Publications by year
In Press
Clifton NE, Collado-Torres L, Burke EE, Pardiñas AF, Harwood JC, Di Florio A, Walters JTR, Owen MJ, O’Donovan MC, Weinberger DR, et al (In Press). Developmental profile of psychiatric risk associated with voltage-gated cation channel activity.
Abstract:
Developmental profile of psychiatric risk associated with voltage-gated cation channel activity
AbstractBackgroundRecent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant.MethodsWe aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used post-mortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple pre- and post-natal timepoints and summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder and major depressive disorder. We prioritised gene sets for overall enrichment of association with each disorder, and then tested the relationship between the association of each of their constituent genes with their relative expression at each developmental stage.ResultsWe observed relationships between the expression of genes involved involtage-gated cation channel activityduring Early Midfetal, Adolescence and Early Adulthood timepoints and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during Early Midfetal development and higher expression during Adolescence and Early Adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, whilst for bipolar disorder the relationship was distributed between calcium and potassium channel activity genes.ConclusionsOur results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk to psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.
Abstract.
Clifton NE, Rees E, Holmans PA, Pardiñas AF, Harwood JC, Di Florio A, Kirov G, Walters JTR, O’Donovan MC, Owen MJ, et al (In Press). Genetic association of FMRP targets with psychiatric disorders.
Abstract:
Genetic association of FMRP targets with psychiatric disorders
AbstractGenes encoding the mRNA targets of Fragile X mental retardation protein (FMRP) are enriched for genetic association with psychiatric disorders. However, many FMRP targets possess functions that are themselves genetically associated with psychiatric disorders, including synaptic transmission and plasticity, making it unclear whether the genetic risk is truly related to binding by FMRP or is alternatively mediated by the sampling of genes better characterised by another trait or functional annotation. Using published common variant, rare coding variant and copy number variant data, we examined the relationship between FMRP binding and genetic association with schizophrenia, major depressive disorder and bipolar disorder. We then explored the partitioning of genetic association between overrepresented functional categories. High-confidence targets of FMRP were enriched for common schizophrenia risk alleles, as well as rare loss-of-function andde novononsynonymous variants in cases. Similarly, through common variation, FMRP targets were associated with major depressive disorder, and we present novel evidence of association with bipolar disorder. These relationships could not be explained by membership of other functional annotations known to be associated with psychiatric disorders, including those related to synaptic structure and function. This study reinforces the evidence that targeting by FMRP captures a subpopulation of genes enriched for genetic association with a range of psychiatric disorders, across traditional diagnostic boundaries.
Abstract.
Clifton N, Schulmann A, Holmans P, O'Donovan M, Vawter M (In Press). The relationship between case-control differential gene expression from brain tissue and genetic associations in schizophrenia.
American Journal of Medical Genetics Part B: Neuropsychiatric GeneticsAbstract:
The relationship between case-control differential gene expression from brain tissue and genetic associations in schizophrenia
Large numbers of genetic loci have been identified that are known to contain common risk alleles for schizophrenia, but linking associated alleles to specific risk genes remains challenging. Given that most alleles that influence liability to schizophrenia are thought to do so by altered gene expression, intuitively, case-control differential gene expression studies should highlight genes with a higher probability of being associated with schizophrenia and could help identify the most likely causal genes within associated loci. Here, we test this hypothesis by comparing transcriptome analysis of the dorsolateral prefrontal cortex from 563 schizophrenia cases and 802 controls with genome-wide association study (GWAS) data from the third wave study of the Psychiatric Genomics Consortium. Genes differentially expressed in schizophrenia were not enriched for common allelic association statistics compared with other brain-expressed genes, nor were they enriched for genes within associated loci previously reported to be prioritized by genetic fine-mapping. Genes prioritized by Summary-based Mendelian Randomisation were underexpressed in cases compared to other genes in the same GWAS loci. However, the overall strength and direction of expression change predicted by SMR were not related to that observed in the differential expression data. Overall, this study does not support the hypothesis that genes identified as differentially expressed from RNA sequencing of bulk brain tissue are enriched for those that show evidence for genetic associations. Such data have limited utility for prioritizing genes in currently associated loci in schizophrenia.
