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2.
Compr Psychiatry ; 94: 152114, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401216

RESUMO

BACKGROUND: Promising biomarkers would be used to improve the determination of diagnosis and severity, as well as the prediction of symptomatic and functional outcomes of schizophrenia. BASIC PROCEDURES: In this study, we used three different mouse models induced by a genetic factor (PV-Cre; ErbB4-/-, G group), an environmental stressor (adolescent social isolation, G group), and a combination of genetic factor and environmental stressor (PV-Cre; ErbB4-/- mice with isolation, G × E group). Attenuated PPI (%) confirmed the successful establishment of three schizophrenia-like mouse models. To evaluate whether neuropeptide levels in plasma would be potential biomarkers of different schizophrenia models in our work, we used MILLIPLEX® MAP method to simultaneously measure 6 critical neuropeptides in plasma. MAIN FINDINGS: Among the evaluated neuropeptides, increased neurotensin tends to be associated with genetic factors of schizophrenia, increased orexin A seems to be a biomarker of an interplay between genetic and social isolation, while higher plasma oxytocin might be more apt to be responsive to social isolation. The potential biomarkers are mostly independent of sex. CONCLUSIONS: This research would provide novel clues to develop circulating biomarkers of plasma neuropeptides for multifactorial schizophrenia.

3.
Neurosci Bull ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388929

RESUMO

The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia. We used prepulse inhibition (PPI) and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls. Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions. Concurrently, we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in first-episode treatment-naïve schizophrenic patients (n = 117) and in age- and sex-matched healthy controls (n = 86). We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia. Significant correlations between gray matter volumes (GMVs) in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice. Furthermore, these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients. The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients. Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation, providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.

4.
Schizophr Res ; 209: 135-140, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31101513

RESUMO

We conducted a 24-week, randomized, double-blind parallel-controlled trial to test whether buspirone is beneficial to improve cognitive deficits of schizophrenia because it remains unclear. Two hundred patients received in random order either co-treatment buspirone with AAPDs or monotherapy with AAPDs. All patients had been treated with a stable dosage of AAPDs for at least three months. The positive and negative syndrome scale (PANSS), Hamilton Depression Scale-24 (HAMD-24), and 14-item Hamilton Rating Scale for Anxiety (HAMA-14) were used to evaluate clinical symptoms. The short version of Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC) was used to assess neurocognitive function. Social function and family burden were evaluated by Social Disability Screening Schedule (SDSS) and Family Burden Interview Schedule (FBIS). All patients were enrolled at baseline and followed up after 12 and 24 weeks. A total of 196 patients completed the trial, with 99 in the combined treatment group and 97 in the control group. During the intervention, the score of PANSS, HAMD-24, and HAMA-14 decreased slightly without group differences. Repeated measures ANOVA showed significant differences between the two groups in the score of arithmetic, similarities, picture completion, block design, SDSS, and FBIS (P < 0.05), but no difference was found with regard to the score of information, digital span test, or digital symbols (P > 0.05). In conclusion, co-treatment with buspirone and APPDs outperformed APPDs alone in improving cognitive deficit and reducing family burden of schizophrenia. Buspirone may be a promising candidate for co-treatment of schizophrenia-associated cognitive deficits.

5.
Sci China Life Sci ; 62(4): 535-543, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30929193

RESUMO

Antipsychotic-induced metabolic disturbance (AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor (MC4R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4R in Chinese population by genotyping two SNPs (rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index (BMI), waist circumference (WC), glucose, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status (drug-naïve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-naïve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.

6.
Psychol Med ; : 1-12, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30722798

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide and influenced by both environmental and genetic factors. Genetic studies of MDD have focused on common variants and have been constrained by the heterogeneity of clinical symptoms. METHODS: We sequenced the exome of 77 cases and 245 controls of Han Chinese ancestry and scanned their brain. Burden tests of rare variants were performed first to explore the association between genes/pathways and MDD. Secondly, parallel Independent Component Analysis was conducted to investigate genetic underpinnings of gray matter volume (GMV) changes of MDD. RESULTS: Two genes (CSMD1, p = 5.32×10-6; CNTNAP5, p = 1.32×10-6) and one pathway (Neuroactive Ligand Receptor Interactive, p = 1.29×10-5) achieved significance in burden test. In addition, we identified one pair of imaging-genetic components of significant correlation (r = 0.38, p = 9.92×10-6). The imaging component reflected decreased GMV in cases and correlated with intelligence quotient (IQ). IQ mediated the effects of GMV on MDD. The genetic component enriched in two gene sets, namely Singling by G-protein coupled receptors [false discovery rate (FDR) q = 3.23×10-4) and Alzheimer Disease Up (FDR q = 6.12×10-4). CONCLUSIONS: Both rare variants analysis and imaging-genetic analysis found evidence corresponding with the neuroinflammation and synaptic plasticity hypotheses of MDD. The mediation of IQ indicates that genetic component may act on MDD through GMV alteration and cognitive impairment.

