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1.
eNeuro ; 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31540999

RESUMO

Bipolar disorder (BP) and schizophrenia (SCZ) are major psychiatric disorders, but the molecular mechanisms underlying the complicated pathologies of these disorders remain unclear. It is difficult to establish adequate in vitro models for pathological analysis because of the heterogeneity of these disorders. In the present study, to recapitulate the pathologies of these disorders in vitro, we established in vitro models by differentiating mature neurons from human induced pluripotent stem cells (hiPSCs) derived from BP and SCZ patients with contributive copy number variations (CNVs): two BP patients with PCDH15 deletion and one SCZ patient with RELN deletion. Glutamatergic neurons and GABAergic neurons were induced from hiPSCs under optimized conditions. Both types of induced neurons from both hiPSCs exhibited similar phenotypes of MAP2-positive dendrite shortening and decreasing synapse numbers. Additionally, we analyzed isogenic PCDH15- or RELN-deleted cells. The dendrite and synapse phenotypes of isogenic neurons were partially similar to those of patient-derived neurons. These results suggest that the observed phenotypes are general phenotypes of psychiatric disorders, and our in vitro models using hiPSC-based technology may be suitable for analysis of the pathologies of psychiatric disorders.Significance Statement Useful in vitro models of psychiatric disorders such as schizophrenia and bipolar disorder are urgently required for pathological analysis and drug discovery. In this study, mature excitatory and inhibitory neurons were induced from patient-derived induced pluripotent stem cells. The patients-derived induced neurons exhibited abnormalities in dendrite and synapse formation in vitro, which are similar to the previously reported findings observed in the postmortem brains. Our in vitro model may reflect general phenotypes of psychiatric disorders and can be used to further examine therapeutic targets.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31461559

RESUMO

AIMS: Recent studies have revealed that the interplay between polygenic risk scores (PRS) and large copy number variants (CNV; >500kb) is essential for the etiology of schizophrenia (SCZ). To replicate previous findings, including those for smaller CNV (>10kb), the PRS between SCZ patients with and without CNV were compared. METHODS: The PRS were calculated for 724 patients with SCZ and 1178 healthy controls (HC), genotyped using array-based comparative genomic hybridization and single nucleotide polymorphisms chips, and comparisons were made between cases and HC, or between subjects with and without 'clinically significant' CNV. RESULTS: First, we replicated the higher PRS in patients with SCZ compared to that in HC (without taking into account the CNV). For clinically significant CNV, as defined by the American College of Medical Genetics ('pathogenic' and 'uncertain clinical significance, likely pathogenic' CNV), 66 patients with SCZ carried clinically significant CNV, whereas 658 SCZ patients had no such CNV. In the comparison of PRS between cases with/without the CNV, despite no significant difference in PRS, significant enrichment of the well-established risk CNV (22q11.2 deletion and 47,XXY/47,XXX) was observed in the lowest decile of PRS in SCZ patients with the CNV. CONCLUSION: Although the present study failed to replicate the significant difference in PRS between SCZ patients with and without clinically significant CNV, SCZ patients with well-established risk CNV tended to have a lower PRS. Therefore, we speculate that the CNV in SCZ patients with lower PRS may contain 'genuine' risk; PRS is a possible tool for prioritizing clinically significant CNV because the power of the CNV association analysis is limited due to their rarity.

3.
Brain ; 142(7): 2127-2136, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096266

RESUMO

Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder's core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, -0.57; 95% CI, -1.27 to 0.13; P = 0.023) and confirmatory trials (-0.41; -0.62 to -0.20; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen's d = -0.78; 95% CI, -1.21 to -0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen's d = -0.46; 95% CI, -0.90 to -0.01) and 6 weeks (P = 0.10, Cohen's d = -0.35; 95% CI, -0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen's d = -1.24; 95% CI, -1.71 to -0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals' facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment.

4.
Transl Psychiatry ; 9(1): 146, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053702

RESUMO

The original Article required a few updates; one co-author name, which was given as Hiroki Kiumura, has been updated to Hiroki Kimura. Furthermore, supplementary information has been updated, and grant numbers have been added. These updates have been made to both the PDF and HTML versions of this Article.