Abstract.
2022
Sperandeo A, Tamburini C, Noakes Z, de la Fuente DC, Keefe F, Petter O, Plumbly W, Clifton NE, Li M, Peall KJ, et al (2022). Cortical neuronal hyperexcitability and synaptic changes in <i>SGCE</i> mutation-positive myoclonus dystonia.
Brain,
146(4), 1523-1541.
Abstract:
Cortical neuronal hyperexcitability and synaptic changes in SGCE mutation-positive myoclonus dystonia
Abstract
. Myoclonus dystonia is a childhood-onset hyperkinetic movement disorder with a combined motor and psychiatric phenotype. It represents one of the few autosomal dominant inherited dystonic disorders and is caused by mutations in the ε-sarcoglycan (SGCE) gene. Work to date suggests that dystonia is caused by disruption of neuronal networks, principally basal ganglia-cerebello-thalamo-cortical circuits. Investigation of cortical involvement has primarily focused on disruption to interneuron inhibitory activity, rather than the excitatory activity of cortical pyramidal neurons. Here, we have sought to examine excitatory cortical glutamatergic activity using two approaches: the CRISPR/Cas9 editing of a human embryonic cell line, generating an SGCE compound heterozygous mutation, and three patient-derived induced pluripotent stem cell lines, each gene edited to generate matched wild-type SGCE control lines. Differentiation towards a cortical neuronal phenotype demonstrated no significant differences in either early- (PAX6, FOXG1) or late-stage (CTIP2, TBR1) neurodevelopmental markers. However, functional characterization using Ca2+ imaging and microelectrode array approaches identified an increase in network activity, while single-cell patch clamp studies found a greater propensity towards action potential generation with larger amplitudes and shorter half-widths associated with SGCE mutations. Bulk RNA sequencing analysis identified gene ontological enrichment for ‘neuron projection development’, ‘synaptic signalling’ and ‘synaptic transmission’. Examination of dendritic morphology found SGCE mutations to be associated with a significantly higher number of branches and longer branch lengths, together with longer ion-channel dense axon initial segments, particularly towards the latter stages of differentiation (Days 80 and 100). Gene expression and protein quantification of key synaptic proteins (synaptophysin, synapsin and PSD95), AMPA and NMDA receptor subunits found no significant differences between the SGCE mutation and matched wild-type lines. By contrast, significant changes to synaptic adhesion molecule expression were identified, namely higher presynaptic neurexin-1 and lower postsynaptic neuroligin-4 levels in the SGCE mutation carrying lines. Our study demonstrates an increased intrinsic excitability of cortical glutamatergic neuronal cells in the context of SGCE mutations, coupled with a more complex neurite morphology and disruption to synaptic adhesion molecules. These changes potentially represent key components to the development of the hyperkinetic clinical phenotype observed in myoclonus dystonia, as well a central feature to the wider spectrum of dystonic disorders, potentially providing targets for future therapeutic development.
Abstract.
Clifton NE, Bosworth ML, Haan N, Rees E, Holmans PA, Wilkinson LS, Isles AR, Collins MO, Hall J (2022). Developmental disruption to the cortical transcriptome and synaptosome in a model of <i>SETD1A</i> loss-of-function.
Human Molecular Genetics,
31(18), 3095-3106.
Abstract:
Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function
Abstract
. Large-scale genomic studies of schizophrenia implicate genes involved in the epigenetic regulation of transcription by histone methylation and genes encoding components of the synapse. However, the interactions between these pathways in conferring risk to psychiatric illness are unknown. Loss-of-function (LoF) mutations in the gene encoding histone methyltransferase, SETD1A, confer substantial risk to schizophrenia. Among several roles, SETD1A is thought to be involved in the development and function of neuronal circuits. Here, we employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins. Using large-scale patient genomics data, we observed no enrichment for genetic association with schizophrenia within differentially expressed transcripts or proteins, suggesting they derive from a distinct mechanism of risk from that implicated by genomic studies. This study highlights biological pathways through which SETD1A LOF may confer risk to schizophrenia. Further work is required to determine whether the effects observed in this model reflect human pathology.
