• APOER2
• Alzheimer’s disease
• DAB1
• RELN
• Reelin
• Schizophrenia

• Reelin Protein
• Humans
• Alzheimer Disease/metabolism
• Alzheimer Disease/genetics
• Schizophrenia/metabolism
• Schizophrenia/genetics
• Cell Adhesion Molecules, Neuronal/metabolism
• Cell Adhesion Molecules, Neuronal/genetics
• Signal Transduction/physiology
• Nerve Tissue Proteins/metabolism
• Nerve Tissue Proteins/genetics
• Serine Endopeptidases/metabolism
• Serine Endopeptidases/genetics
• Extracellular Matrix Proteins/metabolism
• Animals

• Candidate gene association study (CGAS)
• Genetics
• Genome-wide association study (GWAS)
• Schizophrenia
• Single nucleotide polymorphism (SNP)
• Susceptibility gene

• Humans
• Schizophrenia/genetics
• Schizophrenia/diagnosis
• Genome-Wide Association Study
• Genetic Predisposition to Disease/genetics
• Polymorphism, Single Nucleotide
• Genomics
• RNA-Binding Proteins/genetics

• grossesse
• hormones thyroïdiennes
• maladies neurologiques
• neurological diseases
• pregnancy
• reelin
• rééline
• thyroid hormones

Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.

• Neural stem cells
• Adult hippocampal neurogenesis
• Schizophrenia
• Risk genes
• Signaling pathways
• Behavior

Schizophrenia is a severely multifactorial neuropsychiatric disorder, and the majority of cases are due to genetic variations. In this study, we evaluated the genetic association between the C-Maf-inducing protein (CMIP) gene and schizophrenia in the Han Chinese population.

In this case-control study, 761 schizophrenia patients and 775 healthy controls were recruited. Tag single-nucleotide polymorphisms (SNPs; rs12925980, rs2287112, rs3751859 and rs77700579) from the CMIP gene were genotyped via matrix-assisted laser desorption/ionization time of flight mass spectrometry. We used logistic regression to estimate the associations between the genotypes/alleles of each SNP and schizophrenia in males and females, respectively. The in-depth link between CMIP and schizophrenia was explored through linkage disequilibrium (LD) and further haplotype analyses. False discovery rate correction was utilized to control for Type I errors caused by multiple comparisons.

There was a significant difference in rs287112 allele frequencies between female schizophrenia patients and healthy controls after adjusting for multiple comparisons (χ² = 12.296, P_adj = 0.008). Females carrying minor allele G had 4.445 times higher risk of schizophrenia compared with people who carried the T allele (OR = 4.445, 95% CI [1.788–11.046]). Linkage-disequilibrium was not observed in the subjects, and people with haplotype TTGT of rs12925980–rs2287112–rs3751859–rs77700579 had a lower risk of schizophrenia (OR = 0.42, 95% CI [0.19–0.94]) when compared with CTGA haplotypes. However, the association did not survive false discovery rate correction.

This study identified a potential CMIP variant that may confer schizophrenia risk in the female Han Chinese population.

• C-Maf-inducing protein
• CMIP
• Gene polymorphism
• Haplotype analysis
• Schizophrenia

The Reelin (RELN) gene encodes the protein reelin, which is a large extracellular matrix glycoprotein that plays a key role in brain development. Additionally, this protein may be involved in memory formation, neurotransmission, and synaptic plasticity, which have been shown to be disrupted in schizophrenia (SCZ). A decreasing trend in the expression of RELN mRNA in the brain and peripheral blood of SCZ patients has been observed. There is a need to determine whether changes in RELN mRNA expression in SCZ patients are the result of long-term antipsychotic treatment rather than the etiological characteristics of schizophrenia. The expression levels of RELN mRNA in the peripheral blood of 48 healthy controls and 30 SCZ patients before and after 12-weeks of treatment were measured using quantitative real-time PCR.

The expression levels of RELN mRNA in the SCZ group were significantly lower than that of healthy controls; however, after 12-weeks of antipsychotic treatment, RELN mRNA levels were significantly increased in the SCZ group.

The up-regulation of RELN mRNA expression was current in SCZ patients after antipsychotic treatment, suggesting that the changes in RELN mRNA expression were related to the effect of the antipsychotic treatment.

• Antipsychotic treatment
• RELN
• SCZ

• SAD kinase
• axon/dendrite differentiation
• neuronal migration

• Meta-analysis
• Polymorphism
• RELN gene
• Risk
• Schizophrenia

There are great individual differences in the drug responses; however, there are few prognostic drug response biomarkers available. RELN is one of the more extensively examined schizophrenia candidate genes. The purpose of this study was to determine whether RELN can affect antipsychotics response in the Chinese population. This may lead to the discovery of relevant novel drug response markers.

The unrelated 260 Chinese Han inpatients with schizophrenia were enrolled in the present study. The enrolled subjects have been prescribed antipsychotic medication during the study. A total of 15 SNPs of RELN were genotyped by MassARRAY^® platform. The association of the RELN gene with therapeutic response to antipsychotics was analyzed based on sex and age at onset.