7.
Br J Psychiatry ; 214(5): 281-287, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30722794

RESUMO

BACKGROUND: Previous studies have inferred a strong genetic component in schizophrenia. However, the genetic variants involved in the susceptibility to schizophrenia remain unclear.AimsTo detect potential gene pathways and networks associated with schizophrenia, and to explore the relationship between common and rare variants in these pathways and abnormal white matter integrity in schizophrenia. METHOD: The analysis included 100 first-episode treatment-naïve patients with schizophrenia and 140 healthy controls. A network-based analysis was carried out on the data collected from the Psychiatric Genomics Consortium Phase I (PGC-I). Based on our genome-wide association study and whole-exome sequencing data-sets, we performed a gene-set analysis to detect associations between the combining effects of common and rare genetic variants and abnormal white matter integrity in schizophrenia. RESULTS: Patients had significantly reduced functional anisotropy in the left and right anterior cingulate cortex, left and right precuneus and extra-nuclear (t = 4.61-5.10, PFDR < 0.01), compared with controls. Generated from co-expression network analysis of the PGC-1 summary statistics of schizophrenia, a subnetwork of 207 genes associated with schizophrenia was identified (P < 0.01), and 176 genes were co-expressed in four gene modules. Functional enrichment analysis for genes in each module revealed that the yellow module was enriched with highly co-expressed, innate immune response genes. Furthermore, rare variants of enriched genes in the yellow module were associated with reduced functional anisotropy in the left anterior cingulate cortex (P = 0.006; Padjusted = 0.024) in patients only. CONCLUSIONS: The pathogenesis of schizophrenia may be substantially influenced by genes involved in the immune system, via both pathway and network.Declaration of interestsNone.

8.
Pediatr Res ; 85(4): 489-493, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30644443

RESUMO

BACKGROUND: To identify inflammatory cell types by phenotypic analysis of the inflammatory cells in the induced sputum. METHODS: This retrospective study included 1232 children and infants, who were assigned into mild/moderate groups (326) and severe group (602) by clinical symptom scores. Phenotypes of sputum inflammatory cells were analyzed using liquid-based thin-cytologic test and eosinophil-derived neurotoxin (EDN) was quantified by ELISA. RESULTS: Blood eosinophil count, serum total IgE level, and allergen detection rate were significantly higher in the severe group. In the 905 cases of qualified sputum, 526 cases exhibited at least one type of inflammatory cells, including neutrophil (343, 65.2%), eosinophil (161, 30.6%), and mixed granulocytes (22, 4.2%). Levels of neutrophils and eosinophils were significantly higher in the severe group than mild/moderate group, and eosinophil was predominant in the severe group. Serum EDN was 104.8 ± 39.4 µg/l in the eosinophil phenotype group, 112.6 ± 41.2 µg/l in the mixed group, 88.2 ± 36.6 µg/l in the neutrophil phenotype group, and 60.9 ± 34.6 µg/l in the paucigranulocytic phenotype group. CONCLUSION: Induced-sputum inflammatory cell count may be used to determine phenotype of wheezing. The criteria of classifying adult asthma could be applicable for children and infants.

