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Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation and transcriptional regulation, have been identified through human genetic studies, the East Asian ASD cohorts are still under-represented in genome-wide genetic studies. Here, we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin. Using a joint-calling analytical pipeline based on GATK toolkits, we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants, as well as de novo copy number variations containing known ASD-related genes. Importantly, combined with single-cell sequencing data from the developing human brain, we found that the expression of genes with de novo mutations was specifically enriched in the pre-, post-central gyrus (PRC, PC) and banks of the superior temporal (BST) regions in the human brain. By further analyzing the brain imaging data with ASD and healthy controls, we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls, suggesting the potential structural deficits associated with ASD. Finally, we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas, the insula, as well as the frontal lobes in ASD patients. This work indicated that combinatorial analysis with genome-wide screening, single-cell sequencing, and brain imaging data reveal the brain regions contributing to the etiology of ASD.
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Humans , Autism Spectrum Disorder/metabolism , Autistic Disorder , Exome Sequencing , DNA Copy Number Variations , East Asian People , Brain/metabolism , Mutation/genetics , Genetic Predisposition to Disease/geneticsABSTRACT
There are trillions of microbes in human gut, which are related to health and diseases closely.In recent years, with the popularization of the concept of microbiome-gut-brain axis, the influence of intestinal microbiota on central nervous system diseases has drawn increasing attention.Gastrointestinal symptoms are common in children with autism spectrum disorder(ASD), and some studies have also indicated that correcting the dysbiosis of gut microbiome can not only improve the gastrointestinal problems, but also alleviate the symptoms of autism to some extent.Therefore, the relationship between intestinal microbes and ASD has attracted researchers′ attention.This review focuses on several kinds of gut microbesmicrotes that have been extensively studied to reveal the relationship between the microbesmicrotes and autism spectrum disorders and their potential pathogenic or protective mechanisms.
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Objective To explore the relationship between the serum neuropeptide Y (NPY) levels and the pathogenesis,therapeutic intervention of schizophrenia. Methods One hundard twenty-five patients with schizophrenia (case group) with no medication for at least 4-week and 136 healthy controls (control group) were evaluated by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Positive and Negative Syndrome Scala (PANSS). Simultaneously blood tests were performed to detect serum NPY levels. In the case group, PANSS was evaluated and blood collected again after 4 weeks of treatment with olanzapine. Result At the baseline,the serum NPY concentration was significantly lower in the case group than in control group (t=-5.79, P<0.01). The scores of RBANS and its factors were significantly lower in the case group than in control group (all P<0.01). The concentration was positively correlated with the score of the attention factor for RBANS scale (r=0.20, P=0.04). After treatment with olanzapine for 4 weeks,the serum NPY level in the case group was significantly increased (t=-2.23,P=0.03).The scores of PANSS total scale and subscale were significantly decreased(all P<0.01).There was no significant correlation between alterations of the serum level of NPY and PANSS total or subscale scores from baseline to 4-week (all P>0.05). Conclusion The present study has revealed a significant decrease in serum NPY levels in patients with schizophrenia which can be attenuated by treatment of Olanzapine.The action of Olanzapine may be related to the mechanism of action of Olanzapine.However,there is no correlation between alterations of the serum level of NPY and the improvement in the patientˊs clinical symptoms.
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Objective To examine the correlation between the gene of phosphate and tension homology deleted on chromosometen (PTEN gene) polymorphism and schizophrenia (SCZ) associated with the type 2 diabetes mellitus (T2DM ) in Shanghai Han population. Methods The study recruited 591 long-stay schizophrenic inpatients including 304 with and 287 without type 2 diabetes mellitus, 206 patients with the type 2 diabetes mellitus and 205 normal subjects from Shanghai Han population. SNPs of PTEN gene (rs1234225, rs12569998, rs1234223) were genotyped by using Taqman genotyping. The frequency distributions of allele, genotype and haplotype between groups were analyzed. Results There were significant differences in the frequency of rs1234223 genotype (P=0.01) and allele distribution (P=0.02) between the SCZ with type 2 diabetes mellitus group and the SCZ without type 2 diabetes mellitus group. The difference of genotype frequencies remained statistically significant (P=0.03) but the allele distribution was not (P=0.06) after Bonferroni correction. Haplotype analysis showed that TTC haplotype was less common in the SCZ with type 2 diabetes mellitus group than in the SCZ without type 2 diabetes mellitus group (P=0.02). Conclusions PTEN gene may be a susceptibility gene for schizophrenia with type 2 diabetes mellitus in Chinese Han population. The TTC haplotype may be a protective factor for schizophrenia with type 2 diabetes mellitus.
