Corpus callosum microstructural organization mediates the effects of physical neglect on social cognition in schizophrenia.

Exposure to early life adversity is associated with both increased risk of developing schizophrenia and poorer performance on measures of social cognitive functioning. In this study, we examined whether interleukin-6 (IL-6) and Corpus Callosum (CC) microstructure mediated the association between childhood physical neglect and social cognition. Fifty-eight patients with a diagnosis of schizophrenia were included. The CANTAB emotion recognition task (unbiased hit rate) was used to assess social cognition. We found that the microstructural organization of the CC significantly mediated the association between physical neglect and emotion recognition. Furthermore, in a sequential mediation analysis that also considered the role of inflammatory response, the association between physical neglect, and lower emotion recognition performance was sequentially mediated by higher IL-6 and lower fractional anisotropy of the CC. This mediating effect of IL-6 was only present when simultaneously considering the effects of CC microstructural organization and remained significant while controlling for the effects of sex, BMI and medication dosage (but not age). Overall, the findings suggest that the association between physical neglect and poorer emotion recognition in schizophrenia occurs, at least in part, via its association with white matter microstructure.

Early life stress, low-grade systemic inflammation and weaker suppression of the default mode network (DMN) during face processing in Schizophrenia.

Childhood trauma (CT) is associated with lower cognitive and social cognitive function in schizophrenia. Recent evidence suggests that the relationship between CT and cognition is mediated by both low-grade systemic inflammation and reduced connectivity of the default mode network (DMN) during resting state. This study sought to test whether the same pattern of associations was observed for DMN connectivity during task based activity. Fifty-three individuals with schizophrenia (SZ) or schizoaffective disorder (SZA) and one hundred and seventy six healthy participants were recruited from the Immune Response and Social Cognition (iRELATE) project. A panel of pro-inflammatory markers that included IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNFa), and C-reactive protein (CRP), were measured in plasma using ELISA. DMN connectivity was measured during an fMRI social cognitive face processing task. Patients showed evidence of low grade systemic inflammation and significantly increased connectivity between the left lateral parietal (LLP) cortex-cerebellum and LLP-left angular gyrus compared to healthy participants. Across the entire sample, IL-6 predicted increased connectivity between LLP-cerebellum, LLP-precuneus, and mPFC-bilateral-precentral-gyri and left postcentral gyrus. In turn, and again in the entire sample, IL-6 (but no other inflammatory marker) mediated the relationship between childhood physical neglect and LLP-cerebellum. Physical neglect scores also significantly predicted the positive association between IL-6 and LLP-precuneus connectivity. This is to our knowledge the first study that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during task based activity. Consistent with our hypothesis, exposure to trauma is associated with weaker suppression of the DMN during a face processing task, and this association was mediated via increased inflammatory response. The findings may represent part of the biological mechanism by which CT and cognitive performance are related.

Whole blood transcriptome analysis in dairy calves experimentally challenged with bovine herpesvirus 1 (BoHV-1) and comparison to a bovine respiratory syncytial virus (BRSV) challenge.

Bovine herpesvirus 1 (BoHV-1), is associated with several clinical syndromes in cattle, among which bovine respiratory disease (BRD) is of particular significance. Despite the importance of the disease, there is a lack of information on the molecular response to infection via experimental challenge with BoHV-1. The objective of this study was to investigate the whole-blood transcriptome of dairy calves experimentally challenged with BoHV-1. A secondary objective was to compare the gene expression results between two separate BRD pathogens using data from a similar challenge study with BRSV. Holstein-Friesian calves (mean age (SD) = 149.2 (23.8) days; mean weight (SD) = 174.6 (21.3) kg) were either administered BoHV-1 inoculate (1 × 107/mL × 8.5 mL) (n = 12) or were mock challenged with sterile phosphate buffered saline (n = 6). Clinical signs were recorded daily from day (d) -1 to d 6 (post-challenge), and whole blood was collected in Tempus RNA tubes on d six post-challenge for RNA-sequencing. There were 488 differentially expressed (DE) genes (p < 0.05, False Discovery rate (FDR) < 0.10, fold change ≥2) between the two treatments. Enriched KEGG pathways (p < 0.05, FDR <0.05); included Influenza A, Cytokine-cytokine receptor interaction and NOD-like receptor signalling. Significant gene ontology terms (p < 0.05, FDR <0.05) included defence response to virus and inflammatory response. Genes that are highly DE in key pathways are potential therapeutic targets for the treatment of BoHV-1 infection. A comparison to data from a similar study with BRSV identified both similarities and differences in the immune response to differing BRD pathogens.