9.
J Affect Disord ; 245: 205-212, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30408638

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a serious psychiatric illness with unclear pathophysiology. As one of the post-transcriptional regulators, prior research has indicated that miRNAs are involved in the pathophysiology of MDD. The aim of this study was to screen the MDD-related miRNAs in the peripheral blood and investigate the target genes of the differentially expressed miRNAs and their potential functions in MDD pathophysiology. METHODS: miRNA sequencing was performed using the peripheral blood of patients with MDD and matched controls (cohort A, 10 vs 10). The nominal significant results were validated in an independent sample (cohort B, 72 vs 75) by real-time quantitative polymerase chain reaction (PCR). The target genes of verified miRNAs were predicted using Miranda software. Luciferase assay was used to verify one of the predicted target genes. Furthermore, we analyzed the correlations between the expression of pmiR-chr11 and hippocampal volume. RESULTS: Ten miRNAs were nominally significantly dysregulated in patients with MDD in cohort A. One of the 10 miRNAs, pmiR-chr11, was significantly dysregulated in cohort B. The pmiR-chr11 could regulate one of the target genes, BRPF1 (bromodomain and PHD finger containing 1), via binding its 3' untranslated region (UTR). The expression of pmiR-chr11 was negatively correlated with hippocampal volume in patients with MDD. LIMITATIONS: The expression of the miRNAs and mRNAs detected in the peripheral blood may not reflect the expression in the brain. CONCLUSIONS: Our findings suggested that the pmiR-chr11 may influence hippocampal volume by regulating BRPF1 in MDD.

10.
JAMA Psychiatry ; 75(12): 1261-1269, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30422257

RESUMO

Importance: The underlying mechanism for individual differences in patient response to antipsychotic medication remains unknown. Objective: To discover genes and gene sets harboring rare variants associated with short-term antipsychotic medication efficacy. Design, Setting, and Participants: In this multicenter, open-label, randomized clinical trial conducted between July 6, 2010, and December 31, 2011, 3023 patients recruited in China of Chinese Han descent with schizophrenia with total Positive and Negative Syndrome Scale (PANSS) score ≥ 60 received a 6-week treatment of antipsychotic medications randomly chosen from 5 atypical and 2 typical antipsychotic medications. Whole-exome sequencing (WES) was performed in 316 participants (grouped into those with the best response [n=156] and those who had no response [n=160] to the antipsychotic medication prescribed), according to the total PANSS score reduction rate after 6 weeks of treatment. Validation was performed using targeted sequencing in an independent sample of 1920 patients. Data analyses was performed between March 15, 2016, and March 1, 2017. Main Outcomes and Measures: Drug efficacy at week 6 was assessed according to the change in PANSS scores from baseline. Extremely good and extremely poor responders were selected for an initial WES association study, from which a subset of genes showing putative association was selected for independent replication with a targeted sequencing approach. Results: Of the 3023 patients (1549 [51.24%] female and 1474 [48.8%] male; mean [SD] age, 31.2 [7.9] years), 2336 (77.3%) were eligible for genetic analysis. After quality-control exclusions, 316 patients (10.5%) were included for WES and 1920 (63.5%) were included for replication. In the WES discovery stage, 2 gene sets (reduced NMDA [N-methyl-D-aspartate]-mediated synaptic currents and reduced AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid]-mediated synaptic currents) were found to be enriched with rare damaging variants in the nonresponder group, suggesting the involvement of these gene sets in antipsychotic medication efficacy. Reduced NMDA-mediated synaptic currents gene set was further replicated in an independent sample using targeting sequencing. No statistically significant differences in antipsychotic drug response were found among the patients who received different antipsychotic drugs. Conclusions and Relevance: Genetic variation in glutamatergic or NMDA neurotransmission is implicated in short-term antipsychotic medication efficacy; WES may have utility in the study of rare genetic variation in pharmacogenetics. Trial Registration: Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934.

11.
Schizophr Bull ; 2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947804

RESUMO

Recent neuroanatomical pattern recognition studies have shown some promises for developing an objective neuroimaging-based classification related to schizophrenia. This study explored the feasibility of reliably identifying schizophrenia using single and multimodal multivariate neuroimaging features. Multiple brain measures including regional gray matter (GM) volume, cortical thickness, gyrification, fractional anisotropy (FA), and mean diffusivity (MD) were extracted using fully automated procedures. We used Gradient Boosting Decision Tree to identify the most frequently selected features of each set of neuroanatomical metric and fused multimodal measures. The current classification model was trained and validated based on 98 patients with first-episode schizophrenia (FES) and 106 matched healthy controls (HCs). The classification model was trained and tested in an independent dataset of 54 patients with FES and 48 HCs using imaging data acquired on a different magnetic resonance imaging scanner. Using the most frequently selected features from fused structural and diffusion tensor imaging metrics, a classification accuracy of 75.05% was achieved, which was higher than accuracy derived from a single imaging metric. Most prominent discriminative features included cortical thickness of left transverse temporal gyrus and right parahippocampal gyrus, the FA of left corticospinal tract and right external capsule. In the independent cohort, average accuracy was 76.54%, derived from combined features selected from cortical thickness, gyrification, FA, and MD. These features characterized by GM abnormalities and white matter disruptions have discriminative power with respect to the underlying pathological changes in the brain of individuals having schizophrenia. Our results further highlight the potential advantage of multimodal data fusion for identifying schizophrenia.

