Psychiatric Genetics最新文献

Objective: The SCHEMA consortium has identified 10 genes in which protein-truncating variants (PTVs) confer a substantial risk of schizophrenia. This study aimed to determine whether carrying these PTVs was associated with neuropsychiatric impairment in the general population.

Methods: Phenotype fields of exome-sequenced participants in the UK Biobank who carried PTVs in these genes were studied to determine to what extent they demonstrated features of schizophrenia or had neuropsychiatric impairment.

Results: Following automated quality control and visual inspection of reads, 251 subjects were identified as having well-supported PTVs in one of these genes. The frequency of PTVs in CACNA1G was higher than that had been observed in SCHEMA cases, casting doubt on its role in schizophrenia pathogenesis, but otherwise rates were similar to those observed in SCHEMA controls. Numbers were too small to allow formal statistical analysis but in general carriers of PTVs did not appear to have high rates of psychiatric illness or reduced educational or occupational functioning. One subject with a PTV in SETD1A had a diagnosis of schizophrenia, one with a PTV in HERC1 had psychotic depression and two subjects seemed to have developmental disorders, one with a PTV in GRIN2A and one with a PTV in RBCC1. There seemed to be somewhat increased rates of affective disorders among carriers of PTVs in HERC1 and RB1CC1 .

Conclusion: Carriers of PTVs did not appear to have subclinical manifestations of schizophrenia. Although PTVs in these genes can substantially increase schizophrenia risk, their effect seems to be dichotomous and most carriers appear psychiatrically well. This research has been conducted using the UK Biobank Resource.

Background: Autism spectrum disorder (ASD) is a clinically and genetically heterogeneous group of neurodevelopmental disorders. Despite the extensive efforts of scientists, the etiology of ASD is far from completely elucidated. In an effort to enlighten the genetic architecture of ASDs, a meta-analysis of all available genetic association studies (GAS) was conducted.

Methods: We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available case-control GAS of ASDs. The threshold for meta-analysis was two studies per genetic variant. The association between genotype distribution and ASDs was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast.

Results: Overall, 57 candidate genes and 128 polymorphisms were investigated in 159 articles. In total 28 genetic polymorphisms have been shown to be associated with ASDs, that are harbored in 19 genes. Statistically significant results were revealed for the variants of the following genes adenosine deaminase (ADA), bone marrow stromal cell antigen-1 (CD157/BST1), Dopamine receptor D1 (DRD1), engrailed homolog 2 (EN2), met proto-oncogene (MET), methylenetetrahydrofolate reductase (MTHFR), solute carrier family 6 member 4 (SLC6A4), Synaptosomal-associated protein, 25kDa (SNAP-25) and vitamin D receptor (VDR). In the allele contrast model of cases versus healthy controls, significant associations were observed for Adrenoceptor Alpha 1B (ADRA1B), acetyl serotonin O - methyltransferase (ASMT), complement component 4B (C4B), dopamine receptor D3 (DRD3), met proto-oncogene (MET), neuroligin 4, X-linked (NLGN4), neurexin 1 (NRXN1), oxytocin receptor (OXTR), Serine/Threonine-Protein Kinase PFTAIRE-1 (PFTK1), Reelin (RELN) and Ras-like without CAAX 2 (RIT2).

Conclusion: These significant findings provide further evidence for genetic factors' implication in ASDs offering new perspectives in means of prevention and prognosis.

Purpose: Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary and extra-pulmonary multi-morbidity including depression, anxiety and cognitive disorders. Several studies investigated the association of the FKBP5 gene polymorphisms with susceptibility to anxiety, depression, and behavioral disorders. The FKBP5 gene codifies the FKBP51 protein which modulates the glucocorticoid receptor in the adaptive stress response. Genetic variants of the FKBP5 gene have been associated to a higher risk of developing mental disorders. We analyzed the association of genetic variants and stress exposure investigating the susceptibility to psychological distress and the impact on cognitive balance and quality of life (QoL) of COPD patients carrying the rs4713916 polymorphism (G/A) and we examined its association, with COPD rehabilitative outcomes.

Materials and methods: A pilot study evaluated cognitive, psychological, clinical alterations/disorders, QoL, and coping strategies in 70 older adults with COPD, undergoing pulmonary rehabilitation, stratified according to the FKBP5 rs4713916 genotype (GG or GA).

