Informational Analysis and Prediction of Obsessive-Compulsive Disorder Pathogenesis

Objective@#We aimed to predict the possible mechanism of obsessive-compulsive disorder (OCD) by integrating and analyzing mRNA sequencing results from two datasets and to provide direction for future studies into the pathogenesis of OCD. @*Methods@#Two OCD datasets, GSE78104 and GSE60190, were obtained, and the intersection of the two gene sets with differential expression in OCD samples was selected. Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway enrichment and Gene Ontology (GO) analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) online analysis website for the genes at the intersection, and the data were mapped using http://www.bioinformatics.com.cn. After genes with p≤0.05 had been screened out, protein-protein interaction (PPI) interaction analysis was conducted using Metascape to screen the key Molecular Complex Detection (MCODE) genes. MCODE genes were then enriched using the KEGG signaling pathway and GO classification. @*Results@#A total of 3,449 differentially expressed genes (DEGs) were obtained from the GSE78104 and GSE60190 datasets. KEGG, GO, and Gene Set Enrichment Analysis analyses of DEGs showed that the onset of OCD was related to oxidative phosphorylation and other metabolic processes, which may have a similar pathogenesis to other neurodegenerative diseases. Single-gene PPI analysis of SAPAP3 revealed that the mechanism by which SAPAP3 knockout induces OCD may also be caused by affecting oxidative phosphorylation. @*Conclusion@#The mechanism of SAPAP3 knockout-induced OCD in mice may be due to the oxidative phosphorylation process in the body. Future studies on the neural circuit mechanism of OCD should be conducted.

Effects of cortisol-awakening response on multi-target tracking in children with attention deficit hyperactivity disorder: the mediating role of working memory / 中华行为医学与脑科学杂志

Objective:To explore the mediating role of working memory (WM) in the cortisol-awakening response (CAR) and multiple object tracking (MOT) in children with attention deficit hyperactivity disorder (ADHD).Methods:92 children with ADHD (ADHD group) and 94 typically developing children (control group) were selected from January 2022 to October 2022. Salivary cortisol levels were detected and analyzed in all children at four time points after awakening. Children's WM and MOT performance were assessed by the 1-back and MOT paradigms, respectively. SPSS 26.0 software was used for t-test and Pearson correlation analysis of the data, and plug-in PROCESS model 4 of SPSS 26.0 was used for mediated effects analysis. Results:(1) ADHD group showed significantly lower CAR, 1-back accuracy and MOT performance((30.97±5.63), (81.33±10.64) %, (2.36±0.37)) than the control group((32.41±3.48), (91.19±7.12) %, (2.62±0.28))( t=-2.09, -7.22, -5.31, all P<0.05). (2) Pearson analysis showed that CAR was positively correlated with 1-back accuracy ( r=0.293, P<0.01) and MOT performance ( r=0.740, P<0.01). 1-back accuracy was positively correlated with MOT performance ( r=0.368, P<0.01). (3) WM partially mediated the effect of CAR on MOT in children with ADHD, accounting for 6.13% (0.003/0.049) of the total effect. Conclusion:Children with ADHD have deficits in MOT.WM plays a mediating role between CAR and MOT performance in children with ADHD.

Whole exome sequencing analysis of a patient with 45,X/46,XY mosaicism and autism spectrum disorder / 中华医学遗传学杂志

OBJECTIVE@#To carry out genetic testing for a patient with 45,X/46,XY mosaicism and autism spectrum disorder (ASD).@*METHODS@#Peripheral blood samples of the patient and his parents were collected for the extraction of genomic DNA. Trio-based whole exome sequencing and Sanger sequencing were carried out thereafter.@*RESULTS@#The proband and his father were found to harbor a heterozygous c.4781G>A (p.Arg1594Gln) variant of the CACNA1I gene. In addition, the proband was also found to harbor a de novo c.268C>T (p.Arg90Trp) missense variant of the MTRR gene. Based on guidelines of the American College of Medical Genetics and Genomics (ACMG), the c.4781G>A (p.Arg1594Gln) variant of the CACNA1I gene was predicted to be pathogenic (PVS1, PM1, PM2, PP3), while the c.268C>T (p.Arg90Trp) variant of the MTRR gene was predicted to be of uncertain significance.@*CONCLUSION@#Variants of the CACNA1I and MTRR genes, together with the chromosomal mosaicism, may have predisposed to the susceptibility to the ASD in this patient.