12.
Schizophr Bull ; 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29939349

RESUMO

Schizophrenia is genetic in origin and associated with a fecundity disadvantage. The deficits in schizophrenia have been attributed to variation related to the human capacity for language or brain laterality. How sex influences the relative connectivity of the 2 hemispheres is a route to understanding these 2 functions. Using resting-state functional magnetic resonance imaging (fMRI) we searched for sex- and hemisphere-specific changes in whole-brain functional-connectivity in multi-site datasets (altogether 672 subjects including 286 patients, all right-handed) in the first-episode schizophrenia (illness duration ≤ 1 year, mostly drug naive) and in chronic stages of schizophrenia (illness duration > 1 year), respectively. We used meta-analyses to integrate data from different sources concerning individuals at the same illness stage. We found first-episode male patients are predominantly left-lateralized in aberrant connectivity with a focus on Broca's area. Female patients show a lesser degree of lateralization than males, but to the right particularly in orbital frontal cortex. In the chronic stage, the focus of aberrant connectivity shifted from anterior to posterior structures with prominent involvement of the thalamus and pre- and post-central gyri bilaterally and in both sexes. While the "deviant connectivity" is right-sided in both the first-episode and the chronic stages in females, in males there is a shift between stages from the left to the right hemisphere. We hypothesized that the pathophysiology of schizophrenia may lie in the interaction between sex and lateralization, ie, in genetic mechanisms located on the X and Y chromosomes, intrinsic to the evolution of language.

13.
Hum Brain Mapp ; 2018 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-29691943

RESUMO

Disease association studies have characterized altered resting-state functional connectivities describing schizophrenia, but failed to model symptom expression well. We developed a model that could account for symptom severity and meanwhile relate this to disease-related functional pathology. We correlated BOLD signal across brain regions and tested separately for associations with disease (disease edges) and with symptom severity (symptom edges) in a prediction-based scheme. We then integrated them in an "edge bi-color" graph, and adopted mediation analysis to test for causality between the disease and symptom networks and symptom scores. For first-episode schizophrenics (FES, 161 drug-naïve patients and 150 controls), the disease network (with inferior frontal gyrus being the hub) and the symptom-network (posterior occipital-parietal cortex being the hub) were found to overlap in the temporal lobe. For chronic schizophrenis (CS, 69 medicated patients and 62 controls), disease network was dominated by thalamocortical connectivities, and overlapped with symptom network in the middle frontal gyrus. We found that symptom network mediates the relationship between disease network and symptom scores in FEP, but was unable to define a relationship between them for the smaller CS population. Our results suggest that the disease network distinguishing core functional pathology in resting-state brain may be responsible for symptom expression in FES through a wider brain network associated with core symptoms. We hypothesize that top-down control from heteromodal prefrontal cortex to posterior transmodal cortex contributes to positive symptoms of schizophrenia. Our work also suggests differences in mechanisms of symptom expression between FES and CS, highlighting a need to distinguish between these groups.

14.
Brain ; 2018 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-29408968

RESUMO

There is compelling evidence that epigenetic factors contribute to the manifestation of depression, in which microRNA132 (miR-132) is suggested to play a pivotal role in the pathogenesis and neuronal mechanisms underlying the symptoms of depression. Additionally, several depression-associated genes [MECP2, ARHGAP32 (p250GAP), CREB, and period genes] were experimentally validated as miR-132 targets. However, most studies regarding miR-132 in major depressive disorder are based on post-mortem, animal models or genetic comparisons. This work will be the first attempt to investigate how miR-132 dysregulation may impact covariation of multimodal brain imaging data in 81 unmedicated major depressive patients and 123 demographically-matched healthy controls, as well as in a medication-naïve subset of major depressive patients. MiR-132 values in blood (patients > controls) was used as a prior reference to guide fusion of three MRI features: fractional amplitude of low frequency fluctuations, grey matter volume, and fractional anisotropy. The multimodal components correlated with miR-132 also show significant group difference in loadings. Results indicate that (i) higher miR-132 levels in major depressive disorder are associated with both lower fractional amplitude of low frequency fluctuations and lower grey matter volume in fronto-limbic network; and (ii) the identified brain regions linked with increased miR-132 levels were also associated with poorer cognitive performance in attention and executive function. Using a data-driven, supervised-learning method, we determined that miR-132 dysregulation in major depressive disorder is associated with multi-facets of brain function and structure in fronto-limbic network (the key network for emotional regulation and memory), which deepens our understanding of how miR-132 dysregulation in major depressive disorders contribute to the loss of specific brain areas and is linked to relevant cognitive impairments.