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Objective To explore the relationships between neuronal nicotinic acetylcholine receptor subunit gene polymorphisms and type 2 diabetes in Chinese han schizophrenics.Methods Five single nucleotide polymorphisms(SNPs )of CHRNA3 (rs1317286),CHRNA4 (rs1044396),CHRNA 7 (rs6494212) and CHRNA5 (rs16969968,rs684513) gene were analyzed in a sample of 346 schizophrenics with type 2 diabetes and 360 schizophrenics without type 2 diabetes.The five markers were genotyped by the TaqMan fluorogenic detection method with the ABI7900.Results There were no significant differences in alleles and genotypes distribution of the five genes between two groups (P＞0.05).For the CHRNA 7(rs6494212),there were significant difference in genotypes (P=0.039) and alleles distribution (P＜0.021) between two groups in male patients.The haplotypes constructed by markers of CHRNA5 were not associated with the 2 diabetes in Chinese Han male schizophrenics.The interaction analysis revealed a significant association between models made up by rs1317286,rs1044396,rs6494212,rs684513and 2 diabetes in Chinese Han male schizophrenics (P=0.002).Conclusion The CHRNA7(rs6494212) gene may be one of common susceptible genes for 2 diabetes in Chinese Han male schizophrenics.There is a significant association between models made up by rs131726rs1044396,rs6494212,rs684513 and schizophrenics with type 2 diabetes.
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Objective To explore the relationships between neuronal nicotinic acetylcholine receptor subunit gene polymorphisms and type 2 diabetes in Chinese han schizophrenics.Methods Five single nucleotide polymorphisms(SNPs )of CHRNA3 (rs1317286),CHRNA4 (rs1044396),CHRNA 7 (rs6494212) and CHRNA5 (rs16969968,rs684513) gene were analyzed in a sample of 346 schizophrenics with type 2 diabetes and 360 schizophrenics without type 2 diabetes.The five markers were genotyped by the TaqMan fluorogenic detection method with the ABI7900.Results There were no significant differences in alleles and genotypes distribution of the five genes between two groups (P＞0.05).For the CHRNA 7(rs6494212),there were significant difference in genotypes (P=0.039) and alleles distribution (P＜0.021) between two groups in male patients.The haplotypes constructed by markers of CHRNA5 were not associated with the 2 diabetes in Chinese Han male schizophrenics.The interaction analysis revealed a significant association between models made up by rs1317286,rs1044396,rs6494212,rs684513and 2 diabetes in Chinese Han male schizophrenics (P=0.002).Conclusion The CHRNA7(rs6494212) gene may be one of common susceptible genes for 2 diabetes in Chinese Han male schizophrenics.There is a significant association between models made up by rs131726rs1044396,rs6494212,rs684513 and schizophrenics with type 2 diabetes.
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Objective To study the expression levels of aerobic glycolytic enzymes in the cerebellums and its correlation with pathogenesis of autism in patients with autism. Methods The Western blotting was used to quantita-tively examine the expression levels of aerobic glycolytic enzymes, including HK-Ⅰ, HK-Ⅱ, PFKP, PKM1/2, PKM2, GAPDH, PDH and LDHA in the cerebellums of eight patients with autism and eight age-matched controls. Results Compared to controls, PDH expression was significantly decreased [(0.715±0.342) vs.(1.028±0.203), P=0.043], while expression of other seven aerobic glycolytic enzymes remained unchanged ( P>0 . 05 ) in the cerebellums of patients with autism. Conclusion The present study has revealed a decrease in the expression of PDH in the cerebellums of patients with autism, which may be involved in the pathologic process of autism.
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Objective Gamma amino butyric acid (GABA) signaling pathway related genes mRNA expression and promoter methylation of GABRB2 gene in peripheral blood were investigated to explore the mechanisms involved in schizophrenia (SZ) and antipsychotics treatment. Methods DNA was isolated from blood samples of 53 SZ patients and 53 gender-and age-matched healthy controls. 12 out of 25 SZ patients were followed 8 weeks antipsychotic treatment. The quantitative GABRB2 promoter methylation was analyzed using the high-throughput mass spectrometry on matrix-as?sisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array before and after treatment. Results The GA?BRB2 promoter methylation pattern of case and control group was not significantly different (P>0.05). However, signifi?cant differences of the methylation levels of CpG_28 in the GABRB2 promoter between two groups were found in males [(0.215±0.084) vs. (0.264±0.103), P<0.05]. After 8 weeks antipsychotics treatment, a significant decrease of GABRB2 pro?moter methylatin was detected in the patients [(0.088±0.037) vs. (0.121±0.063), P<0.01]. Conclusion A down regulation of GABRB2 promoter methylation in blood of SZ patients after-treatment supports that GABRB2 promoter methylation in blood may be associated with the mechanisms of antipsychotics treatment in SZ.
