1Am. J. Hum. Genet. 2008 Oct 83: 504-10
PMID18940311
TitleRecurrent CNVs disrupt three candidate genes in schizophrenia patients.
Abstractschizophrenia is a severe psychiatric disease with complex etiology, affecting approximately 1% of the general population. Most genetics studies so far have focused on disease association with common genetic variation, such as single-nucleotide polymorphisms (SNPs), but it has recently become apparent that large-scale genomic copy-number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrix's GeneChip 250K SNP arrays. We identified 90 CNVs in total, 77 of which have been reported previously in unaffected control cohorts. Among the genes disrupted by the remaining rare CNVs are MYT1L, CTNND2, NRXN1, and ASTN2, genes that play an important role in neuronal functioning but--except for NRXN1--have not been associated with schizophrenia before. We studied the occurrence of CNVs at these four loci in an additional cohort of 752 patients and 706 normal controls from The Netherlands. We identified eight additional CNVs, of which the four that affect coding sequences were found only in the patient cohort. Our study supports a role for rare CNVs in schizophrenia susceptibility and identifies at least three candidate genes for this complex disorder.
SCZ Keywordsschizophrenia, schizophrenic
2Mol. Psychiatry 2010 Jan 15: 29-37
PMID19844207
TitleReplication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample.
AbstractA recent genome-wide association study reported association between schizophrenia and the ZNF804A gene on chromosome 2q32.1. We attempted to replicate these findings in our Irish Case-Control Study of schizophrenia (ICCSS) sample (N=1021 cases, 626 controls). Following consultation with the original investigators, we genotyped three of the most promising single-nucleotide polymorphisms (SNPs) from the Cardiff study. We replicate association with rs1344706 (trend test one-tailed P=0.0113 with the previously associated A allele) in ZNF804A. We detect no evidence of association with rs6490121 in NOS1 (one-tailed P=0.21), and only a trend with rs9922369 in RGRIP1L (one-tailed P=0.0515). On the basis of these results, we completed genotyping of 11 additional linkage disequilibrium-tagging SNPs in ZNF804A. Of 12 SNPs genotyped, 11 pass quality control criteria and 4 are nominally associated, with our most significant evidence of association at rs7597593 (P=0.0013) followed by rs1344706. We observe no evidence of differential association in ZNF804A on the basis of family history or sex of case. The associated SNP rs1344706 lies in approximately 30 bp of conserved mammalian sequence, and the associated A allele is predicted to maintain binding sites for the brain-expressed transcription factors MYT1L and POU3F1/OCT-6. In controls, expression is significantly increased from the A allele of rs1344706 compared with the C allele. Expression is increased in schizophrenic cases compared with controls, but this difference does not achieve statistical significance. This study replicates the original reported association of ZNF804A with schizophrenia and suggests that there is a consistent link between the A allele of rs1344706, increased expression of ZNF804A and risk for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
3Mol. Psychiatry 2010 Jan 15: 29-37
PMID19844207
TitleReplication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample.
AbstractA recent genome-wide association study reported association between schizophrenia and the ZNF804A gene on chromosome 2q32.1. We attempted to replicate these findings in our Irish Case-Control Study of schizophrenia (ICCSS) sample (N=1021 cases, 626 controls). Following consultation with the original investigators, we genotyped three of the most promising single-nucleotide polymorphisms (SNPs) from the Cardiff study. We replicate association with rs1344706 (trend test one-tailed P=0.0113 with the previously associated A allele) in ZNF804A. We detect no evidence of association with rs6490121 in NOS1 (one-tailed P=0.21), and only a trend with rs9922369 in RGRIP1L (one-tailed P=0.0515). On the basis of these results, we completed genotyping of 11 additional linkage disequilibrium-tagging SNPs in ZNF804A. Of 12 SNPs genotyped, 11 pass quality control criteria and 4 are nominally associated, with our most significant evidence of association at rs7597593 (P=0.0013) followed by rs1344706. We observe no evidence of differential association in ZNF804A on the basis of family history or sex of case. The associated SNP rs1344706 lies in approximately 30 bp of conserved mammalian sequence, and the associated A allele is predicted to maintain binding sites for the brain-expressed transcription factors MYT1L and POU3F1/OCT-6. In controls, expression is significantly increased from the A allele of rs1344706 compared with the C allele. Expression is increased in schizophrenic cases compared with controls, but this difference does not achieve statistical significance. This study replicates the original reported association of ZNF804A with schizophrenia and suggests that there is a consistent link between the A allele of rs1344706, increased expression of ZNF804A and risk for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
4Am. J. Med. Genet. A 2011 Nov 155A: 2739-45
PMID21990140
TitleMYT1L is a candidate gene for intellectual disability in patients with 2p25.3 (2pter) deletions.