15.
Neuropsychiatr Dis Treat ; 14: 37-41, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29302190

RESUMO

Elevation of plasma inflammatory factors in major depressive disorder (MDD) has been repeatedly observed, but contradictory results have also been reported. Alteration of complement components in MDD may also contribute to the pathophysiology of MDD by participating in inflammation. The recent findings that complement component 4 (C4) was involved in neural synapse elimination and associated with schizophrenia implicated the potential roles of C4 in MDD. In this study, we analyzed the plasma concentration of complement C4 and inflammatory factors, including interleukin (IL)-1ß, IL-6, IL-8, IL-10, interferon-α, interferon-γ and tumor necrosis factor-α, of 53 patients with MDD and 60 healthy individuals. The plasma of 17 patients out of 51 after antidepressant medication was also collected for analysis. The results showed that peripheral C4 in MDD was higher than that in healthy controls. No significant correlation of inflammatory factors or C4 with depressive or anxiety symptoms was found. Antidepressant medication significantly reduced plasma C4 of patients with MDD. Our results were consistent with previous findings that complement components were elevated in MDD and suggested that C4 might play a role in pathophysiology of MDD and could be a candidate in the research of biomarker and the pathophysiology of MDD.

16.
Eur Arch Psychiatry Clin Neurosci ; 268(7): 641-651, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29128871

RESUMO

Developing a mechanistic insight into the specific brain processes that underpin improvement in negative symptoms can help us design novel chemical and physical treatments against these unrelenting symptoms. The aim of the present study is to explore the longitudinal changes in the brain's regional functional efficiency that accompany improvement in negative symptoms seen in first-episode patients with schizophrenia when treated with antipsychotic for 1 year. Forty-seven first-episode patients with schizophrenia were scanned at a drug-naive baseline state and followed up for 1 year to identify negative symptom responders (Rn) and non-responders (NRn). Fractional amplitude of low-frequency fluctuations (fALFF) and Granger analysis of effective connectivity (EC) were used to examine the different patterns of regional function and connectivity between Rn and NRn during the 1 year follow-up. Increase of fALFF in the left superior temporal gyrus (STG) and increase of EC from the left STG to the dorsolateral prefrontal cortex (DLPFC) was found in Rn compared to NRn. We further validated that the identified changes in fALFF/EC of STG occur specifically in relation to negative symptoms only (i.e., not pseudo-specific in relation to positive, extrapyramidal or depressive symptoms), and occur irrespective of arbitrary clinical categorization of treatment response. An increase in fALFF in the precuneus and the inferior parietal lobule, and a decrease in EC from the left STG to the occipital cortex, were also found at the 1 year follow-up irrespective of improvement in negative symptoms. Interventions that improve the functional efficiency of left STG and its prefrontal connectivity may show efficacy in alleviating negative symptoms in first-episode schizophrenia.

17.
Am J Med Genet B Neuropsychiatr Genet ; 177(1): 50-67, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29135068

RESUMO

In this study, we investigated the association between bipolar I disorder (BDI) and between cognitive deficits therein and SNPs in GABAergic receptor genes. The sample comprised 477 patients with BDI and 438 healthy controls, with three neurocognitive tests being administered in 123 patients and 164 controls. For three SNPs, rs505474, rs1398175, and rs4868029 in the GABRA2, GABRA4, and GABRP genes, respectively, their allele frequencies were significantly different between patients and controls (Bonferroni-adjusted p = values 3.84 × 10-4 , 9.92 × 10-3 , and 1.22 × 10-2 , respectively). Four haplotypes were significantly associated with BDI (TA and AG for rs3815762 and rs4868029 in GABRP, GG for rs11636988 and rs8024256 in GABRB3 and GAGG for rs2197414, rs4921195, rs13188991, and rs11956731 in GABRA6, with p values of 0.0038, 0.044, 0.0176, and 0.0267, respectively, on 10,000 permutations). Furthermore, the SNP (rs2912585) within 250 kb upstream of the GABRB3 gene displayed a strong association with the Tower of Hanoi (TOH) executive time in the patient group (p = 2.844 × 10-6 ). One other SNP (rs754661), which is located at the intronic region of the same gene, was associated with the global trait of the executive function and post hoc analysis showed significant SNP by group effect (p = 0.0094). Our study supports previous findings that GABAA receptor genes are associated with bipolar disorder; it also suggests that the GABAA genes, especially the GABRB3 gene, might play a role in the executive function deficit in bipolar disorder, although future replication with a larger sample size is needed.


