| 1 | Mol. Psychiatry 2008 Mar 13: 261-6 |
|---|---|
| PMID | 17646849 |
| Title | CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. |
| Abstract | A homozygous mutation of the CNTNAP2 gene has been associated with a syndrome of focal epilepsy, mental retardation, language regression and other neuropsychiatric problems in children of the Old Order Amish community. Here we report genomic rearrangements resulting in haploinsufficiency of the CNTNAP2 gene in association with epilepsy and schizophrenia. Genomic deletions of varying sizes affecting the CNTNAP2 gene were identified in three non-related Caucasian patients. In contrast, we did not observe any dosage variation for this gene in 512 healthy controls. Moreover, this genomic region has not been identified as showing large-scale copy number variation. Our data thus confirm an association of CNTNAP2 to epilepsy outside the Old Order Amish population and suggest that dosage alteration of this gene may lead to a complex phenotype of schizophrenia, epilepsy and cognitive impairment. |
| SCZ Keywords | schizophrenia |
| 2 | Trends Neurosci. 2009 Feb 32: 69-72 |
| PMID | 19135727 |
| Title | Contact in the genetics of autism and schizophrenia. |
| Abstract | Although autism and schizophrenia are considered to be distinct neuropsychiatric developmental disorders, recent studies indicate that they share genetic factors. The same chromosomal rearrangements and several single genes have emerged as genetic risks in both disorders. One such gene is contactin-associated protein-2 (CNTNAP2). These findings raise the possibility that these neuropsychiatric disorders share pathogenic mechanisms and that similar defects in biological pathways of brain development might underlie the phenotypic spectrum of these disorders. |
| SCZ Keywords | schizophrenia |
| 3 | Am. J. Hum. Genet. 2009 Nov 85: 655-66 |
| PMID | 19896112 |
| Title | CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. |
| Abstract | Heterozygous copy-number variants and SNPs of CNTNAP2 and NRXN1, two distantly related members of the neurexin superfamily, have been repeatedly associated with a wide spectrum of neuropsychiatric disorders, such as developmental language disorders, autism spectrum disorders, epilepsy, and schizophrenia. We now identified homozygous and compound-heterozygous deletions and mutations via molecular karyotyping and mutational screening in CNTNAP2 and NRXN1 in four patients with severe mental retardation (MR) and variable features, such as autistic behavior, epilepsy, and breathing anomalies, phenotypically overlapping with Pitt-Hopkins syndrome. With a frequency of at least 1% in our cohort of 179 patients, recessive defects in CNTNAP2 appear to significantly contribute to severe MR. Whereas the established synaptic role of NRXN1 suggests that synaptic defects contribute to the associated neuropsychiatric disorders and to severe MR as reported here, evidence for a synaptic role of the CNTNAP2-encoded protein CASPR2 has so far been lacking. Using Drosophila as a model, we now show that, as known for fly Nrx-I, the CASPR2 ortholog Nrx-IV might also localize to synapses. Overexpression of either protein can reorganize synaptic morphology and induce increased density of active zones, the synaptic domains of neurotransmitter release. Moreover, both Nrx-I and Nrx-IV determine the level of the presynaptic active-zone protein bruchpilot, indicating a possible common molecular mechanism in Nrx-I and Nrx-IV mutant conditions. We therefore propose that an analogous shared synaptic mechanism contributes to the similar clinical phenotypes resulting from defects in human NRXN1 and CNTNAP2. |
| SCZ Keywords | schizophrenia |
| 4 | Schizophr Bull 2010 May 36: 443-7 |
| PMID | 20421335 |
| Title | TCF4, schizophrenia, and Pitt-Hopkins Syndrome. |