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Objective To explore the association between the polymorphisms of TSC1,TSC2,PTEN genes and autism in Chinese Han population.Methods 274 autism patients and 386 heahh controls were recruited,and SnaPshot technique was used to genotype the 13 tagSNPs of TSC1,TSC2 and PTEN genes.The allele,genotype and haplotype frequencies of the SNPs were compared using SHEsis and SNPStats softwares.Results Mter Bonferroni correction,the allele distribution of rs2809244 (TSC1) (x2 =9.537,P=0.002,adjusted P=0.016),rs1050700 (TSC1) (x2 =9.313,P=0.002,adjusted P=0.016),rs2072314(TSC2) (P＜0.01,adjusted P＜0.01) and rs8063461 (TSC2) (P＜0.01,adjusted P＜0.01)showed significant difference between two groups (P＜0.05).The genotype frequencies of rs2072314(TSC2)and rs8063461(TSC2) showed significant difference between two groups(P＜0.05).Moreover,the frequency of haplotype A-G (OR =14.548,95％ CI =5.450-38.830) in the haplotype block rs2809244-rs3761840 showed significant difference between two groups(P＜0.05),A-G significantly increases the risk of autism.The frequencies of haplotype A-A (OR=0.608,95％ CI =0.409-0.903,P=0.013),G-A (OR=7.812,95％ CI =5.338-11.459,P＜0.01)and G-G (OR=0.356,95％ CI =0.274-0.463,P＜0.01) in the haplotype block rs2074969-rs8063461 were identified,which were significant difference between two groups(P＜0.05),and AA and G-G significantly reduced but G-A increased the risk of autism.Conclusion The polymorphisms of TSC1 and TSC2 genes might associate with autism in Chinese Han population.
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Objective To explore the correlation of single nucleotide polymorphism (SNP) with PTEN gene involving in mammalian target of rapamycin (mTOR) C1 signaling genes polymorphisms and autism in children.Methods A total of 97 cases with autism were enrolled from Mar.2011 to Dec.2012 in this study,who came from the child and adolescent out-patient department in Shanghai Mental Health Center of Shanghai Jiaotong University School of Medicine.Single SNP association and haplotype association analysis were performed using the family-based association test and Haploview software.Results 1.In a family-based association test,two SNPs showed significant association with autism(rs17107001 G:Z =2.982,P =0.003 ; rs2299941 G:Z =2.524,P =0.012).After the correction of false discovery rate,they all remained significant.2.Haplotype association analysis showed significant transmission disequilibrium in haplotype T-T-G and C-T-A generated from rs532678-rs17562384-rs2299941 (block2) in LD Block,and haplotype T-T-G was over transmitted to offspring(Z =-2.986,P =0.003) while haplotype C-T-A was the opposite (Z =-2.197,P =0.028).Conclusion The SNPs of PTEN genes might have a correlation with autism in children.
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Objective To investigate the relationship between cognitive function of first-episode schizophrenic patients and dopamine D1 receptor gene. Methods A total of 112 first-episode schizophrenic patients and 60 healthy controls were evaluated with Wechsler adult intelligence scale ( WAIS-R), Wechsler memory scale (WMS) and Wisconsin card sort test (WCST) ,and genotyped one polymorphism (rs4532) within DRD1 gene using TaqMan SNP genotyping assay. Results There were no significant differences on the frequencies of the genotypes and alleles of rs4532 polymorphism between patients with schizophrenia and normal controls ( x2 =2.90, P=0.35; x2 = 0.01, P= 0. 93 ). There were significant differences in all index of WCST between two groups (P ＜0.01 ). Patients with rs4532G allele had worse WCST performance than those without G allele ((60.9 ± 13.2)%vs (44.9 ±21.3)%, t=4.79, P=0.00002). Conclusion Rs4532 polymorphism of DRD1 gene may be associated with executive function impairment in schizophrenic patients.
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Objective:To explore the clinical features of subtyp es of ADHD in DSM-Ⅳ.Method:126 children fulfilled ADHD criteria of D S M-Ⅳ were further divided into 3 subtypes:predominantly inattentive(PI,61 cases) , predominantly hyperactive-impulsive(HI,9 cases)and combined type(CT,56 cases).C om orbid mental disorders were compared among the three groups.Parents and teacher s of children in each group completed CBCL(child behavior checklist)and TRF(teach er's report form).CWISC(Wechsler intelligence scale for children,Chinese versio n )and attention tests were also applied in each group.Results:Childr e n in CT group had more conduct disorder,more externalizing,delinquent and aggres sive behaviors rating by parents and teachers,and more inattentive than children in PI group.School performance of children in PI group was better than that of the other two groups evaluated by teachers.Conclusion:ADHD CT subty pe had highest rate of comorbid conduct disorder.They have more externalizing b ehavior,more academic problems and more inattentive.This subtype may be the mos t impaired subtype.