Assuntos
Transtorno Bipolar/genética , Função Executiva/fisiologia , Receptores de GABA/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Transtornos Cognitivos/genética , Grupos Étnicos/genética , Feminino , GABAérgicos , Neurônios GABAérgicos , Frequência do Gene/genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Receptores de GABA-A/genética
18.
Sci Rep ; 7(1): 10267, 2017 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-28860557

RESUMO

The current study aimed to explore age-variant trait differences of cortical gray matter volume (GMV) in a unique sample of first-episode and treatment-naïve patients with schizophrenia. A total of 158 subjects, including 26 adolescent-onset patients and 49 adult-onset patients as well as 83 age- and gender-matched controls were scanned using a 3T MRI scanner. Voxel-based morphometry (VBM) following Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL) was used to explore group differences between patients and controls in regional GMV. We found that patients with schizophrenia had decreased GMV in the left parietal postcentral region that extended to the left frontal regions, the right middle temporal gyrus, the occipital lobe and the right cerebellum posterior pyramis. Further analysis showed a distinct pattern of gray matter alterations in adolescent-onset patients compared with both healthy controls and adult-onset patients. Relative to healthy controls, adolescent-onset patients showed GMV alterations in the left parietal postcentral gyrus, parahippocampal gyrus and right cerebellum posterior pyramis, while GMV deficits in adult-onset patients were focused on the cingulo-fronto-temporal module and right occipital regions. Our study identified differential cortical gray matter deficits between adolescent- and adulthood-onset patients with schizophrenia, which suggests that the cortical abnormalities in schizophrenia are likely adjusted by the developmental community structure of the human brain.

19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 34(4): 592-596, 2017 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-28777866

RESUMO

OBJECTIVE: To assess the association of cognitive impairment and clinical symptoms in first-episode schizophrenia with the Val66Met (rs6265) polymorphism of brain-derived neurotrophic factor (BDNF) gene. METHODS: For 87 patients with first-episode schizophrenia and 76 healthy controls, the Val66Met polymorphism was determined with a Taqman Assay-on-Demand method. Wechsler intelligence test was carried out for all participants. Correlation of cognitive impairment with clinical severity was also analyzed. RESULTS: The patients were significantly lower in total IQ, verbal IQ and performance IQ compared to the controls. The lower total IQ (F=4.59, P= 0.01) and verbal IQ (F=4.44, P=0.01) were influenced by genetic factors and diagnostic interaction. The vertal IQ of Val/Val patients was significantly lower than those of Val/Met and Met/Met carriers. For the control group, the verbal IQ of Met/Met carriers was lower than that of Val/Met carriers, and the total IQ of Met/Met carriers was lower than those of Val/Met and Val/Val carriers. For the patient group, the total IQ of Val/Val carriers was negatively correlated with positive symptoms (r=-0.65, P=0.03) and thought disorders (r=-0.61, P=0.02). CONCLUSION: Cognitive impairment in first-episode schizophrenic patients is associated with the Val66Met polymorphism of the BDNF gene, and has an important clinical relevance.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Disfunção Cognitiva/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Esquizofrenia/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Sci Rep ; 7(1): 5327, 2017 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-28706186

RESUMO

The gray matter volumes of 58 pairs of twins ranging in age from 12 to 18 were measured by MRI to explore the genetic and environmental impacts on gray matter volume in twin children and adolescents. By means of A/C/E structural equation modeling, it was found that the gray matter volume in children and adolescents was jointly affected by genetic (A: 0.89) and environmental factors while genetic factors play a greater role. The gray matter volume in frontal lobe, parietal lobe, occipital lobe and lateral temporal lobe was mainly affected by genetics (A: 0.7-0.89), where as the gray matter volume in medial temporal lobe and cingulate cortex was affected by both genetics and environment.

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