| Abstract | Genome-wide association studies allied with the identification of rare copy number variants have provided important insights into the genetic risk factors for schizophrenia. Recently, a meta-analysis of several genome-wide association studies found, in addition to several other markers, a single nucleotide polymorphism in intron 4 of the TCF4 gene that was associated with schizophrenia. TCF4 encodes a basic helix-loop-helix transcription factor that interacts with other transcription factors to activate or repress gene expression. TCF4 mutations also cause Pitt-Hopkins Syndrome, an autosomal-dominant neurodevelopmental disorder associated with severe mental retardation. Variants in the TCF4 gene may therefore be associated with a range of neuropsychiatric phenotypes, including schizophrenia. Recessive forms of Pitt-Hopkins syndrome are caused by mutations in NRXN1 and CNTNAP2. Interestingly, NRXN1 deletions have been reported in schizophrenia, whereas CNTNAP2 variants are associated with several neuropsychiatric phenotypes. These data suggest that TCF4, NRXN1, and CNTNAP2 may participate in a biological pathway that is altered in patients with schizophrenia and other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 5 | Schizophr. Res. 2010 Dec 124: 192-9 |
| PMID | 20889312 |
| Title | A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder. |
| Abstract | schizophrenia and bipolar disorder both have strong inherited components. Recent studies have indicated that schizophrenia and bipolar disorder may share more than half of their genetic determinants. In this study, we performed a meta-analysis (combined analysis) for genome-wide association data of the Affymetrix Genome-Wide Human SNP array 6.0 to detect genetic variants influencing both schizophrenia and bipolar disorder using European-American samples (653 bipolar cases and 1034 controls, 1172 schizophrenia cases and 1379 controls). The best associated SNP rs11789399 was located at 9q33.1 (p=2.38 × 10(-6), 5.74 × 10(-4), and 5.56 × 10(-9), for schizophrenia, bipolar disorder and meta-analysis of schizophrenia and bipolar disorder, respectively), where one flanking gene, ASTN2 (220kb away) has been associated with attention deficit/hyperactivity disorder and schizophrenia. The next best SNP was rs12201676 located at 6q15 (p=2.67 × 10(-4), 2.12 × 10(-5), 3.88 × 10(-8) for schizophrenia, bipolar disorder and meta-analysis, respectively), near two flanking genes, GABRR1 and GABRR2 (15 and 17kb away, respectively). The third interesting SNP rs802568 was at 7q35 within CNTNAP2 (p=8.92 × 10(-4), 1.38 × 10(-5), and 1.62 × 10(-7) for schizophrenia, bipolar disorder and meta-analysis, respectively). Through meta-analysis, we found two additional associated genes NALCN (the top SNP is rs2044117, p=4.57 × 10(-7)) and NAP5 (the top SNP is rs10496702, p=7.15 × 10(-7)). Haplotype analyses of above five loci further supported the associations with schizophrenia and bipolar disorder. These results provide evidence of common genetic variants influencing schizophrenia and bipolar disorder. These findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia |
| 6 | Mol. Psychiatry 2010 Jun 15: 637-46 |
| PMID | 19546859 |
| Title | Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. |
| Abstract | Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD. |
| SCZ Keywords | schizophrenia |
| 7 | PLoS Genet. 2010 May 6: e1000962 |
| PMID | 20502679 |
| Title | Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. |
| Abstract | Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy. |
| SCZ Keywords | schizophrenia |
| 8 | Cytogenet. Genome Res. 2011 -1 135: 228-40 |
| PMID | 22085975 |
| Title | Disentangling the myriad genomics of complex disorders, specifically focusing on autism, epilepsy, and schizophrenia. |
| Abstract | Analyses of structural genome variation by array-CGH have dramatically enhanced our ability to detect copy number variations (CNVs). De novo CNVs and those co-segregating with disease in a family are generally interpreted as pathogenic. Yet, often CNVs, such as recurrent microdeletions in region 15q13.3, are not so clearly pathogenic. Here we discuss potential confounding mechanisms that may lead to the phenotypic pleiotropy of CNVs, such as unmasking of recessive alleles by hemizygous deletions, interaction of CNVs with other loci and genes, genetic epistasis, allelic exclusion, and somatic mosaicism. We illustrate some of these mechanisms with a detailed analysis of recent studies of CNVs involving MCPH1, AUTS2, CNTNAP2, and mutations in GRIN2B. Next we discuss the clinical ramifications of these findings and urge workers to avoid 'diagnostic fatalism' (i.e., halting all genetic investigation after the detection of a single CNV) and address some of the future challenges likely to result from implementations of next generation sequencing techniques. |