A study on KIF1A gene missense variant analysis and its protein expression and structure profiles of an autism spectrum disorder family trio / 中华医学遗传学杂志

OBJECTIVE@#To analyze the pathogenic variants of the KIF1A gene and its corresponding protein structure in an autism spectrum disorder (ASD) family trio carrying harmful missense variants in the KIF1A gene.@*METHODS@#The peripheral blood DNA of the patient and his parents was extracted and sequenced using whole exome sequencing (WES) technology and verified by Sanger sequencing. Bioinformatics software SIFT, PolyPhen-2, Mutation Taster, and CADD software were used to analyze the harmfulness and conservation of variants. The Human Brain Transcriptome (HBT) database was used to analyze the expression of the KIF1A gene in the brain. PredictProtein and SWISS-MODEL were further used to predict the secondary structure and tertiary structure of KIF1A wild-type protein and variant protein. PyMOL V2.4 was utilized to investigate the change of hydrogen bond connection after protein variant.@*RESULTS@#The WES sequencing revealed a missense variant c.664A>C (p.Asn222His) in the child's KIF1A gene, and this variant was a de novo variant. The harmfulness prediction results suggest that this variant is harmful. By analyzing expression level of KIF1A gene in the brain. It is found that KIF1A gene widely expressed in various brain regions during embryonic development. By analyzing the variant protein structure, the missense variant of KIF1A will cause many changes in the secondary structure of protein, such as alpha-helix, beta-strand, and protein binding domain. The connection of hydrogen bond and spatial structure will also change, thereby changing the original biological function.@*CONCLUSION@#The KIF1A gene may be a risk gene for ASD.

Analysis of common genetic variants associated with neuro-synapse development among 60 family trios affected with sporadic autism spectrum disorders / 中华医学遗传学杂志

Objective@#To explore susceptibility genes for autism spectrum disorders (ASD).@*Methods@#Whole-exome sequencing was carried out for 60 family trios affected with sporadic ASD. Genetic variants discovered in over 10% of the patients were selected for genotype-phenotype correlation and pathway enrichment analysis using Phenolyzer software and metascape database. Combining gene-phenotypic scores, pathway-related genes associated with neural and neurite triggering were screened for the candidates.@*Results@#A total of 170 common variants were found to be associated with the ASD phenotype. Among these, there was only one high-confidence gene [SHANK2 (0.8146)] and four medium-confidence genes [ERBB2 (0.1322), LAMC3 (0.1117), PPFIA4 (0.1059), DISC1 (0.1002)]. Twenty-pathways and four biological processes were found to be statistically significant by pathway enrichment analysis, which included neuron projection morphogenesis (GO: 0048812), regulation of neuroblast proliferation (GO: 1902692), modulation of excitatory postsynaptic potential (GO: 0098815), and dendrite morphogenesis (GO: 0048813). Twenty-one genes were found to be closely associated with neurological and neurite triggering, among which only SHANK2, ERBB2, and DISC1 had above-medium confidence correlation scores with the ASD phenotypes.@*Conclusion@#Abnormal neuron projection morphogenesis (GO: 0048812) may be closely related to the occurrence of ASD. SHANK2, ERBB2, and DISC1 are susceptibility genes for ASD.

Analysis of common genetic variants associated with neuro-synapse development among 60 family trios affected with sporadic autism spectrum disorders / 中华医学遗传学杂志

OBJECTIVE@#To explore susceptibility genes for autism spectrum disorders (ASD).@*METHODS@#Whole-exome sequencing was carried out for 60 family trios affected with sporadic ASD. Genetic variants discovered in over 10% of the patients were selected for genotype-phenotype correlation and pathway enrichment analysis using Phenolyzer software and metascape database. Combining gene-phenotypic scores, pathway-related genes associated with neural and neurite triggering were screened for the candidates.@*RESULTS@#A total of 170 common variants were found to be associated with the ASD phenotype. Among these, there was only one high-confidence gene [SHANK2(0.8146)] and four medium-confidence genes [ERBB2(0.1322), LAMC3(0.1117), PPFIA4(0.1059), DISC1(0.1002)]. Twenty-pathways and four biological processes were found to be statistically significant by pathway enrichment analysis, which included neuron projection morphogenesis (GO: 0048812), regulation of neuroblast proliferation (GO: 1902692), modulation of excitatory postsynaptic potential (GO: 0098815), and dendrite morphogenesis (GO: 0048813). Twenty-one genes were found to be closely associated with neurological and neurite triggering, among which only SHANK2, ERBB2, and DISC1 had above-medium confidence correlation scores with the ASD phenotypes.@*CONCLUSION@#Abnormal neuron projection morphogenesis (GO: 0048812) may be closely related to the occurrence of ASD. SHANK2, ERBB2, and DISC1 are susceptibility genes for ASD.