5.
Transl Psychiatry ; 9(1): 126, 2019 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-31011151

RESUMO

Although a number of studies have identified several convincing candidate genes or molecules, the pathophysiology of schizophrenia (SCZ) has not been completely elucidated. Therapeutic optimization based on pathophysiology should be performed as early as possible to improve functional outcomes and prognosis; to detect useful biomarkers for SCZ, which reflect pathophysiology and can be utilized for timely diagnosis and effective therapy. To explore biomarkers for SCZ, we employed fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) of lymphoblastoid cell lines (LCLs) (1st sample set: 30 SCZ and 30 CON). Differentially expressed proteins were sequenced by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and identified proteins were confirmed by western blotting (WB) (1st and 2nd sample set: 60 SCZ and 60 CON). Multivariate logistic regression analysis was performed to identify an optimal combination of biomarkers to create a prediction model for SCZ. Twenty protein spots were differentially expressed between SCZ and CON in 2D-DIGE analysis and 22 unique proteins were identified by LC-MS/MS. Differential expression of eight of 22 proteins was confirmed by WB. Among the eight candidate proteins (HSPA4L, MX1, GLRX3, UROD, MAPRE1, TBCB, IGHM, and GART), we successfully constructed logistic regression models comprised of 4- and 6-markers with good discriminative ability between SCZ and CON. In both WB and gene expression analysis of LCL, MX1 showed reproducibly significant associations. Moreover, Mx1 and its related proinflamatory genes (Mx2, Il1b, and Tnf) were also up-regulated in poly I:C-treated mice. Differentially expressed proteins might be associated with molecular pathophysiology of SCZ, including dysregulation of immunological reactions and potentially provide diagnostic and prognostic biomarkers.

6.
Transl Psychiatry ; 9(1): 85, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755587

RESUMO

Psychiatric symptoms of schizophrenia suggest alteration of cerebral neurons. However, the physical basis of the schizophrenia symptoms has not been delineated at the cellular level. Here, we report nanometer-scale three-dimensional analysis of brain tissues of schizophrenia and control cases. Structures of cerebral tissues of the anterior cingulate cortex were visualized with synchrotron radiation nanotomography. Tissue constituents visualized in the three-dimensional images were traced to build Cartesian coordinate models of tissue constituents, such as neurons and blood vessels. The obtained Cartesian coordinates were used for calculating curvature and torsion of neurites in order to analyze their geometry. Results of the geometric analyses indicated that the curvature of neurites is significantly different between schizophrenia and control cases. The mean curvature of distal neurites of the schizophrenia cases was ~1.5 times higher than that of the controls. The schizophrenia case with the highest neurite curvature carried a frame shift mutation in the GLO1 gene, suggesting that oxidative stress due to the GLO1 mutation caused the structural alteration of the neurites. The differences in the neurite curvature result in differences in the spatial trajectory and hence alter neuronal circuits. It has been shown that the anterior cingulate cortex analyzed in this study has emotional and cognitive functions. We suggest that the structural alteration of neurons in the schizophrenia cases should reflect psychiatric symptoms of schizophrenia.

7.
Bioinformatics ; 35(17): 3092-3101, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649245

RESUMO

MOTIVATION: Recent sequence-based analyses have identified a lot of gene variants that may contribute to neurogenetic disorders such as autism spectrum disorder and schizophrenia. Several state-of-the-art network-based analyses have been proposed for mechanical understanding of genetic variants in neurogenetic disorders. However, these methods were mainly designed for modeling and analyzing single networks that do not interact with or depend on other networks, and thus cannot capture the properties between interdependent systems in brain-specific tissues, circuits and regions which are connected each other and affect behavior and cognitive processes. RESULTS: We introduce a novel and efficient framework, called a 'Network of Networks' approach, to infer the interconnectivity structure between multiple networks where the response and the predictor variables are topological information matrices of given networks. We also propose Graph-Oriented SParsE Learning, a new sparse structural learning algorithm for network data to identify a subset of the topological information matrices of the predictors related to the response. We demonstrate on simulated data that propose Graph-Oriented SParsE Learning outperforms existing kernel-based algorithms in terms of F-measure. On real data from human brain region-specific functional networks associated with the autism risk genes, we show that the 'Network of Networks' model provides insights on the autism-associated interconnectivity structure between functional interaction networks and a comprehensive understanding of the genetic basis of autism across diverse regions of the brain. AVAILABILITY AND IMPLEMENTATION: Our software is available from https://github.com/infinite-point/GOSPEL. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

8.
Schizophr Bull ; 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30285260

RESUMO

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.