| SCZ Keywords | schizophrenia |
| 9 | J. Neurogenet. 2011 Oct 25: 88-103 |
| PMID | 21797804 |
| Title | Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells. |
| Abstract | Induced pluripotent stem cell (iPSC) technology has the potential to transform regenerative medicine. It also offers a powerful tool for establishing in vitro models of disease, in particular, for neuropsychiatric disorders where live human neurons are essentially impossible to procure. Using iPSCs derived from three schizophrenia (SZ) patients, one of whom has 22q11.2del (velocardiofacial syndrome; VCFS), the authors developed a culture system to study SZ on a molecular and cellular level. SZ iPSCs were differentiated into functional, primarily glutamatergic neurons that were able to fire action potentials after ?8 weeks in culture. Early differentiating neurons expressed a number of transcription factors/chromatin remodeling proteins and synaptic proteins relevant to SZ pathogenesis, including ZNF804A, RELN, CNTNAP2, CTNNA2, SMARCA2, and NRXN1. Although a small number of lines were developed in this preliminary study, the SZ line containing 22q11.2del showed a significant delay in the reduction of endogenous OCT4 and NANOG expression that normally occurs during differentiation. Constitutive expression of OCT4 has been observed in Dgcr8-deficient mouse embryonic stem cells (mESCs); DGCR8 maps to the 22q11.2-deleted region. These findings demonstrate that the method of inducing neural differentiation employed is useful for disease modeling in SZ and that the transition of iPSCs with 22q11.2 deletions towards a differentiated state may be marked by subtle changes in expression of pluripotency-associated genes. |
| SCZ Keywords | schizophrenia |
| 10 | BMC Med. Genet. 2011 -1 12: 106 |
| PMID | 21827697 |
| Title | Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. |
| Abstract | Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability. 99 patients with severe intellectual disability and resemblance to Pitt-Hopkins syndrome and/or suspected recessive inheritance were screened for mutations in CNTNAP2 and NRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in either CNTNAP2 or NRXN1, the remaining allele was sequenced. By molecular karyotyping and mutational screening of CNTNAP2 and NRXN1 in a group of severely intellectually disabled patients we identified a heterozygous deletion in NRXN1 in one patient and heterozygous splice-site, frameshift and stop mutations in CNTNAP2 in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions within NRXN1 or CNTNAP2 we could identify a defect on the second allele. One deletion in NRXN1 and one deletion in CNTNAP2 occurred de novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation. We report on patients with heterozygous defects in CNTNAP2 or NRXN1 associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not necessarily located in the same gene. |
| SCZ Keywords | schizophrenia |
| 11 | Mol. Psychiatry 2011 Mar 16: 286-92 |
| PMID | 20157312 |
| Title | Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. |
| Abstract | Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants, each of small effect. Identifying whether risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the single-nucleotide polymorphism (SNP) ratio test, which compares the ratio of nominally significant (P<0.05) to nonsignificant SNPs in a given pathway to identify the 'enrichment' for association signals. We applied this approach to the discovery (the International schizophrenia Consortium (n=6909)) and validation (Genetic Association Information Network (n=2729)) of schizophrenia genome-wide association study (GWAS) data sets. We investigated each of the 212 experimentally validated pathways described in the Kyoto Encyclopaedia of Genes and Genomes in the discovery sample. Nominally significant pathways were tested in the validation sample, and five pathways were found to be significant (P=0.03-0.001); only the cell adhesion molecule (CAM) pathway withstood conservative correction for multiple testing. Interestingly, this pathway was also significantly associated with bipolar disorder (Wellcome Trust Case Control Consortium (n=4847)) (P=0.01). At a gene level, CAM genes associated in all three samples (NRXN1 and CNTNAP2), which were previously implicated in specific language disorder, autism and schizophrenia. The CAM pathway functions in neuronal cell adhesion, which is critical for synaptic formation and normal cell signaling. Similar pathways have also emerged from a pathway analysis of autism, suggesting that mechanisms involved in neuronal cell adhesion may contribute broadly to neurodevelopmental psychiatric phenotypes. |