Results: Carriers of rs4713916 polymorphisms (G/A) show better cognitive performances, a higher degree of independence in the daily living activities, better QoL, no presence of depressive mood and anxiety symptoms, no family history of psychiatric disorders, more ability to cope with stressors by avoiding emotions but demanding emotional support, and lesser use of anti-anxiety, anti-depressant, anti-psychotic, hypnotic-sedative drugs. No difference was found in the number of comorbidities.

Conclusion: These results offer valuable insights into the role of FKBP5 in the complex network of mechanisms associated to clinical, psychological and behavioral features of COPD patients.

Introduction: The agreement between clinicians diagnosing major depressive disorder (MDD) is poor. The objective of this study was to identify a reproducible and robust gene expression marker capable of differentiating MDD from healthy control (HC) subjects.

Materials and methods: Brain and blood gene expression datasets were searched, which included subjects with MDD and HC. The largest database including different areas of brain samples (GSE80655) was used to identify an initial gene expression marker. Tests of robustness and reproducibility were then implemented in 13 brain and 7 blood independent datasets. Correlations between expression in brain and blood samples were also examined. Finally, an enrichment analysis to explore the marker biological meaning was completed.

Results: Twenty-eight genes were differentially expressed in GSE80655, of which 23 were critical to differentiate MDD from HC. The accuracy obtained using the 23 genes was 0.77 and 0.8, before and after the forward selection model, respectively. The gene marker's robustness and reproducibility were between the range of 0.46 and 0.63 in the other brain datasets and between 0.45 and 0.78 for the blood datasets. Brain and blood expression tended to correlate in some samples. Thirteen of the 23 genes were related to stress and immune response.

Conclusion: A 23 gene expression marker was able to distinguish subjects with MDD from HC, with adequate reproducibility and low robustness in the independent databases investigated. This gene set was similarly expressed in the brain and blood and involved genes related to stress and immune response.

Objective: Studies showed that rare copy number variations (CNVs) encompassing the vasoactive intestinal peptide receptor 2 gene (VIPR2) were associated with schizophrenia, indicating VIPR2 is a risk gene for schizophrenia. We hypothesized that besides CNV, rare pathogenic single-nucleotide variant (SNV) or small insertion/deletion (Indel) of VIPR2 might be present in some patients and contribute to the pathogenesis of schizophrenia.

Methods: We performed genome-wide CNV analysis to screen CNV at the VIPR2 locus and targeted sequencing of all the exons of VIPR2 to search for SNV and indel in a sample of patients with chronic schizophrenia from Taiwan.

Results: We detected a 230-kb microduplication encompassing the VIPR2 in 1 out of 200 patients. Furthermore, we identified six ultrarare SNVs, including one splicing SNV and five missense SNVs, in 516 patients. In-silico analyses showed these SNVs had a damaging effect on the function of VIPR2.

Conclusion: Our findings support the idea that besides CNV, rare pathogenic SNVs of VIPR2 might contribute to the pathogenesis of schizophrenia in some patients.

Objectives: Angelman syndrome is a neurogenetic disorder resulting from the loss of expression of the ubiquitin-protein ligase E3A gene on chromosome 15. Problematic behaviors including attention-deficit/hyperactivity disorder (ADHD) symptoms of hyperactivity, impulsivity and inattention are highly prevalent in Angelman syndrome. The efficacy, safety and tolerability of stimulant medications in children with Angelman syndrome for the treatment of ADHD symptoms have not been previously reported.

Methods: We describe three boys with Angelman syndrome who were treated with open-label stimulant medications for ADHD symptoms.

Results: Stimulant medications were highly intolerable, and treatment had to be discontinued after limited dosing in all three cases due to marked increases in hyperactivity and impulsivity along with worsened distractibility.

Conclusion: The findings of this study suggest that stimulant medications may be ineffective and poorly tolerated in children with Angelman syndrome.