AbstractA partial deletion of chromosome band 2p25.3 (2pter) is a rarely described cytogenetic aberration in patients with intellectual disability (ID). Using microarrays we identified deletions of 2p25.3, sized 0.37-3.13 Mb, in three adult siblings and three unrelated patients. All patients had ID, obesity or overweight and/or a square-shaped stature without overt facial dysmorphic features. Combining our data with phenotypic and genotypic data of three patients from the literature we defined the minimal region of overlap which contained one gene, i.e., MYT1L. MYT1L is highly transcribed in the mouse embryonic brain where its expression is restricted to postmitotic differentiating neurons. In mouse-induced pluripotent stem cell (iPS) models, MYT1L is essential for inducing functional mature neurons. These resemble excitatory cortical neurons of the forebrain, suggesting a role for MYT1L in development of cognitive functions. Furthermore, MYT1L can directly convert human fibroblasts into functional neurons in conjunction with other transcription factors. MYT1L duplication was previously reported in schizophrenia, indicating that the gene is dosage-sensitive and that shared neurodevelopmental pathways may be affected in ID and schizophrenia. Finally, deletion of MYT1, another member of the Myelin Transcription Factor family involved in neurogenesis and highly similar to MYT1L, was recently described in ID as well. The identification of MYT1L as candidate gene for ID justifies further molecular studies aimed at detecting mutations and for mechanistic studies on its role in neuron development and on neuropathogenic effects of haploinsufficiency.
SCZ Keywordsschizophrenia, schizophrenic
5Psychiatr. Genet. 2012 Aug 22: 206-9
PMID22547139
TitleMicroduplications disrupting the MYT1L gene (2p25.3) are associated with schizophrenia.
AbstractChildhood-onset schizophrenia (COS) is a rare severe form of schizophrenia that may have greater salient genetic risk. Despite evidence for high heritability, conclusive genetic causes of schizophrenia remain elusive. Recent genomic technologies in concert with large case-control cohorts have led to several associations of highly penetrant rare copy number variants (CNVs) and schizophrenia. We previously reported two patients with COS who carried a microduplication disrupting the PXDN and MYT1L genes at 2p25.3. This rate of duplications within our COS population (N=92) is significantly higher than that in 2026 healthy controls (P=0.002). As a replication, we report a meta-analysis of four recently published studies that together provide strong evidence for an association between variably sized microduplications involving the MYT1L gene and schizophrenia. None have reported this separately. Altogether, among 5325 patients and 9279 controls, 10 microduplications were observed: nine in patients and one in a control (odds ratio=15.7, P=0.001). Further, the 2% rate observed in our COS patients is also significantly higher than the rate in adult-onset cases (0.14%, odds ratio=16.6, P=0.01). This report adds to the growing body of literature implicating rare CNVs as risk factors for schizophrenia and shows that some risk CNVs are more common among extreme early-onset cases.
SCZ Keywordsschizophrenia, schizophrenic
6Psychiatr. Genet. 2012 Jun 22: 137-40
PMID22157634
TitleGermline mosaic transmission of a novel duplication of PXDN and MYT1L to two male half-siblings with autism.
AbstractAutism is a neurodevelopmental disorder with a strong genetic component to susceptibility. In this study, we report the molecular characterization of an apparent de-novo 281 kb duplication of chromosome 2p25.3 in two male half-siblings with autism. The 2p25.3 duplication was first identified through a low-density microarray, validated with fluorescent in-situ hybridization, and duplication breakpoints were delineated using an Affymetrix 6.0 single-nucleotide polymorphism microarray. The fluorescent in-situ hybridization results validated the novel copy number variant and revealed the mother to be mosaic, with ?33% of her lymphoblast cells carrying the duplication. Therefore, the duplication was transmitted through the mechanism of germline mosaicism. In addition, duplication breakpoints were refined and showed that PXDN is fully duplicated, whereas seven exons of the terminal portion of the 25 exon gene MYT1L are within the duplicated region. MYT1L, a gene predominately expressed in the brain, has recently been linked with other neuropsychiatric illness such as schizophrenia and depression. Results from this study indicate that the 2p25.3 duplication disrupting PXDN and MYT1L is a potential autism-causing variant in the pedigree reported here and should receive further consideration as a candidate for autism.
SCZ Keywordsschizophrenia, schizophrenic
7Genes Brain Behav. 2012 Feb 11: 87-93
PMID21923761
TitleAssociation study of myelin transcription factor 1-like polymorphisms with schizophrenia in Han Chinese population.
Abstractschizophrenia (SZ) is characterized by a variety of complex positive, negative and cognitive symptoms that are differentially expressed in individual patients. Variability in symptom presentation indicates that multiple genes, many involved in neurodevelopment, contribute to the etiology of SZ. The myelin transcription factor 1-like (MYT1L) gene encodes the MYT1L protein that participates in several neurodevelopment pathways. The copy number variant of MYT1L gene is associated with SZ, and single-nucleotide polymorphisms (SNPs) of MYT1L contribute to major depressive disorder. To explore the association of MYT1L polymorphisms with SZ, we examined six SNPs of MYT1L in a Han Chinese population consisting of 528 paranoid schizophrenic patients and 528 healthy subjects. Our results showed that rs17039584 was significantly associated with SZ (A>G), even after Bonferroni correction. When subjects were divided by gender, the rs10190125 allele and genotype remained significantly associated with SZ in female patients. Moreover, we found that rs6742365 was associated with a family history of SZ in females. Other SNPs did not achieve statistical significance for SZ but were associated with individual phenotypes, as measured by the Positive and Negative Syndrome Scale (PANSS) inventory. Our findings suggest that MYT1L may represent a susceptibility gene for SZ in the Han Chinese population and show that a specific SNP may increase susceptibility in females.