| SCZ Keywords | schizophrenia |
| 12 | Psychiatry Res 2013 May 207: 225-8 |
| PMID | 23123147 |
| Title | CNTNAP2 is significantly associated with schizophrenia and major depression in the Han Chinese population. |
| Abstract | CNTNAP2, located on 7q35-36.1, encodes a single-pass transmembrane protein mediating cell-cell interactions in the nervous system. CNTNAP2 has been suggested to play an important role in mental diseases such as autism and language disorder. However, we still do not know whether it also confers risk to major psychiatric disorders such as schizophrenia, major depression and bipolar disorder. We analysed single nucleotide polymorphisms (SNPs) previously reported to be associated with autism or language impairment in 1135 schizophrenia patients, 1135 unrelated major depression patients, 1135 unrelated bipolar disorder patients and 1135 unrelated normal controls recruited from the Han Chinese population. We found that the genotypes of rs17236239 were significantly associated with schizophrenia and the alleles of rs2710102 and rs2710117 were significantly associated with major depression. According to the location of significant signals, our study indicated that exon 13-15 of CNTNAP2 may play important roles in both schizophrenia and major depression in the Han Chinese population. |
| SCZ Keywords | schizophrenia |
| 13 | J Psychiatr Res 2013 Oct 47: 1349-56 |
| PMID | 23871450 |
| Title | CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study. |
| Abstract | CNTNAP2 is a gene on chromosome 7 that has shown associations with autism and schizophrenia, and there is evidence that it plays an important role for neuronal synchronization and brain connectivity. In this study, we assessed the relationship between Diffusion Tensor Imaging (DTI), a putative marker of anatomical brain connectivity, and multiple single nucleotide polymorphisms (SNPs) spread out over this large gene. 81 healthy controls and 44 patients with schizophrenia (all Caucasian) underwent DTI and genotyping of 31 SNPs within CNTNAP2. We employed Tract-based Spatial Statistics (TBSS) for inter-subject brain registration and computed average diffusivity values for six major white matter tracts. Analyses of Covariance (ANCOVAs) were computed to test for possible associations with genotypes. The strongest association, which survived rigorous Bonferroni correction, was between rs2710126 genotype and Fractional Anisotropy (FA) in the uncinate fasciculus (p = .00003). This anatomical location is particularly interesting given the enriched fronto-temporal expression of CNTNAP2 in the developing brain. For this SNP, no phenotype association has been reported before. There were several further genotype-DTI associations that were nominally significant but did not survive Bonferroni correction, including an association between axial diffusivity in the dorsal cingulum bundle and a region in intron 13 (represented by rs2710102, rs759178, rs2538991), which has previously been reported to be associated with anterior-posterior functional connectivity. We present new evidence about the effects of CNTNAP2 on brain connectivity, whose disruption has been hypothesized to be central to schizophrenia pathophysiology. |
| SCZ Keywords | schizophrenia |
| 14 | J Mol Psychiatry 2013 -1 1: 4 |
| PMID | 25408897 |
| Title | NRXN1 deletions identified by array comparative genome hybridisation in a clinical case series - further understanding of the relevance of NRXN1 to neurodevelopmental disorders. |