Morphine/heroin may increase oxidative stress in drug-dependent persons. The imbalance between oxidative stress and antioxidant defense mechanisms can accelerate the shortening of telomere length. This article reports two sets of data; comparison of relative telomere length between heroin-dependent patients and healthy control group, as well as, investigation of the effect of morphine on the relative telomere length of human SH-SY5Y cells treated by morphine. Study participants were composed of 163 heroin-dependent patients and 166 unrelated healthy controls. SH-SY5Y cells were treated with (5 μM) morphine hydrochloride and incubated for 40 and 60 days. The relative telomere length was calculated as the T/S (telomere/single-copy gene) ratio using 36B4 as a reference for each sample, using quantitative real-time PCR. The mean (± SE) value of relative telomere length was 4.81 ± 0.21 and 6.38 ± 0.23 in leukocytes of heroin-dependent and control groups, respectively. The telomere length was significantly decreased in heroin-dependent participants (t = 4.97; df = 327; P < 0.0001). The relative telomere length in cells treated with morphine for 60 days was 4.50 ± 0.14 and in untreated cells was 5.75 ± 0.08. The difference was highly significant (t  =  7.68; df = 4; P = 0.002). Our present findings indicate that morphine and dependency on heroin are significantly associated with shorter telomeres. The present findings may help to explain some of the adverse effects of drug dependency on health such as accelerating biologic processes related to aging.

Social anxiety disorder (SAD) is a common psychiatric disorder, often associated with avoidant temperament. Research studies have implicated a strong genetic architecture of SAD. We have conducted a systematic review on the genetics of SAD and yielded 66 articles. In general, prior research studies have focused on the serotonin transporter, oxytocin receptor, brain-derived neurotrophic factor and catechol-O-methyltransferase genes. Mixed and inconsistent results have been reported. Additional approaches and phenotypes have also been investigated, including pharmacogenetics of treatment response, imaging genetics and gene-environment interactions. Future directions warrant further international collaborative efforts, deep-phenotyping of clinical characteristics including consistent and reliable measurement-based symptom severity, and larger sample sizes to ensure sufficient power for stratification due to the heterogeneity of this chronic and often debilitating condition.

Objective: Genome-wide association studies have found that rs12966547 polymorphism was associated with susceptibility to schizophrenia in European populations. Recent studies showed that a genetic overlap may exist in schizophrenia and bipolar disorder. Here, we analyzed the associations between LOC105372125 rs12966547 polymorphism and schizophrenia and bipolar disorder in the Han Chinese population.

Methods: Our study recruited 548 schizophrenia patients, 512 bipolar disorder patients, and 598 healthy controls. Genotyping of rs12966547 were performed using the Sequenom MassARRAY platform.

Results: A significant association between rs12966547 polymorphism and susceptibility to bipolar disorder was observed after adjusting for sex and age (additive model: Padj = 0.040, recessive model: Padj = 0.044). However, no significant association was found between rs12966547 polymorphism and schizophrenia risk (all P > 0.05). In the analysis of gender, rs12966547 polymorphism was significantly associated with bipolar disorder (additive model: Padj = 0.027) and schizophrenia (dominant model: Padj = 0.039) in women. However, no significant association was found between rs12966547 polymorphism and the risk of bipolar disorder or schizophrenia in men (all Padj > 0.05).

Conclusions: Polymorphism of rs12966547 on the long noncoding RNA LOC10537215 are a shared genetic variant of schizophrenia and bipolar disorder in Han Chinese women.

Introduction: Diazepam is one of the most commonly prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). However, diazepam therapy often turns out to be ineffective, and some patients experience dose-dependent adverse drug reactions. Previous studies have shown that the metabolism of diazepam involves the CYP2C19 isoenzyme, whose activity is highly dependent on polymorphism of the encoding gene.

Objective: The study aimed to investigate the effects of CYP2C19*17 genetic polymorphisms on plasma and saliva concentrations of diazepam as well as its impact on the efficacy and safety rates of therapy in patients with AWS.

Material and methods: The study was conducted on 100 Russian male patients suffering from the AWS who received diazepam injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time PCR with allele-specific hybridization. The efficacy and safety assessment was performed using psychometric scales.

Results: Based on the results of the study, we revealed differences in the efficacy and safety of therapy in patients with different CYP2C19 -806C>T genotypes. Therapeutic drug monitoring revealed the statistically significant difference in the levels of diazepam plasma concentration: (CC) 251.76 (214.43; 310.61) vs. (CT+TT) 89.74 (54.18; 179.13); P = 0.003, and diazepam saliva concentration: (CC) 3.86 (3.22; 5.12) vs. (CT+TT) 0.79 (0.44; 1.56); P = 0.003.

Conclusion: Our study showed the effects of CYP2C19*17 genetic polymorphisms on the efficacy and safety rates of diazepam. Furthermore, we revealed the statistically significant differences in plasma and saliva concentration levels of diazepam in patients carrying different genotypes.