9.
Cell Rep ; 24(11): 2838-2856, 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30208311

RESUMO

Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.

10.
Sci Rep ; 8(1): 13046, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158644

RESUMO

Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

11.
Stem Cell Res ; 31: 240-243, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30144654

RESUMO

Duplications at the 15q11.2-q13.1 region are associated with psychiatric disorders such as developmental delay and autism spectrum disorder. However, the specific influence of these duplications on human neuronal cells remains unclear. Here we generated induced pluripotent stem cells (iPSCs) derived from a patient with 15q11.2-q13.1 duplication syndrome. The generated iPSCs carried 15q11.2-q13.1 duplication and showed typical iPSC morphology and pluripotency marker expression, and the capacity to differentiate into three germ layers. These iPSC lines will contribute to further understanding the pathology of 15q11.2-q13.1 duplication syndrome and help develop drugs to treat psychiatric disorders.

12.
Psychiatry Res Neuroimaging ; 278: 35-41, 2018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29981940

RESUMO

Resting-state (rs) functional magnetic resonance imaging (fMRI) studies have revealed dysfunctional thalamocortical functional connectivity (FC) in schizophrenia. However, the relationship between thalamocortical FC and cognitive impairment has not been thoroughly investigated. We hypothesized that aberrant thalamocortical FC is related to attention deficits in schizophrenia. Thirty-eight patients with schizophrenia and 38 matched healthy controls underwent rs-fMRI and task fMRI while performing a Flanker task. We observed decreased left thalamic activation in patients with schizophrenia using task fMRI to determine the thalamic seed. A seed-based analysis using this seed was performed in the whole brain to assess differences in thalamocortical FC between the groups. Significantly worse performance was observed in the patient group. The rs-fMRI analysis revealed significantly increased FC between the left thalamus seed and the occipital cortices/postcentral gyri in patients when compared to controls. In the patient group, significant positive correlations were observed between the degree of FC from the left thalamus to the bilateral occipital gyri, which correspond to the visual cortex, and the Flanker effect. No significant correlation was detected in the control group. These results indicate that aberrant FC between the left thalamus and the visual cortex is related to attention deficits in schizophrenia.

13.
Transl Psychiatry ; 8(1): 129, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30022058

RESUMO

Reelin is a protein encoded by the RELN gene that controls neuronal migration in the developing brain. Human genetic studies suggest that rare RELN variants confer susceptibility to mental disorders such as schizophrenia. However, it remains unknown what effects rare RELN variants have on human neuronal cells. To this end, the analysis of human neuronal dynamics at the single-cell level is necessary. In this study, we generated human-induced pluripotent stem cells carrying a rare RELN variant (RELN-del) using targeted genome editing; cells were further differentiated into highly homogeneous dopaminergic neurons. Our results indicated that RELN-del triggered an impaired reelin signal and decreased the expression levels of genes relevant for cell movement in human neurons. Single-cell trajectory analysis revealed that control neurons possessed directional migration even in vitro, while RELN-del neurons demonstrated a wandering type of migration. We further confirmed these phenotypes in neurons derived from a patient carrying the congenital RELN-del. To our knowledge, this is the first report of the biological significance of a rare RELN variant in human neurons based on individual neuron dynamics. Collectively, our approach should be useful for studying reelin function and evaluating mental disorder susceptibility, focusing on individual human neuronal migration.

14.
J Neurochem ; 147(3): 395-408, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30025158

RESUMO

Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.

15.
Psychiatr Genet ; 28(5): 90-93, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29975244

RESUMO

Enhanced carbonyl stress has been observed in a subgroup of patients with schizophrenia. Glyoxalase I, which is encoded by GLO1, is an enzyme that protects against carbonyl stress. In this study, we focused on the association between rare genetic variants of GLO1 and schizophrenia. First, we identified one heterozygous frameshift variant, p.P122fs, in 370 Japanese schizophrenia cases with allele frequencies of up to 1% by exon-targeted mutation screening of GLO1. We then performed an association analysis on 1282 cases and 1764 controls with this variant. The variant was found in three cases and eight controls. There was no statistically significant association between p.P122fs in GLO1 and schizophrenia (P=0.25). This frameshift variant in GLO1 might occur at near-polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant.