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Genes regulated by BCL11B during T-cell development are enriched for de novo mutations found in schizophrenia patients.

While abnormal neurodevelopment contributes to schizophrenia (SCZ) risk, there is also evidence to support a role for immune dysfunction in SCZ. BCL11B, associated with SCZ in genome-wide association study (GWAS), is a transcription factor that regulates the differentiation and development of cells in the central nervous and immune systems. Here, we use functional genomics data from studies of BCL11B to investigate the contribution of neuronal and immune processes to SCZ pathophysiology. We identified the gene targets of BCL11B in brain striatal cells (n = 223 genes), double negative 4 (DN4) developing T cells (n = 114 genes) and double positive (DP) developing T cells (n = 518 genes) using an integrated analysis of RNA-seq and ChIP-seq data. No gene-set was enriched for genes containing common variants associated with SCZ but the DP gene-set was enriched for genes containing missense de novo mutations (DNMs; p = .001) using data from 3,447 SCZ trios. Post hoc analysis revealed the enrichment to be stronger for DP genes negatively regulated by BCL11B. Biological processes enriched for genes negatively regulated by BCL11B in DP gene-set included immune system development and cytokine signaling. These analyses, leveraging a GWAS-identified SCZ risk gene and data on gene expression and transcription factor binding, indicate that DNMs in immune pathways contribute to SCZ risk.

Correction to: Diagnostic yield of a custom-designed multi-gene cancer panel in Irish patients with breast cancer.

The originally published version of this article contained typesetting errors in Figs. 2 and 3 legends. The correct figure legends are presented here. The original article has been corrected.

Diagnostic yield of a custom-designed multi-gene cancer panel in Irish patients with breast cancer.

BACKGROUND: Breast cancer is genetically heterogeneous, and parellel multi-gene sequencing is the most cost- and time-efficient manner to investigate breast cancer predisposition. Numerous multi-gene panels (MGPs) are commercially available, but many include genes with weak/unproven associaton with breast cancer, or with predisposition to cancer of other types. This study investigates the utility of a custom-designed multi-gene panel in an Irish cohort with breast cancer. METHODS: A custom panel comprising 83 genes offered by 19 clinical "breast cancer predisposition" MGPs was designed and applied to germline DNA from 91 patients with breast cancer and 77 unaffected ethnicially matched controls. Variants were identified and classified using a custom pipeline. RESULTS: Nineteen loss-of-function (LOF) and 334 missense variants were identified. After removing common and/or benign variants, 15 LOF and 30 missense variants were analysed. Variants in known breast cancer susceptibility genes were identified, including in BRCA1 and ATM in cases, and in NF1 and CHEK2 in controls. Most variants identified were in genes associated with predisposition to cancers other than breast cancer (BRIP1, RAD50, MUTYH, and mismatch repair genes), or in genes with unknown or unproven association with cancer. CONCLUSION: Using multi-gene panels enables rapid, cost-effective identification of individuals with high-risk cancer predisposition syndromes. However, this approach also leads to an increased amount of uncertain results. Clinical management of individuals with particular genetic variants in the absence of a matching phenotype/family history is challenging. Further population and functional evidence is required to fully elucidate the clinical relevance of variants in genes of uncertain significance.

Altered gene regulation as a candidate mechanism by which ciliopathy gene SDCCAG8 contributes to schizophrenia and cognitive function.

Mutations in genes that encode centrosomal/ciliary proteins cause severe cognitive deficits, while common single-nucleotide polymorphisms in these genes are associated with schizophrenia (SZ) and cognition in genome-wide association studies. The role of these genes in neuropsychiatric disorders is unknown. The ciliopathy gene SDCCAG8 is associated with SZ and educational attainment (EA). Genome editing of SDCCAG8 caused defects in primary ciliogenesis and cilium-dependent cell signalling. Transcriptomic analysis of SDCCAG8-deficient cells identified differentially expressed genes that are enriched in neurodevelopmental processes such as generation of neurons and synapse organization. These processes are enriched for genes associated with SZ, human intelligence (IQ) and EA. Phenotypic analysis of SDCCAG8-deficent neuronal cells revealed impaired migration and neuronal differentiation. These data implicate ciliary signalling in the aetiology of SZ and cognitive dysfunction. We found that centrosomal/ciliary genes are enriched for association with IQ, suggesting altered gene regulation as a general model for neurodevelopmental impacts of centrosomal/ciliary genes.

Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case-control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8(+) memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.

Neural effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk "A" allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified "A" risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk.

