| 1 | Schizophr. Res. 2014 Mar 153: 225-30 |
|---|
| PMID | 24556472 |
| Title | Transcriptional consequences of schizophrenia candidate miR-137 manipulation in human neural progenitor cells. |
| Abstract | MIR137, transcribed as the microRNA miR-137, is one of the leading candidate schizophrenia susceptibility genes to arise from large genome-wide association studies (GWAS) of the disorder. Recent data suggest that miR-137 modulates the expression of other schizophrenia susceptibility genes. Although bioinformatic resources are available with which to predict genes regulated by individual microRNA, there has been a lack of empirical data on genome-wide gene expression changes following miR-137 manipulation. We have therefore performed a genome-wide assessment of transcriptional changes in a human neural progenitor cell line after miR-137 over-expression and inhibition in order to elucidate molecular pathways by which genetic perturbation of miR-137 could promote susceptibility to schizophrenia. Bioinformatically-predicted miR-137 targets showed a small but highly significant down-regulation following miR-137 over-expression. Genes that were significantly down-regulated in association with miR-137 over-expression were enriched for involvement in neuronal differentiation. Differentially expressed genes that were confirmed by qPCR included others at genome-wide significant risk loci for schizophrenia (MAD1L1 and DPYD) and BDNF. These data point to molecular pathways through which genetic variation at the MIR137 locus could confer risk for schizophrenia. |
| SCZ Keywords | schizophrenia |
| 2 | Mol. Psychiatry 2014 Sep 19: 1017-24 |
|---|
| PMID | 24280982 |
| Title | Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia. |
| Abstract | Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19?779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19?423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically. |
| SCZ Keywords | schizophrenia |
| 3 | PLoS ONE 2015 -1 10: e0133404 |
|---|
| PMID | 26193471 |
| Title | Network-Based Analysis of Schizophrenia Genome-Wide Association Data to Detect the Joint Functional Association Signals. |
| Abstract | schizophrenia is a common psychiatric disorder with high heritability and complex genetic architecture. Genome-wide association studies (GWAS) have identified several significant loci associated with schizophrenia. However, the explained heritability is still low. Growing evidence has shown schizophrenia is attributable to multiple genes with moderate effects. In-depth mining and integration of GWAS data is urgently expected to uncover disease-related gene combination patterns. Network-based analysis is a promising strategy to better interpret GWAS to identify disease-related network modules. We performed a network-based analysis on three independent schizophrenia GWASs by using a refined analysis framework, which included a more accurate gene P-value calculation, dynamic network module searching algorithm and detailed functional analysis for the obtained modules genes. The result generated 79 modules including 238 genes, which form a highly connected subnetwork with more statistical significance than expected by chance. The result validated several reported disease genes, such as MAD1L1, MCC, SDCCAG8, VAT1L, MAPK14, MYH9 and FXYD6, and also obtained several novel candidate genes and gene-gene interactions. Pathway enrichment analysis of the module genes suggested they were enriched in several neural and immune system related pathways/GO terms, such as neurotrophin signaling pathway, synaptosome, regulation of protein ubiquitination, and antigen processing and presentation. Further crosstalk analysis revealed these pathways/GO terms were cooperated with each other, and identified several important genes, which might play vital roles to connect these functions. Our network-based analysis of schizophrenia GWASs will facilitate the understanding of genetic mechanisms of schizophrenia. |
| SCZ Keywords | schizophrenia |
| 4 | Neurosci. Lett. 2016 Jan 610: 98-103 |
|---|
| PMID | 26528791 |
| Title | Genetic association of GWAS-supported MAD1L1 gene polymorphism rs12666575 with schizophrenia susceptibility in a Chinese population. |