16.
Mol Psychiatry ; 2018 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-29955161

RESUMO

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18-48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P < .001) but placebo also reduced the score (8.3 to 7.2; P < .001), no between-group difference was found (effect size -0.08; 95% CI, -0.46 to 0.31; P = .69); however, plasma oxytocin was only elevated from baseline to endpoint in the oxytocin-group compared with the placebo-group (effect size -1.12; -1.53 to -0.70; P < .0001). Among the secondary endpoints, oxytocin reduced ADOS repetitive behavior (2.0 to 1.5; P < .0001) compared with placebo (2.0 to 1.8; P = .43) (effect size 0.44; 0.05 to 0.83; P = .026). In addition, the duration of gaze fixation on socially relevant regions, another secondary endpoint, was increased by oxytocin (41.2 to 52.3; P = .03) compared with placebo (45.7 to 40.4; P = .25) (effect size 0.55; 0.10 to 1.0; P = .018). No significant effects were observed for the other secondary endpoints. No significant difference in the prevalence of adverse events was observed between groups, although one participant experienced temporary gynecomastia during oxytocin administration. Based on the present findings, we cannot recommend continuous intranasal oxytocin treatment alone at the current dose and duration for treatment of the core social symptoms of high-functioning ASD in adult men, although this large-scale trial suggests oxytocin's possibility to treat ASD repetitive behavior.

17.
Stem Cell Res ; 30: 81-84, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29803967

RESUMO

Astrotactin-2, encoded by ASTN2, is implicated in neuronal migration. Although genetic studies of schizophrenia (SCZ) patients have suggested that exonic deletions of ASTN2 are associated with neurodevelopmental and psychiatric disorders, their biological significance remains unclear. Herein, we generated human induced pluripotent stem cells (iPSCs) from a SCZ patient with an exonic deletion of ASTN2. The generated iPSCs carried ASTN2 deletion and showed typical iPSC morphology, pluripotency marker expression, normal chromosomal aneuploidy, and the capacity to differentiate into three germ layers. This iPSC line may be suitable for evaluating Astrotactin-2 function relevant for SCZ onset in the human brain.

18.
Cell Rep ; 22(3): 734-747, 2018 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-29346770

RESUMO

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.

19.
Transl Psychiatry ; 8(1): 12, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29317596

RESUMO

In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-D-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.

20.
Int J Neuropsychopharmacol ; 21(5): 405-409, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29126171

RESUMO

Background: Adenosine kinase (ADK) is supposed to be a schizophrenia susceptibility gene based on the findings that ADK is an enzyme that catalyzes transfer of the gamma-phosphate from ATP to adenosine, which interacts with dopamine and glutamate neurotransmitters. However, no reports of schizophrenia cases with loss of function variants in the ADK region have been published. In our previous study investigating copy number variants in schizophrenia, we detected a copy number variant in the ADK region in 1 of 1699 schizophrenia patients. Methods: We validated the ADK deletion by determining the breakpoint. Then, we compared the relative expression of ADK in 32 schizophrenia patients, including a schizophrenia patient with deletion of ADK, with 29 healthy controls using lymphoblastoid cell lines. Furthermore, we evaluated the clinical phenotypes of the schizophrenia with ADK deletion. Result: We validated the copy number variants with Sanger sequencing and predicted that this copy number variant results in loss of function of ADK. Furthermore, expression analysis of mRNA from peripheral blood in this schizophrenia patient with the ADK deletion showed an extremely low level of ADK. Here we describe a case report of a patient with ADK deletion with phenotypes (schizophrenia, parkinsonism, epilepsy) that are predicted when ADK function is disrupted. Conclusion: Considering that the patient had a low ADK mRNA level and showed a phenotype that may be related to ADK deficiency, the copy number variants in the region of ADK may be strongly related to the phenotypes described here, such as schizophrenia, Parkinsonism, and epilepsy.

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