| Abstract | Microdeletions in the NRXN1 gene have been associated with a range of neurodevelopmental disorders, including autism spectrum disorders, schizophrenia, intellectual disability, speech and language delay, epilepsy and hypotonia. In the present study we performed array CGH analysis on 10,397 individuals referred for diagnostic cytogenetic analysis, using a custom oligonucleotide array, which included 215 NRXN1 probes (median spacing 4.9 kb). We found 34 NRXN1 deletions (0.33% of referrals) ranging from 9 to 942 kb in size, of which 18 were exonic (0.17%). Three deletions affected exons also in the beta isoform of NRXN1. No duplications were found. Patients had a range of phenotypes including developmental delay, learning difficulties, attention deficit hyperactivity disorder (ADHD), autism, speech delay, social communication difficulties, epilepsy, behaviour problems and microcephaly. Five patients who had deletions in NRXN1 had a second CNV implicated in neurodevelopmental disorder: a CNTNAP2 and CSMD3 deletion in patients with exonic NRXN1 deletions, and a Williams-Beuren syndrome deletion and two 22q11.2 duplications in patients with intronic NRXN1 deletions. Exonic deletions in the NRXN1 gene, predominantly affecting the alpha isoform, were found in patients with a range of neurodevelopmental disorders referred for diagnostic cytogenetic analysis. The targeting of dense oligonucleotide probes to the NRXN1 locus on array comparative hybridisation platforms provides detailed characterisation of deletions in this gene, and is likely to add to understanding of the importance of NRXN1 in neural development. |
| SCZ Keywords | schizophrenia |
| 15 | Nature 2014 Jul 511: 236-40 |
| PMID | 24870235 |
| Title | Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission. |
| Abstract | Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (?-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 16 | Eur. J. Hum. Genet. 2014 Feb 22: 171-8 |
| PMID | 23714751 |
| Title | Shining a light on CNTNAP2: complex functions to complex disorders. |
| Abstract | The genetic basis of complex neurological disorders involving language are poorly understood, partly due to the multiple additive genetic risk factors that are thought to be responsible. Furthermore, these conditions are often syndromic in that they have a range of endophenotypes that may be associated with the disorder and that may be present in different combinations in patients. However, the emergence of individual genes implicated across multiple disorders has suggested that they might share similar underlying genetic mechanisms. The CNTNAP2 gene is an excellent example of this, as it has recently been implicated in a broad range of phenotypes including autism spectrum disorder (ASD), schizophrenia, intellectual disability, dyslexia and language impairment. This review considers the evidence implicating CNTNAP2 in these conditions, the genetic risk factors and mutations that have been identified in patient and population studies and how these relate to patient phenotypes. The role of CNTNAP2 is examined in the context of larger neurogenetic networks during development and disorder, given what is known regarding the regulation and function of this gene. Understanding the role of CNTNAP2 in diverse neurological disorders will further our understanding of how combinations of individual genetic risk factors can contribute to complex conditions. |
| SCZ Keywords | schizophrenia |
| 17 | Biol. Psychiatry 2015 Jul 78: 116-25 |
| PMID | 25444170 |
| Title | Utility of Scalp Hair Follicles as a Novel Source of Biomarker Genes for Psychiatric Illnesses. |
| Abstract | Identifying beneficial surrogate genetic markers in psychiatric disorders is crucial but challenging. Given that scalp hair follicles are easily accessible and, like the brain, are derived from the ectoderm, expressions of messenger RNA (mRNA) and microRNA in the organ were examined between schizophrenia (n for first/second = 52/42) and control subjects (n = 62/55) in two sets of cohort. Genes of significance were also analyzed using postmortem brains (n for case/control = 35/35 in Brodmann area 46, 20/20 in cornu ammonis 1) and induced pluripotent stem cells (n = 4/4) and pluripotent stem cell-derived neurospheres (n = 12/12) to see their role in the central nervous system. Expression levels of mRNA for autism (n for case/control = 18/24) were also examined using scalp hair follicles. Among mRNA examined, FABP4 