-onset mood disorders was tested using the transmission disequilibrium test, which measures the transmission frequency of alleles, or haplotypes, from parents to affected offspring.Two of the AVPR1B SNPs showed association individually (Lys65Asn: chi(2) = 7.81, P = .005; S4: chi(2) = 4.58, P = .03); of particular interest is Lys65Asn, which causes an amino acid change in an intracellular protein domain. Haplotype analysis demonstrated significant overtransmission of the most frequent haplotype (chi(2)(3) = 22.42, P.001). Furthermore, stratifying the sample by sex established that the association was predominantly in affected females, which is consistent with previous observations.We have found evidence to implicate the AVPR1B gene in the etiology of mood disorders, particularly in females. Antagonists of AVPR1b exhibit antidepressant qualities; hence, genetic variation in AVPR1B may have implications in HPA axis dysregulation in mood disorders.