Functional assessment of a promoter polymorphism in S100B, a putative risk variant for bipolar disorder.

Calcium-binding protein S100B has been implicated in the pathology of bipolar affective disorder (BPAD) and schizophrenia (SZ). S100B protein levels are elevated in serum of patients with both disorders compared to controls. We previously reported genetic association of a SNP in the promoter of S100B, rs3788266, with a psychotic form of BPAD. To test for genotypic effects of rs3788266 in vivo, S100B serum protein levels were measured in 350 Irish and German subjects of known S100B genotype. The functional effect of rs3788266 on S100B promoter activity was studied using the luciferase reporter system in U373MG glioblastoma and SH-SY5Y neuroblastoma cell lines. Allelic effects of rs3788266 on protein complex formation at the S100B promoter were investigated by an electrophoretic mobility shift assay. Higher mean serum S100B levels were associated with the risk G allele of rs3788266 in BPAD cases (P = 0.0001), unaffected relatives of BPAD cases (P < 0.0001) and unrelated controls (P < 0.0001). Consistent with the in vivo findings, luciferase gene expression was significantly increased in the presence of the G allele compared to the A allele in SH-SY5Y (P = <0.0001), and in U373MG (P = <0.0008) cell lines. The binding affinity of both SH-SY5Y and U373MG protein complexes for the S100B promoter was significantly stronger in the presence of G allele compared to the A allele promoter fragments. These data support rs3788266 as a functional promoter variant in the S100B gene where the presence of the G allele promotes increased gene expression and is associated with increased serum levels of the protein.

Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.

Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.

Chitinase-3-like 1 (CHI3L1) gene and schizophrenia: genetic association and a potential functional mechanism.

BACKGROUND: Gene expression data and association analyses in two Chinese samples implicate chitinase 3-like 1 (CHI3L1), a cellular survival gene, in schizophrenia susceptibility. METHODS: We tested whether the association data are robust to replication in a Caucasian schizophrenia sample and performed a comprehensive investigation of common genetic variation at the locus. RESULTS: In a sample of 375 case and 812 control subjects we identified significant association with the same risk allele at the promoter single nucleotide polymorphism (SNP) associated in the original study (rs10399805; p = .018) and with another SNP at intron 7 of CHI3L1 (rs2275351; p = .008). The rs10399805 SNP is located at position -247 and disrupts the C/EBP-AML-1 binding site in the gene promoter; the risk allele is predicted to increase CHI3L1 expression, as has been reported in several postmortem schizophrenia studies. Carriers of the risk variant presented with fewer positive symptoms and relatively spared cognitive performance compared with other schizophrenia patients. CONCLUSIONS: These findings support a functional mechanism for involvement of CHI3L1 in schizophrenia susceptibility, possibly contributing to a less severe illness. The associated variants in this study are not well tagged by all Whole-Genome Association (WGA) platforms, suggesting additional genotyping may be necessary despite the imminent availability of WGA data from large SZ samples. Because CHI3L1 may be involved in transmission of stress-induced cellular responses, studies of interaction with known environmental risk factors may also be warranted.

Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma.

Cytogenetic analysis in myeloma reveals marked chromosomal instability. Both widespread genomic alterations and evidence of aberrant class switch recombination, the physiological process that regulates maturation of the antibody response, implicate the DNA repair pathway in disease pathogenesis. We therefore assessed 27 SNPs in three genes (XRCC3, XRCC4 and XRCC5) central to DNA repair in patients with myeloma and controls from the EpiLymph study and from an Irish hospital registry (n = 306 cases, 263 controls). For the haplotype-tagging SNP (htSNP) rs963248 in XRCC4, Allele A was significantly more frequent in cases than in controls (86.4 versus 80.8%; odds ratio 1.51; 95% confidence interval 1.10-2.08; P = 0.0133), as was the AA genotype (74 versus 65%) (P = 0.026). Haplotype analysis was performed using Unphased for rs963248 in combination with additional SNPs in XRCC4. The strongest evidence of association came from the A-T haplotype from rs963248-rs2891980 (P = 0.008). For XRCC5, the genotype GG from rs1051685 was detected in 10 cases from different national populations but in only one control (P = 0.015). This SNP is located in the 3'-UTR of XRCC5. Overall, these data provide support for the hypothesis that common variation in the genes encoding DNA repair proteins contributes to susceptibility to myeloma.

Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia.

There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 "Icelandic" schizophrenia risk haplotype and erbB4 (P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16-7.64), P = 0.01, although it only showed a trend in the Dublin sample alone (P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia.