| 1 | Schizophr. Res. 2015 Oct 168: 421-8 |
|---|---|
| PMID | 26215504 |
| Title | Rare variants in the neurotrophin signaling pathway implicated in schizophrenia risk. |
| Abstract | Multiple lines of evidence corroborate impaired signaling pathways as relevant to the underpinnings of schizophrenia. There has been an interest in neurotrophins, since they are crucial mediators of neurodevelopment and in synaptic connectivity in the adult brain. Neurotrophins and their receptors demonstrate aberrant expression patterns in cortical areas for schizophrenia cases in comparison to control subjects. There is little known about the contribution of neurotrophin genes in psychiatric disorders. To begin to address this issue, we conducted high-coverage targeted exome capture in a subset of neurotrophin genes in 48 comprehensively characterized cases with schizophrenia-related psychosis. We herein report rare missense polymorphisms and novel missense mutations in neurotrophin receptor signaling pathway genes. Furthermore, we observed that several genes have a higher propensity to harbor missense coding variants than others. Based on this initial analysis we suggest that rare variants and missense mutations in neurotrophin genes might represent genetic contributions involved across psychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 2 | Schizophr. Res. 2016 Apr 172: 94-100 |
| PMID | 26925801 |
| Title | Prefrontal neuronal integrity predicts symptoms and cognition in schizophrenia and is sensitive to genetic heterogeneity. |
| Abstract | schizophrenia is a genetically complex syndrome with substantial inter-subject variability in multiple domains. Person-specific measures to resolve its heterogeneity could focus on the variability in prefrontal integrity, which this study indexed as relative rostralization within the anterior cingulate cortex (ACC). Twenty-two schizophrenia cases and 11 controls underwent rigorous diagnostic procedures, symptom assessments (PANSS, Deficit Syndrome Scale) and intelligence testing. All underwent multivoxel MRSI at 3T to measure concentrations of the neuronal-specific biomarker N-acetylaspartate (NAA) in all of the voxels of the ACC. The concentrations of NAA were separately calculated and then compared across the rostral and caudal subregions to generate a rostralization ratio, which was examined with respect to the study measures and to which cases carried a missense coding polymorphism in PTPRG, SCL39A13, TGM5, NTRK1 or ARMS/KIDINS220. Rostralization significantly differed between cases and controls (?(2)=18.40, p<.0001). In cases, it predicted verbal intelligence (r=.469, p=.043) and trait negative symptoms (diminished emotional range (r=-.624, p=.010); curbed interests, r=-.558, p=.025). Rostralization was similar to controls for missense coding variants in TGM5 and was significantly greater than controls for the PTPRG variant carrier. This is the first study examining the utility of MRS metrics in describing pathological features at both group and person-specific levels. Rostralization predicted core illness features and differed based on which signaling genes were disrupted. While future studies in larger populations are needed, ACC rostralization appears to be a promising measure to reduce the heterogeneity of schizophrenia for genetic research and selecting cases for treatment studies. |
| SCZ Keywords | schizophrenia |
| 3 | EBioMedicine 2016 Apr 6: 206-14 |
| PMID | 27211562 |
| Title | Phenotypically distinct subtypes of psychosis accompany novel or rare variants in four different signaling genes. |
| Abstract | Rare gene variants are important sources of schizophrenia vulnerability that likely interact with polygenic susceptibility loci. This study examined if novel or rare missense coding variants in any of four different signaling genes in sporadic schizophrenia cases were associated with clinical phenotypes in an exceptionally well-characterized sample. Structured interviews, cognition, symptoms and life course features were assessed in 48 ethnically-diverse cases with psychosis who underwent targeted exome sequencing of PTPRG (Protein Tyrosine Phosphatase, Receptor Type G), SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13), TGM5 (transglutaminase 5) and ARMS/KIDINS220 (Ankyrin repeat-rich membrane spanning protein or Kinase D-Interacting Substrate of 220kDa). Cases harboring rare missense coding polymorphisms or novel mutations in one or more of these genes were compared to other cases not carrying any rare missense coding polymorphisms or novel mutations in these genes and healthy controls. Fifteen of 48 cases (31.25%) carried rare or novel missense coding variants in one or more of these genes. The subgroups significantly differed in important features, including specific working memory deficits for PTPRG (n=5); severe negative symptoms, global cognitive deficits and poor educational attainment, suggesting a developmental disorder, for SLC39A13 (n=4); slow processing speed, childhood attention deficit disorder and milder symptoms for TGM5 (n=4); and global cognitive deficits with good educational attainment suggesting neurodegeneration for ARMS/KIDINS220 (n=5). Case vignettes are included in the appendix. Genes prone to missense coding polymorphisms and/or mutations in sporadic cases may highlight influential genes for psychosis and illuminate heterogeneous pathways to schizophrenia. Ethnicity appears less important at the level of genetic variability. The sequence variations that potentially alter the function of specific genes or their signaling partners may contribute to particular subtypes of psychosis. This approach may be applicable to other complex disorders. |
| SCZ Keywords | schizophrenia |