was downregulated in schizophrenia subjects by two independent sample sets. Receiver operating characteristic curve analysis determined that the sensitivity and specificity were 71.8% and 66.7%, respectively. FABP4 was expressed from the stage of neurosphere. Additionally, microarray-based microRNA analysis showed a trend of increased expression of hsa-miR-4449 (p = .0634) in hair follicles from schizophrenia. hsa-miR-4449 expression was increased in Brodmann area 46 from schizophrenia (p = .0007). Finally, we tested the expression of nine putative autism candidate genes in hair follicles and found decreased CNTNAP2 expression in the autism cohort. Scalp hair follicles could be a beneficial genetic biomarker resource for brain diseases, and further studies of FABP4 are merited in schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia |
| 18 | Proc. Natl. Acad. Sci. U.S.A. 2015 May 112: 6176-81 |
| PMID | 25918374 |
| Title | Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons. |
| Abstract | Central glutamatergic synapses and the molecular pathways that control them are emerging as common substrates in the pathogenesis of mental disorders. Genetic variation in the contactin associated protein-like 2 (CNTNAP2) gene, including copy number variations, exon deletions, truncations, single nucleotide variants, and polymorphisms have been associated with intellectual disability, epilepsy, schizophrenia, language disorders, and autism. CNTNAP2, encoded by CNTNAP2, is required for dendritic spine development and its absence causes disease-related phenotypes in mice. However, the mechanisms whereby CNTNAP2 regulates glutamatergic synapses are not known, and cellular phenotypes have not been investigated in CNTNAP2 knockout neurons. Here we show that CNTNAP2 is present in dendritic spines, as well as axons and soma. Structured illumination superresolution microscopy reveals closer proximity to excitatory, rather than inhibitory synaptic markers. CNTNAP2 does not promote the formation of synapses and cultured neurons from CNTNAP2 knockout mice do not show early defects in axon and dendrite outgrowth, suggesting that CNTNAP2 is not required at this stage. However, mature neurons from knockout mice show reduced spine density and levels of GluA1 subunits of AMPA receptors in spines. Unexpectedly, knockout neurons show large cytoplasmic aggregates of GluA1. Here we characterize, for the first time to our knowledge, synaptic phenotypes in CNTNAP2 knockout neurons and reveal a novel role for CNTNAP2 in GluA1 trafficking. Taken together, our findings provide insight into the biological roles of CNTNAP2 and into the pathogenesis of CNTNAP2-associated neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 19 | Behav. Brain Res. 2015 Oct 293: 241-51 |
| PMID | 26192912 |
| Title | A novel relationship for schizophrenia, bipolar and major depressive disorder Part 7: A hint from chromosome 7 high density association screen. |
| Abstract | Convergent evidence from genetics, symptology and psychopharmacology imply that there are intrinsic connection between schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD). Also, any two or even three of these disorders could co-existe in some families. A total of 47,144 single nucleotide polymorphism (SNPs) on chromosome 7 were genotyped by Affymetrix Genome-Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (type-I), 177 MDD, and 1000 controls. Associated SNP loci were comprehensively revealed and outstanding susceptibility genes were identified including CNTNAP2. a neurexin family gene. Unexpectedly, flanking genes for up to 94.74 % of of the associated SNPs were replicated (P?9.9 E-8) in an enlarged cohort of 986 SCZ patients. Considering other convergent evidence, our results further implicate that BPD and MDD are subtypes of SCZ. |
| SCZ Keywords | schizophrenia |
| 20 | Front Hum Neurosci 2015 -1 9: 100 |
| PMID | 25784871 |
| Title | Genetic markers of white matter integrity in schizophrenia revealed by parallel ICA. |