| Abstract | schizophrenia (SCZ) is a severe neuropsychiatric disorder with high heritability. A recent European genome-wide association study has reported that mitotic arrest deficient-like 1 (MAD1L1) polymorphism rs12666575 is associated with SCZ susceptibility. This study aims to test the association of MAD1L1 variant rs12666575 with SCZ susceptibility in a Chinese population. A total of 1400 participants, which include 700 SCZ patients and 700 sex- and age-matched controls (Zhuang: 300, Han: 400, respectively), were genotyped using the Sequenom MassARRAY iPLEX platform. 591 SCZ patients underwent positive and negative syndrome scale (PANSS) assessment. Genetic association analysis was performed using the PLINK program. The results showed MAD1L1 rs12666575 polymorphism was significantly associated with SCZ susceptibility in the recessive model (p(adj)=0.013). Also, rs12666575 was significantly associated with general psychopathology sub-scale score (p(adj)=0.043) and thought disturbance factor score (p(adj)=0.045). Our data suggested that MAD1L1 rs12666575 polymorphism may play a protective role against SCZ in the Chinese population. Furthermore, rs12666575 may be associated with general psychopathology and thought disturbance in SCZ patients. |
| SCZ Keywords | schizophrenia |
| 5 | Schizophr. Res. 2016 Apr 172: 60-7 |
|---|
| PMID | 26851141 |
| Title | Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity. |
| Abstract | Ndel1 is a DISC1-interacting oligopeptidase that cleaves in vitro neuropeptides as neurotensin and bradykinin, and which has been associated with both neuronal migration and neurite outgrowth. We previously reported that plasma Ndel1 enzyme activity is lower in patients with schizophrenia (SCZ) compared to healthy controls (HCs). To our knowledge, no previous study has investigated the genetic factors associated with the plasma Ndel1 enzyme activity. In the current analyses, samples from 83 SCZ patients and 92 control subjects that were assayed for plasma Ndel1 enzyme activity were genotyped on Illumina Omni Express arrays. A genetic relationship matrix using genome-wide information was then used for ancestry correction, and association statistics were calculated genome-wide. Ndel1 enzyme activity was significantly lower in patients with SCZ (t=4.9; p<0.001) and was found to be associated with CAMK1D, MAGI2, CCDC25, and GABGR3, at a level of suggestive significance (p<10(-6)), independent of the clinical status. Then, we performed a model to investigate the observed differences for case/control measures. 2 SNPs at region 1p22.2 reached the p<10(-7) level. ZFPM2 and MAD1L1 were the only two genes with more than one hit at 10(-6) order of p value. Therefore, Ndel1 enzyme activity is a complex trait influenced by many different genetic variants that may contribute to SCZ physiopathology. |
| SCZ Keywords | schizophrenia |
| 6 | Neuropsychopharmacology 2016 May -1: -1 |
|---|
| PMID | 27184339 |
| Title | Investigating the Impact of a Genome-Wide Supported Bipolar Risk Variant of MAD1L1 on the Human Reward System. |
| Abstract | Recent genome-wide association studies have identified MAD1L1 (mitotic arrest deficient-like 1) as a susceptibility gene for bipolar disorder and schizophrenia. The minor allele of the single nucleotide polymorphism (SNP) rs11764590 in MAD1L1 was associated with bipolar disorder. Both diseases, bipolar disorder and schizophrenia are linked to functional alterations of the reward system. We aimed at investigating possible effects of the MAD1L1 rs11764590 risk allele on reward systems functioning in healthy adults. A large homogenous sample of 224 young (aged 18 to 31 years) participants was genotyped and underwent functional magnetic resonance imaging (fMRI). All participants performed the 'Desire-Reason Dilemma' paradigm investigating the neural correlates that underlie reward processing and active reward dismissal in favor of a long-term goal. We found significant hypoactivations of the ventral tegmental area (VTA), the bilateral striatum and bilateral frontal and parietal cortices in response to conditioned reward stimuli in the risk allele carriers compared to major allele carriers. In the dilemma situation, functional connectivity between prefrontal brain regions and the ventral striatum was significantly diminished in the risk allele carriers. Healthy risk allele carriers show a significant deficit of their bottom-up response to conditioned reward stimuli in the bilateral VTA and striatum. Furthermore, functional connectivity between the ventral striatum and prefrontal areas exerting top-down control on the mesolimbic reward system was reduced in this group. Similar alterations in reward processing and disturbances of prefrontal control mechanisms on mesolimbic brain circuits have also been reported in bipolar disorder and schizophrenia. Together, these findings suggest the existence of an intermediate phenotype associated with MAD1L1.Neuropsychopharmacology accepted article preview online, 13 May 2016. doi:10.1038/npp.2016.70. |
| SCZ Keywords | schizophrenia |