Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, ...it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA (miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex (BA 46) (n = 74 matched pairs of schizophrenia, schizoaffective, and control samples) was integrated with miRNA expression in the same cohort to identify gene–miRNA regulatory networks. A significant gene–miRNA interaction network was identified, including miR-92a, miR-495, and miR-134, which converged with differentially expressed genes in pathways involved in neurodevelopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expression through respective binding sites in BCL11A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support the hypothesis that miRNA dysregulation is an important factor in the complex pathophysiology of schizophrenia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Genome-wide association studies (GWAS) of schizophrenia have strongly implicated a risk locus in close proximity to the gene for miR-137. While there are candidate single-nucleotide ...polymorphisms (SNPs) with functional implications for the microRNA’s expression encompassed by the common haplotype tagged by rs1625579, there are likely to be others, such as the variable number tandem repeat (VNTR) variant rs58335419, that have no proxy on the SNP genotyping platforms used in GWAS to date. Using whole-genome sequencing data from schizophrenia patients (n = 299) and healthy controls (n = 131), we observed that the MIR137 4-repeats VNTR (VNTR4) variant was enriched in a cognitive deficit subtype of schizophrenia and associated with altered brain morphology, including thicker left inferior temporal gyrus and deeper right postcentral sulcus. These findings suggest that the MIR137 VNTR4 may impact neuroanatomical development that may, in turn, influence the expression of more severe cognitive symptoms in patients with schizophrenia.
Objectives:
Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further ...investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories.
Methods:
We performed a case–control genome-wide association study in 429 schizophrenia samples and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome.
Results:
The strongest finding (p = 2.01 × 10−6, odds ratio = 1.82, 95% confidence interval = 1.42, 2.33) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance (p = 2.78 × 10−6).
Conclusion:
The identification of FZD1, as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, ...it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA (miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorso-lateral cortex (BA 46) (n=74 matched pairs of schizophrenia, schizoaffective, and control samples) was integrated with miRNA expression in the same cohort to identify gene-miRNA regulatory net-works. A significant gene-miRNA interaction network was identified, including miR-92a, miR-495, and miR-134, which converged with differentially expressed genes in pathways involved in neurode-velopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expres-sion through respective binding sites in BCL11A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support thehypothesis that miRNA dysregulation is an important factor in the complex pathophysiology of schizophrenia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Brain white matter abnormalities are evident in individuals with schizophrenia, and also their first-degree relatives, suggesting that some alterations may relate to underlying genetic risk. The ST8 ...alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 (ST8SIA2) gene, which encodes the alpha-2,8-sialyltransferase 8B enzyme that aids neuronal migration and synaptic plasticity, was previously implicated as a schizophrenia susceptibility gene. This study examined the extent to which specific haplotypes in ST8SIA2 influence white matter microstructure using diffusion-weighted imaging of individuals with schizophrenia (n = 281) and healthy controls (n = 172), recruited across five Australian sites. Interactions between diagnostic status and the number of haplotype copies (0 or ≥1) were tested across all white matter voxels with cluster-based statistics. Fractional anisotropy (FA) in the right parietal lobe was found to show a significant interaction between diagnosis and ST8SIA2 protective haplotype (p < 0.05, family-wise error rate (FWER) cluster-corrected). The protective haplotype was associated with increased FA in controls, but this effect was reversed in people with schizophrenia. White matter fiber tracking revealed that the region-of-interest was traversed by portions of the superior longitudinal fasciculus, corona radiata, and posterior limb of internal capsule. Post hoc analysis revealed that reduced FA in this regional juncture correlated with reduced IQ in people with schizophrenia. The ST8SIA2 risk haplotype copy number did not show any differential effects on white matter. This study provides a link between a common disease-associated haplotype and specific changes in white matter microstructure, which may relate to resilience or risk for mental illness, providing further compelling evidence for involvement of ST8SIA2 in the pathophysiology of schizophrenia.
Diabetes is a common comorbidity in cancer patients, and is associated with poorer survival in colorectal cancer (CRC). However, there is little data to describe the experience of diabetic patients ...during chemotherapy. We have compared a diabetic population of cancer patients with matched controls receiving chemotherapy in a single centre.
We performed a retrospective case note analysis using an electronic patient record database (Patient Pathway Manager) and chemotherapy prescription software (ChemoCare) between 2001 and 2011. Diabetic patients starting first line chemotherapy for advanced CRC and advanced gynaecological cancers (GC) were identified. For each case a non-diabetic control was selected, matched for age (<65 vs ≥65), disease site (GC vs CRC) and chemotherapy type (single agent vs combination). Data for dose adjustments, acute admissions, stoppages, subsequent therapy and survival were compared, corrected for performance status (PS), comorbidity and primary site.
146 diabetic patients and 146 matched controls were included. Median age was 67 years; 95% of diabetic patients had type 2 diabetes, 18.5% were receiving insulin. Performance status was similar (diabetic 66% PS0-1, 29% PS2-3; non-diabetic 64% PS0-1, 34% PS2-3); more diabetic patients had comorbidity (60% vs 45%). A non-significant difference was observed in dose reductions (upfront 31.5% vs 23.9% p = 0.15; on-treatment 23.3 vs 13.7% p = 0.35). Only 5% of diabetic patients had upfront steroid reduction. Diabetes was independently associated with an increased risk of acute admission (OR = 3.32, 95%CI 1.8-5.8, p < 0.0001), early stopping of chemotherapy (OR = 2.17, 95%CI 1.25-3.85, p = 0.006) and reduced use of 2nd line treatment (OR = 0.56, 95%CI 0.34-0.95, p = 0.03). The most common causes of admission in the diabetic group were infection (41%) and poor glycaemic control (17%). Poor PS was also an independent risk factor for the above factors in multivariable analysis. Primary site, PS and age, but not diabetes, were independently prognostic for survival.
Diabetic patients experienced more acute complications on chemotherapy possibly limiting further treatment options. A prospective study would clarify the contributing factors and inform planning and monitoring of diabetic patients with cancer.
All authors have declared no conflicts of interest.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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