| Abstract | It is becoming a consensus that white matter integrity is compromised in schizophrenia (SZ), however the underlying genetics remains elusive. Evidence suggests a polygenic basis of the disorder, which involves various genetic variants with modest individual effect sizes. In this work, we used a multivariate approach, parallel independent component analysis (P-ICA), to explore the genetic underpinnings of white matter abnormalities in SZ. A pre-filtering step was first applied to locate 6527 single nucleotide polymorphisms (SNPs) discriminating patients from controls with a nominal uncorrected p-value of 0.01. These potential susceptibility loci were then investigated for associations with fractional anisotropy (FA) images in a cohort consisting of 73 SZ patients and 87 healthy controls (HC). A significant correlation (r = -0.37, p = 1.25 × 10(-6)) was identified between one genetic factor and one FA component after controlling for scanning site, ethnicity, age, and sex. The identified FA-SNP association remained stable in a 10-fold validation. A 5000-run permutation test yielded a p-value of 2.00 × 10(-4). The FA component reflected decreased white matter integrity in the forceps major for SZ patients. The SNP component was overrepresented in genes whose products are involved in corpus callosum morphology (e.g., CNTNAP2, NPAS3, and NFIB) as well as canonical pathways of synaptic long term depression and protein kinase A signaling. Taken together, our finding delineates a part of genetic architecture underlying SZ-related FA reduction, emphasizing the important role of genetic variants involved in neural development. |
| SCZ Keywords | schizophrenia |
| 21 | Front Behav Neurosci 2015 -1 9: 87 |
| PMID | 25941478 |
| Title | Interaction effect between handedness and CNTNAP2 polymorphism (rs7794745 genotype) on voice-specific frontotemporal activity in healthy individuals: an fMRI study. |
| Abstract | Recent neuroimaging studies have demonstrated that Contactin-associated protein-like2 (CNTNAP2) polymorphisms affect left-hemispheric function of language processing in healthy individuals, but no study has investigated the influence of these polymorphisms on right-hemispheric function involved in human voice perception. Further, although recent reports suggest that determination of handedness is influenced by genetic effect, the interaction effect between handedness and CNTNAP2 polymorphisms for brain activity in human voice perception and language processing has not been revealed. We aimed to investigate the interaction effect of handedness and CNTNAP2 polymorphisms in respect to brain function for human voice perception and language processing in healthy individuals. Brain function of 108 healthy volunteers (74 right-handed and 34 non-right-handed) was examined while they were passively listening to reverse sentences (rSEN), identifiable non-vocal sounds (SND), and sentences (SEN). Full factorial design analysis was calculated by using three factors: (1) rs7794745 (A/A or A/T), (2) rs2710102 [G/G or A carrier (A/G and A/A)], and (3) voice-specific response (rSEN or SND). The main effect of rs7794745 (A/A or A/T) was significantly revealed at the right middle frontal gyrus (MFG) and bilateral superior temporal gyrus (STG). This result suggests that rs7794745 genotype affects voice-specific brain function. Furthermore, interaction effect was significantly observed among MFG-STG activations by human voice perception, rs7794745 (A/A or A/T), and handedness. These results suggest that CNTNAP2 polymorphisms could be one of the important factors in the neural development related to vocal communication and language processing in both right-handed and non-right-handed healthy individuals. |
| SCZ Keywords | schizophrenia |
| 22 | NPJ Schizophr 2015 Jun 1: -1 |
| PMID | 26985448 |
| Title | Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells. |