SCZ Keywordsschizophrenia, schizophrenic
8Genes Brain Behav. 2012 Feb 11: 87-93
PMID21923761
TitleAssociation study of myelin transcription factor 1-like polymorphisms with schizophrenia in Han Chinese population.
Abstractschizophrenia (SZ) is characterized by a variety of complex positive, negative and cognitive symptoms that are differentially expressed in individual patients. Variability in symptom presentation indicates that multiple genes, many involved in neurodevelopment, contribute to the etiology of SZ. The myelin transcription factor 1-like (MYT1L) gene encodes the MYT1L protein that participates in several neurodevelopment pathways. The copy number variant of MYT1L gene is associated with SZ, and single-nucleotide polymorphisms (SNPs) of MYT1L contribute to major depressive disorder. To explore the association of MYT1L polymorphisms with SZ, we examined six SNPs of MYT1L in a Han Chinese population consisting of 528 paranoid schizophrenic patients and 528 healthy subjects. Our results showed that rs17039584 was significantly associated with SZ (A>G), even after Bonferroni correction. When subjects were divided by gender, the rs10190125 allele and genotype remained significantly associated with SZ in female patients. Moreover, we found that rs6742365 was associated with a family history of SZ in females. Other SNPs did not achieve statistical significance for SZ but were associated with individual phenotypes, as measured by the Positive and Negative Syndrome Scale (PANSS) inventory. Our findings suggest that MYT1L may represent a susceptibility gene for SZ in the Han Chinese population and show that a specific SNP may increase susceptibility in females.
SCZ Keywordsschizophrenia, schizophrenic
9Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Apr 162B: 273-82
PMID23505263
TitleIdentification of rare copy number variants in high burden schizophrenia families.
AbstractOver the last years, genome-wide studies consistently showed an increased burden of rare copy number variants (CNVs) in schizophrenia patients, supporting the "common disease, rare variant" hypothesis in at least a subset of patients. We hypothesize that in families with a high burden of disease, and thus probably a high genetic load influencing disease susceptibility, rare CNVs might be involved in the etiology of schizophrenia. We performed a genome-wide CNV analysis in the index patients of eight families with multiple schizophrenia affected members, and consecutively performed a detailed family analysis for the most relevant CNVs. One index patient showed a DRD5 containing duplication. A second index patient presented with an NRXN1 containing deletion and two adjacent duplications containing MYT1L and SNTG2. Detailed analysis in the subsequent families showed segregation of the identified CNVs. With this study we show the importance of screening high burden families for rare CNVs, which will not only broaden our knowledge concerning the molecular genetic mechanisms involved in schizophrenia but also allow the use of the obtained genetic data to provide better clinical care to these families in general and to non-symptomatic causal CNV carriers in particular.
SCZ Keywordsschizophrenia, schizophrenic
10BBA Clin 2015 Jun 3: 36-43
PMID26673096
TitleGenetic variants in Nogo receptor signaling pathways may be associated with early life adversity in schizophrenia susceptibility.
Abstractschizophrenia is a severe neuropsychiatric disorder thought to result from abnormal brain development. Nogo, an oligodendrocyte bound molecule, signals by binding to the Nogo receptor (NgR) located on axonal membranes. The NgR co-receptors include p75 neurotrophin receptor or TNF receptor orphan Y (TROY). Nogo signaling is responsible for central nervous system myelin regulation and neurite outgrowth during neurodevelopment, and plasticity in the mature brain.
We examined single nucleotide polymorphisms (SNPs) in NgR, p75, and TROY receptor genes and downstream signaling partner With No Lysine (K) (WNK1) and Myelin transcription factor 1-like (MYT1L) genes in an Australian case-control schizophrenia cohort (n=268/group). High-throughput SNP genotyping was performed using the MassARRAY genotyping assay.
Analysis revealed a significant association between the MYT1L SNP rs2304008 and female schizophrenia subjects. The WNK1 SNP rs1468326 and the MYT1L SNP rs3748988 showed significant associations with schizophrenia in subjects with a maternal mental history and in subjects who experienced childhood trauma respectively. Following Bonferroni correction, all significance was lost.
Despite the lack of positive findings in our population after correction for multiple testing, previous gene expression and association studies in schizophrenia suggest the implication of NgR signaling pathway genes in the etiology of schizophrenia remains topical and timely.
Further investigations will be necessary to fully assess the role of these genes in the pathophysiology of schizophrenia. However these genes may prove useful in further understanding the mechanism by which negative experiences early in life can affect myelin-related processes in the context of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic