Showing papers by "Murray J. Cairns published in 2018"

Analysis of shared heritability in common disorders of the brain

Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

The genetic architecture of the human cerebral cortex

Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the specific genetic loci influencing human cortical structure. To identify genetic variants impacting cortical structure, we conducted a genome-wide association meta-analysis of brain MRI data from 35,660 individuals with replication in 15,578 individuals. We analysed the surface area and average thickness of the whole cortex and 34 regions with known functional specialisations. We identified 206 nominally significant loci (P ≤ 5 x 10 -8 ); 150 survived multiple testing correction (P ≤ 8.3 x 10 -10 ; 140 surface area; 10 thickness). We found significant enrichment for loci influencing total surface area within regulatory elements active during prenatal cortical development, supporting the radial unit hypothesis. Loci impacting regional surface area cluster near genes in Wnt signalling pathways, known to influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson9s disease, insomnia, depression and ADHD. NOTE: K.L.G. and N.J. contributed to this work as co-first authors for this preprint. J.N.P., L.C.-C., J.B., D.P.H., P.A.L., F.P. contributed to this work as co-second authors for this preprint. J.L.S., P.M.T., S.E.M. contributed to this work as co-last authors for this preprint.

Temporally specific miRNA expression patterns in the dorsal and ventral striatum of addiction-prone rats

Abstract: MicroRNAs (miRNAs) within the ventral and dorsal striatum have been shown to regulate addiction-relevant behaviours. However, it is unclear how cocaine experience alone can alter the expression of addiction-relevant miRNAs within striatal subregions. Further, it is not known whether differential expression of miRNAs in the striatum contributes to individual differences in addiction vulnerability. We first examined the effect of cocaine self-administration on the expression of miR-101b, miR-137, miR-212 and miR-132 in nucleus accumbens core and nucleus accumbens shell (NAcSh), as well as dorsomedial striatum and dorsolateral striatum (DLS). We then examined the expression of these same miRNAs in striatal subregions of animals identified as being ‘addiction-prone’, either immediately following self-administration training or following extinction and relapse testing. Cocaine self-administration was associated with changes in miRNA expression in a regionally discrete manner within the striatum, with the most marked changes occurring in the nucleus accumbens core. When we examined the miRNA profile of addiction-prone rats following self-administration, we observed increased levels of miR-212 in the dorsomedial striatum. After extinction and relapse testing, addiction-prone rats showed significant increases in the expression of miR-101b, miR-137, miR-212 and miR-132 in NAcSh, and miR-137 in the DLS. This study identifies temporally specific changes in miRNA expression consistent with the engagement of distinct striatal subregions across the course of the addiction cycle. Increased dysregulation of miRNA expression in NAcSh and DLS at late stages of the addiction cycle may underlie habitual drug seeking, and may therefore aid in the identification of targets designed to treat addiction.

Differential effect of disease-associated ST8SIA2 haplotype on cerebral white matter diffusion properties in schizophrenia and healthy controls

Abstract: 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.

miR-518f-5p decreases tetraspanin CD9 protein levels and differentially affects non-tumourigenic prostate and prostate cancer cell migration and adhesion.

Abstract: // Danielle R. Bond 1, 4 , Crystal Naudin 1, 3 , Adam P. Carroll 1, 5 , Belinda J. Goldie 1, 2 , Joshua S. Brzozowski 1 , Helen M. Jankowski 1 , Murray J. Cairns 1, 5 , Leonie K. Ashman 1 , Christopher J. Scarlett 4 and Judith Weidenhofer 1 1 School of Biomedical Science and Pharmacy, The University of Newcastle and Hunter Medical Research Institute (HMRI), NSW, Newcastle, Australia 2 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia 3 Department of Pediatrics, Emory University, Atlanta, GA, USA 4 School of Environmental and Life Sciences, The University of Newcastle and Hunter Medical Research Institute (HMRI), NSW, Newcastle, Australia 5 Schizophrenia Research Institute, Sydney, NSW, Australia Correspondence to: Judith Weidenhofer, email: judith.weidenhofer@newcastle.edu.au Keywords: miR-518f-5p; prostate cancer; CD9; transcript regulation; metastasis Received: May 26, 2017 Accepted: November 15, 2017 Published: December 07, 2017 ABSTRACT Tetraspanin CD9 is generally considered to be a metastasis suppressor, with decreased levels associated with progression and metastasis in many advanced stage cancers. Little is known about the cause of CD9 dysregulation in prostate cancer, however there are several miRNA-binding sites in the 3´UTR of the transcript suggesting it could be post-transcriptionally regulated. Using microarrays and luciferase assays in tumourigenic and non-tumourigenic prostate cell lines we identified miR-518f-5p as a regulator of the CD9 3'UTR gene expression, and decreased expression of endogenous CD9 in non-tumorigenic prostate RWPE1 and prostate cancer DU145 cells. This resulted in differential functional effects, in which RWPE1 cells showed increased migration and decreased adhesion to extracellular matrix substrates, whereas DU145 cells showed decreased migration and increased adhesion. Moreover, overexpression of miR-518f-5p significantly increased proliferation between 48h and 72h in normal RWPE1 cells, with no effect on tumourigenic DU145 cell proliferation. These results show that tetraspanin CD9 is regulated by miRNAs in prostate cell lines and that due to differential functional effects in non-tumourigenic versus tumourigenic prostate cells, miR-518f-5p may be an effective biomarker and/or therapeutic target for prostate cancer progression.

The Medical Genome Reference Bank: Whole genomes and phenotype of 2,570 healthy elderly

Abstract: Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2,570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analysed the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. Individuals in the MGRB had fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK BioBank cohorts, consistent with risk depletion. Pervasive age-related somatic changes were correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing. This research has been conducted using the UK Biobank Resource under Application Number 17984.

S194. investigating peripheral microrna-mrna interactions in schizophrenia

Abstract: BackgroundSchizophrenia is a severe neuropsychiatric disorder, characterised by positive and negative symptoms, and cognitive deficits. High throughput technologies such as microarrays, and more recently next-generation sequencing have identified numerous genetic variants and transcriptional signatures associated with schizophrenia. Over the last decade, microRNAs (miRNAs) have been found differentially expressed in both peripheral and post-mortem grey matter tissue in schizophrenia, and three genome-wide significant schizophrenia-associated variants occur within two miRNA loci – MIR137 and MIR548AJ2. These small, non-coding RNAs are potent regulators of translation, can target a wide variety of transcripts, and are therefore of particular interest in polygenic disorders such as schizophrenia.MethodsWe obtained total RNA isolated from peripheral blood mononuclear cell (PBMC) samples from the Australian Schizophrenia Research Bank (ASRB). The samples included 36 individuals with schizophrenia and 15 healthy controls. We utilised small RNA and mRNA sequencing technology to examine both the miRNA and mRNA expression profiles of these sample. Raw reads were aligned to the human genome (hg38), annotated, counted and analysed for differential expression using an open source software pipeline. Correlations between miRNA and mRNA expression were found and matched to predicted TargetScan miRNA-mRNA interactions using the miRComb R package. Ingenuity Pathway Analysis and Gene Set Enrichment Analysis were performed to identify pathways and gene ontologies enriched for differentially expressed genes.Results35 miRNAs and 97 genes were differentially expressed (FDR<0.1); most miRNAs (21 out of 35) were downregulated, while the vast majority of mRNAs (80 out of 97) were upregulated. When males and females were analysed separately, we found 14 miRNAs and 365 genes differentially expressed in males, while females only showed 7 miRNAs and 1 gene (NRCAM – neuronal cell adhesion molecule) differentially expressed. Several miRNAs in males were found to significantly correlate with differentially expressed genes, including miR-1271-5p with schizophrenia candidate gene DGCR2. Furthermore, many differentially expressed genes and miRNAs have previously been linked to schizophrenia and neuronal function. Among males, several immune- and inflammation pathways were enriched for differentially expressed genes. Interestingly, while upregulated genes were enriched for immune-related gene ontologies, downregulated genes were enriched for gene ontologies relating to development.DiscussionThese results contribute to a growing body of evidence that suggest peripheral miRNA and mRNA expression is altered in schizophrenia. We identify a general downregulation of miRNAs and upregulation of mRNAs in peripheral tissue in schizophrenia. Several significant correlations between miRNAs and mRNAs previously linked to schizophrenia and brain function suggest potential miRNA-mRNA interactions that may be significant for disease pathophysiology.

S188. dysregulation of circular rna expression in schizophrenia observed in postmortem dorsolateral prefrontal cortex.

Abstract: Abstract Background The last few years has witnessed the emergence of a novel class of long non-coding RNA known as circular RNA (circRNA). These molecules are characterised by their circularity formed through the back splicing of 3’ and 5’ ends of transcript segments produced by one or more of its exons. CircRNAs function as transcriptional modulators, microRNA regulators, as well as template for translation. In our current study, we profiled circRNA expression in post-mortem brain samples from Schizophrenia (SZ) and control subjects using next-generation sequencing technology to discover the association of these novel RNA molecules with the pathogenesis of SZ. Methods Total RNA from cerebral cortex (BA46) of 17 SZ patients and 18 healthy controls were subjected to ribosomal RNA depletion and then RNase R treatment to further deplete linear RNA and enrich for exonuclease resistant circRNA transcripts. Sequencing libraries were constructed using Illumina TruSeq RNA Library Prep Kit (LT) (150 cycles) and sequenced by an Illumina NexSeq500. Sequencing data was analysed by the CIRCexplorer2 pipeline to identify circRNA transcripts. To validate the sequencing findings, real-time PCR was performed using outward primers sets designed to specifically amplify circular transcripts. Results We discovered a large number of distinct circRNAs (95,212), many of which were highly expressed throughout the cohort. Surprisingly, a large proportion (52%) of the identified circRNAs sequences were novel or not previously reported. Differential expression analysis suggested that there was substantial alteration in circRNA expression in SZ. More than two thirds of these molecules displayed decreased expression, whereas the remainder were upregulated. Functional annotation of the host genes was significantly enrichment for terms-related to neurobiology and neurocognitive impairment including clusters such as neurogenesis, differentiation and synapse. Many of these circRNAs were also predicted to interact with miRNAs, supporting a potential miRNA sponging function for these circRNA. Discussion RNA sequencing in the human postmortem DLPFC revealed dysregulation of circRNA expression in schizophrenia. This alteration was characterized by a substantial decrease in circRNA expression in the disorder. Bioinformatic predictions of circRNA interaction suggest they function as miRNA regulators and may have a broader role in etiology or pathophysiology of the disorder.