Two novel SNPs of RELN were found to be associated with antipsychotic treatment response (rs155333, p = 0.010 and rs6465938, p = 0.049) at nominal significance threshold, but not after multiple correction. Our study also revealed highly significant association of a haplotype consisting of three SNPs (rs362814-rs362626-rs2237628) with antipsychotic treatment response. Even after permutation, the p-value indicated significant association (rs362814-rs362626-rs2237628: ACT, χ² = 6.353, p = 0.0117, permuted p = 0.04). Furthermore, a novel SNP, rs2535764, was found to be associated with antipsychotic response under overdominant genetic model at a marginal significant level of 0.046 (C/T vs. C/C + T/T: p = 0.046, AIC = 314.7, BIC = 321.6).

Our data indicated that RELN can affect antipsychotic treatment outcomes in the Chinese population. SNPs of RELN could be used as predictive biomarkers for future personalized medicine of antipsychotic drug treatment. However, none of the three novel SNPs (rs155333, rs6465938, and rs2535764) remained significant after Bonferroni correction. Therefore, validation is needed in larger pharmacogenetic studies.

• RELN
• antipsychotics
• drug response
• pharmacogenetics
• schizophrenia

• LRP8
• Schizophrenia
• mRNA
• rs5177

• RELN
• SNP
• association analysis
• bioinformatics tools
• psychiatric symptoms
• quantitative trait loci analyses
• schizophrenia

• Biomarker
• DISC1
• GABA
• Reelin
• SELENBP1

• Biomarkers/blood
• Biomarkers/cerebrospinal fluid
• Biomarkers/metabolism
• Brain/metabolism
• Brain-Derived Neurotrophic Factor/blood
• Brain-Derived Neurotrophic Factor/cerebrospinal fluid
• Brain-Derived Neurotrophic Factor/metabolism
• Catechol O-Methyltransferase/blood
• Catechol O-Methyltransferase/cerebrospinal fluid
• Catechol O-Methyltransferase/metabolism
• Cell Adhesion Molecules, Neuronal/blood
• Cell Adhesion Molecules, Neuronal/cerebrospinal fluid
• Cell Adhesion Molecules, Neuronal/metabolism
• Dysbindin/blood
• Dysbindin/cerebrospinal fluid
• Dysbindin/metabolism
• Extracellular Matrix Proteins/blood
• Extracellular Matrix Proteins/cerebrospinal fluid
• Extracellular Matrix Proteins/metabolism
• Humans
• Nerve Growth Factors/blood
• Nerve Growth Factors/cerebrospinal fluid
• Nerve Growth Factors/metabolism
• Nerve Tissue Proteins/blood
• Nerve Tissue Proteins/cerebrospinal fluid
• Nerve Tissue Proteins/metabolism
• Neurotrophin 3
• Prefrontal Cortex/metabolism
• Reelin Protein
• Schizophrenia/blood
• Schizophrenia/cerebrospinal fluid
• Schizophrenia/diagnostic imaging
• Serine Endopeptidases/blood
• Serine Endopeptidases/cerebrospinal fluid
• Serine Endopeptidases/metabolism
• Vascular Endothelial Growth Factor A

• anxiety
• behavioral test battery
• conditional knockout
• laminar structure

Schizophrenia (SZ) is a complex polygenic psychiatric disorder caused in part by abnormal dopamine levels. Cerebral dopamine neurotrophic factor (CDNF) 2 is known to protect and repair the dopaminergic system. Dopamine dysfunction is one of the pathogenesis of SZ. However, the relationship between CDNF2 and SZ has not been previously investigated. We speculated that CDNF2 may be a susceptibility factor for SZ.

To address this issue, we carried out a study to investigate the association between CDNF2 and SZ in the total sample 1371 (670 SZ patients and 701 healthy controls) Han Chinese population. Stage 1 included 528 SZ patients and 528 healthy controls; and stage 2 included 142 SZ patients and 173 healthy controls. The allele and genotype frequencies of five single nucleotide polymorphisms (rs2577074, rs2577075, rs2249810, rs6506891, and rs2118343) of CDNF2 were compared between patients and controls.

We found a significant association in allele and genotype frequencies between the two groups at rs2249810 (χ² = 4.38 and 6.45, respectively; P = 0.03 and 0.04, respectively). An association was also observed in males at rs2249810 (χ² = 8.76; P = 0.03). Haplotype TGATC differed between SZ and controls in stage 2 samples (χ² = 6.38; P = 0.01), and rs2118343 genotypes were associated with negative factor scores (F = 4.396; P = 0.01).

These results suggest that rs2249810 and haplotype TGATC of CDNF2 are an SZ susceptibility locus and factor, respectively, and that rs2118343 genotypes are associated with negative symptoms of SZ in the Han Chinese population.

