58 research outputs found
SLITRK1-mediated noradrenergic projection suppression in the neonatal prefrontal cortex
SLITRK1 is an obsessive-compulsive disorder spectrum-disorders-ssociated gene that encodes a neuronal transmembrane protein. Here we show that SLITRK1 suppresses noradrenergic projections in the neonatal prefrontal cortex, and SLITRK1 functions are impaired by SLITRK1 mutations in patients with schizophrenia (S330A, a revertant of Homo sapiensspecific residue) and bipolar disorder (A444S). Slitrk1-KO newborns exhibit abnormal vocalizations, and their prefrontal cortices show excessive noradrenergic neurites and reduced Semaphorin3A expression, which suppresses noradrenergic neurite outgrowth in vitro. Slitrk1 can bind Dynamin1 and L1 family proteins (Neurofascin and L1CAM), as well as suppress Semaphorin3A-induced endocytosis. Neurofascin-binding kinetics is altered in S330A and A444S mutations. Consistent with the increased obsessive-compulsive disorder prevalence in males in childhood, the prefrontal cortex of male Slitrk1-KO newborns show increased noradrenaline levels, and serotonergic varicosity size. This study further elucidates the role of noradrenaline in controlling the development of the obsessive-compulsive disorder-related neural circuit
Decreased serum pyridoxal levels in schizophrenia : meta-analysis and Mendelian randomization analysis
Background: Alterations in one-carbon metabolism have been associated with schizophrenia, and vitamin B6 is one of the key components in this pathway. Methods: We first conducted a case–control study of serum pyridoxal levels and schizophrenia in a large Japanese cohort (n = 1276). Subsequently, we conducted a meta-analysis of association studies (n = 2125). Second, we investigated whether rs4654748, which was identified in a genome-wide association study as a vitamin B6-related single nucleotide polymorphism, was genetically implicated in patients with schizophrenia in the Japanese population (n = 10 689). Finally, we assessed the effect of serum pyridoxal levels on schizophrenia risk using a Mendelian randomization (MR) approach. Results: Serum pyridoxal levels were significantly lower in patients with schizophrenia than in controls, not only in our cohort, but also in the pooled data set of the meta-analysis of association studies (standardized mean difference –0.48, 95% confidence interval [CI] –0.57 to –0.39, p = 9.8 × 10–24). We failed to find a significant association between rs4654748 and schizophrenia. Furthermore, an MR analysis failed to find a causal relationship between pyridoxal levels and schizophrenia risk (odds ratio 0.99, 95% CI 0.65–1.51, p = 0.96). Limitations: Food consumption and medications may have affected serum pyridoxal levels in our cross-sectional study. Sample size, number of instrumental variables and substantial heterogeneity among patients with schizophrenia are limitations of an MR analysis. Conclusion: We found decreased serum pyridoxal levels in patients with schizophrenia in this observational study. However, we failed to obtain data supporting a causal relationship between pyridoxal levels and schizophrenia risk using the MR approach
Cdh23 and Prepulse Inhibition
We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility
Fabp7 Maps to a Quantitative Trait Locus for a Schizophrenia Endophenotype
Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. Fabp7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported Fabp7 as a potential PPI-QTL gene, particularly in male mice. Disruption of Fabp7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming
Genome-Wide Association Study of Schizophrenia in Japanese Population
Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs) in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions). The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila)-like 2] gene located on 9p21.3 (p = 0.00087). In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals) of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026). The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology
Association of Transcription Factor Gene LMX1B with Autism
Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report
Ablation of Mrds1/Ofcc1 Induces Hyper-γ-Glutamyl Transpeptidasemia without Abnormal Head Development and Schizophrenia-Relevant Behaviors in Mice
Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as “the Japan Mouse Clinic”. No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum γ-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-γ-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-γ-glutamyl transpeptidasemia and schizophrenia
Association study of the KCNJ3 gene as a susceptibility candidate for schizophrenia in the Chinese population
We recently reported the results of a genome-wide association study (GWAS) of schizophrenia in the Japanese population. In that study, a single nucleotide polymorphism (SNP) (rs3106653) in the KCNJ3 (potassium inwardly rectifying channel, subfamily J, member 3) gene located at 2q24.1 showed association with schizophrenia in two independent sample sets. KCNJ3, also termed GIRK1 or Kir3.1, is a member of the G protein-activated inwardly rectifying K+ channel (GIRK) group. GIRKs are widely distributed in the brain and play an important role in regulating neural excitability through the activation of various G protein-coupled receptors. In this study, we set out to examine this association using a different population. We first performed a gene-centric association study of the KCNJ3 gene, by genotyping 38 tagSNPs in the Chinese population. We detected nine SNPs that displayed significant association with schizophrenia (lowest P = 0.0016 for rs3106658, Global significance = 0.036). The initial marker SNP (rs3106653) examined in our prior GWAS in the Japanese population also showed nominally significant association in the Chinese population (P = 0.028). Next, we analyzed transcript levels in the dorsolateral prefrontal cortex of postmortem brains from patients with schizophrenia and bipolar disorder and from healthy controls, using real-time quantitative RT-PCR. We found significantly lower KCNJ3 expression in postmortem brains from schizophrenic and bipolar patients compared with controls. These data suggest that the KCNJ3 gene is genetically associated with schizophrenia in Asian populations and add further evidence to the “channelopathy theory of psychiatric illnesses”
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