| Abstract | Neurodevelopmental disorders, such as autism spectrum disorders (ASD) and schizophrenia (SZ), are complex disorders with a high degree of heritability. Genetic studies have identified several candidate genes associated with these disorders, including contactin-associated protein-like 2 (CNTNAP2). Traditionally, in animal models or in vitro, the function of CNTNAP2 has been studied by genetic deletion or transcriptional knockdown, which reduce the expression of the entire gene; however, it remains unclear whether the mutations identified in clinical settings are sufficient to alter CNTNAP2 expression in human neurons. Here, using human induced pluripotent stem cells (hiPSCs) derived from two individuals with a large (289kb) and heterozygous deletion in CNTNAP2 (affecting exons 14-15) and discordant clinical outcomes, we have characterized CNTNAP2 expression patterns in hiPSC neural progenitor cells (NPCs), two independent populations of hiPSC-derived neurons and hiPSC-derived oligodendrocyte precursor cells (OPCs). First, we observed exon-specific changes in CNTNAP2 expression in both carriers; although the expression of exons 14-15 is significantly decreased, the expression of other exons is upregulated. Second, we observed significant differences in patterns of allele-specific expression in CNTNAP2 carriers that were consistent with clinical outcome. Third, we observed a robust neural migration phenotype that correlated with diagnosis and exon- and allele-specific CNTNAP2 expression patterns, but not with genotype. In all, our data highlight the importance of considering the nature, location and regulation of mutated alleles when attempting to connect GWAS studies to gene function. |
| SCZ Keywords | schizophrenia |
| 23 | Mol Syndromol 2015 Feb 6: 7-22 |
| PMID | 25852443 |
| Title | Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders. |
| Abstract | Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward. |
| SCZ Keywords | schizophrenia |
| 24 | Genet. Mol. Res. 2016 -1 15: -1 |
| PMID | 26909962 |
| Title | Single nucleotide polymorphisms in the CNTNAP2 gene in Brazilian patients with autistic spectrum disorder. |
| Abstract | The role of some genes and their single nucleotide polymorphisms (SNPs) as genetic contributors of complex diseases is still a topic of much investigation. Research on genes related to autism susceptibility has been somewhat challenging, but also promising. Common genomic variants of CNTNAP2 have been associated with autism, and a range of autistic phenotypes such as impaired language function, abnormal social behavior, intellectual deficiency, epilepsy, and schizophrenia have been associated with this gene. Earlier findings have suggested that SNPs in the CNTNAP2 gene may be used as genetic markers for predisposition to autism spectrum disorder (ASD). We analyzed the SNPs (rs7794745 and rs2710102) in the CNTNAP2 gene of 210 individuals with idiopathic ASD and 200 non-autistic individuals by polymerase chain reaction-restriction fragment length polymorphism. The results revealed higher frequency distributions statistically significant (P = 0.034) of the homozygous SNP rs7794745 (presumed risk genotype) in ASD patients as compared with control subjects. The results also showed an association (OR = 1.802, 95%CI = 1.054-3.083, P = 0.042) between the same homozygous genotype and ASD, suggesting that it is a susceptibility factor for autism in this Brazilian population. |
| SCZ Keywords | schizophrenia |
| 25 | BMC Med. Genet. 2016 -1 17: 8 |
| PMID | 26843181 |
| Title | Characterisation of CASPR2 deficiency disorder--a syndrome involving autism, epilepsy and language impairment. |
| Abstract | Heterozygous mutations in CNTNAP2 have been identified in patients with a range of complex phenotypes including intellectual disability, autism and schizophrenia. However heterozygous CNTNAP2 mutations are also found in the normal population. Conversely, homozygous mutations are rare in patient populations and have not been found in any unaffected individuals. We describe a consanguineous family carrying a deletion in CNTNAP2 predicted to abolish function of its protein product, CASPR2. Homozygous family members display epilepsy, facial dysmorphisms, severe intellectual disability and impaired language. We compared these patients with previously reported individuals carrying homozygous mutations in CNTNAP2 and identified a highly recognisable phenotype. We propose that CASPR2 loss produces a syndrome involving early-onset refractory epilepsy, intellectual disability, language impairment and autistic features that can be recognized as CASPR2 deficiency disorder. Further screening for homozygous patients meeting these criteria, together with detailed phenotypic and molecular investigations will be crucial for understanding the contribution of CNTNAP2 to normal and disrupted development. |
| SCZ Keywords | schizophrenia |