• CDNF2
• PANSS
• Polymorphism
• Schizophrenia

Numerous developmental genes have been linked to schizophrenia (SZ) by case-control and genome-wide association studies, suggesting that neurodevelopmental disturbances are major pathogenic mechanisms. However, no neurodevelopmental deficit has been definitively linked to SZ occurrence, likely due to disease heterogeneity and the differential effects of various gene variants across ethnicities. Hence, it is critical to examine linkages in specific ethnic populations, such as Han Chinese. The newly identified RhoGAP ARHGAP18 is likely involved in neurodevelopment through regulation of RhoA/C. Here we describe four single nucleotide polymorphisms (SNPs) in ARHGAP18 associated with SZ across a cohort of >2000 cases and controls from the Han population. Two SNPs, rs7758025 and rs9483050, displayed significant differences between case and control groups both in genotype (P = 0.0002 and P = 7.54×10⁻⁶) and allelic frequencies (P = 4.36×10⁻⁵ and P = 5.98×10⁻⁷), respectively. The AG haplotype in rs7758025−rs9385502 was strongly associated with the occurrence of SZ (P = 0.0012, OR = 0.67, 95% CI = 0.48–0.93), an association that still held following a 1000-times random permutation test (P = 0.022). In an independently collected validation cohort, rs9483050 was the SNP most strongly associated with SZ. In addition, the allelic frequencies of rs12197901 remained associated with SZ in the combined cohort (P = 0.021), although not in the validation cohort alone (P = 0.251). Collectively, our data suggest the ARHGAP18 may confer vulnerability to SZ in the Chinese Han population, providing additional evidence for the involvement of neurodevelopmental dysfunction in the pathogenesis of schizophrenia.

Proper neuronal migration and laminar formation during corticogenesis is essential for normal brain function. Disruption of these developmental processes is thought to be involved in the pathogenesis of some neuropsychiatric conditions. Especially, Reelin, a glycoprotein mainly secreted by the Cajal-Retzius cells and a subpopulation of GABAergic interneurons, has been shown to play a critical role, both during embryonic and postnatal periods. Indeed, animal studies have clearly revealed that Reelin is an essential molecule for proper migration of cortical neurons and finally regulates the cell positioning in the cortex during embryonic and early postnatal stages; by contrast, Reelin signaling is closely involved in synaptic function in adulthood. In humans, genetic studies have shown that the reelin gene (RELN) is associated with a number of psychiatric diseases, including Schizophrenia (SZ), bipolar disorder (BP) and autistic spectrum disorder. Indeed, Reln haploinsufficiency has been shown to cause cognitive impairment in rodents, suggesting the expression level of the Reelin protein is closely related to the higher brain functions. However, the molecular abnormalities in the Reelin pathway involved in the pathogenesis of psychiatric disorders are not yet fully understood. In this article, we review the current progress in the understanding of the Reelin functions that could be related to the pathogenesis of psychiatric disorders. Furthermore, we discuss the basis for selecting Reelin and molecules in its downstream signaling pathway as potential therapeutic targets for psychiatric illnesses.

• animal model
• psychiatric disorder
• reeler
• reelin
• schizophrenia

• Meta-analysis
• Polymorphism
• Reelin
• Risk
• Schizophrenia

• Chinese
• Paliperidone
• Schizophrenia
• Symptoms
• Time to relapse

• Development
• Gene expression
• Lead
• Neurotoxicity
• Reelin
• Zebrafish

• Animals
• Apoptosis/drug effects
• Brain/drug effects
• Brain/growth & development
• Brain/metabolism
• Cell Adhesion Molecules, Neuronal/biosynthesis
• Dose-Response Relationship, Drug
• Embryo, Nonmammalian/drug effects
• Embryo, Nonmammalian/metabolism
• Extracellular Matrix Proteins/biosynthesis
• Gene Expression Regulation, Developmental/drug effects
• Lead/toxicity
• Nerve Tissue Proteins/biosynthesis
• Reelin Protein
• Serine Endopeptidases/biosynthesis
• Spinal Cord/drug effects
• Spinal Cord/growth & development
• Spinal Cord/metabolism
• Time Factors
• Zebrafish/growth & development
• Zebrafish/metabolism

• reelin
• schizophrenia
• autism
• bipolar disorder
• major depression
• lissencephaly
• treatment

• Autistic Disorder/genetics
• Autistic Disorder/metabolism
• Brain/metabolism
• Cell Adhesion Molecules, Neuronal/genetics
• Cell Adhesion Molecules, Neuronal/metabolism
• Cognition
• Extracellular Matrix Proteins/genetics
• Extracellular Matrix Proteins/metabolism
• Humans
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• Receptors, Cell Surface/genetics
• Receptors, Cell Surface/metabolism
• Reelin Protein
• Schizophrenia/genetics
• Schizophrenia/metabolism
• Serine Endopeptidases/genetics
• Serine Endopeptidases/metabolism

• R01 HD052074 NICHD NIH HHS
• R01 MH086000 NIMH NIH HHS
• 5R01MH086000-01A2 NIMH NIH HHS
• 5R01HD052074-01A2 NICHD NIH HHS