Abstract.
Moon AL, Clifton NE, Wellard N, Thomas KL, Hall J, Brydges NM (2022). Social interaction following prepubertal stress alters prefrontal gene expression associated with cell signalling and oligodendrocytes.
Translational Psychiatry,
12(1).
Abstract:
Social interaction following prepubertal stress alters prefrontal gene expression associated with cell signalling and oligodendrocytes
AbstractEarly-life adversity is associated with an increased risk of psychopathology, including mood disorders, later in life. Early-life stress affects several physiological systems, however, the exact mechanisms underlying pathological risk are not fully understood. This knowledge is crucial in developing appropriate therapeutic interventions. The prepubertal period is documented as a key developmental period for the maturation of the prefrontal cortex (PFC), a brain region involved in higher cognitive functions, including social function. In this study, we performed RNA sequencing on the PFC of adult rats who had experienced prepubertal stress (PPS) and controls to investigate the genome-wide consequences of this stress. PPS alters social behaviour in adulthood, therefore we also performed RNA sequencing on PPS and control rats following a social interaction test to determine social activity-dependent gene changes. At a baseline state (1 week following a social interaction test), no genes were differentially expressed in the PPS group. However, 1603 genes were differentially expressed in PPS rats compared to controls following a social interaction. These genes were enriched in biological pathways associated with cell signalling and axon myelination dynamics. Cell enrichment analysis showed these genes were associated with oligodendrocytes, and a comparison with an existing early-life stress sequencing dataset showed that pathways linked to oligodendrocyte morphology are impacted in a range of models of early-life stress in rodents. In conclusion, we identify pathways, including those involved in axon myelination, that are differentially activated in the adult in response to social stimulation following PPS. These differential responses may contribute to vulnerability to psychiatric pathology.
Abstract.
2021
Clifton NE, Collado-Torres L, Burke EE, Pardinas AF, Harwood JC, Di Florio A, Walters JTR, Owen MJ, O'Donovan MC, Weinberger DR, et al (2021). Developmental Profile of Psychiatric Risk Associated with Voltage-Gated Cation Channel Activity.
BIOLOGICAL PSYCHIATRY,
90(6), 399-408.
Author URL.
Clifton NE, Rees E, Holmans PA, Pardiñas AF, Harwood JC, Di Florio A, Kirov G, Walters JTR, O’Donovan MC, Owen MJ, et al (2021). Genetic association of FMRP targets with psychiatric disorders.
Molecular Psychiatry,
26(7), 2977-2990.
Abstract:
Genetic association of FMRP targets with psychiatric disorders
Genes encoding the mRNA targets of fragile X mental retardation protein (FMRP) are enriched for genetic association with psychiatric disorders. However, many FMRP targets possess functions that are themselves genetically associated with psychiatric disorders, including synaptic transmission and plasticity, making it unclear whether the genetic risk is truly related to binding by FMRP or is alternatively mediated by the sampling of genes better characterised by another trait or functional annotation. Using published common variant, rare coding variant and copy number variant data, we examined the relationship between FMRP binding and genetic association with schizophrenia, major depressive disorder and bipolar disorder. High-confidence targets of FMRP, derived from studies of multiple tissue types, were enriched for common schizophrenia risk alleles, as well as rare loss-of-function and de novo nonsynonymous variants in schizophrenia cases. Similarly, through common variation, FMRP targets were associated with major depressive disorder, and we present novel evidence of association with bipolar disorder. These relationships could not be explained by other functional annotations known to be associated with psychiatric disorders, including those related to synaptic structure and function. This study reinforces the evidence that targeting by FMRP captures a subpopulation of genes enriched for genetic association with a range of psychiatric disorders.
Abstract.
Notter T, Schalbetter SM, Clifton NE, Mattei D, Richetto J, Thomas K, Meyer U, Hall J (2021). Neuronal activity increases translocator protein (TSPO) levels.
MOLECULAR PSYCHIATRY,
26(6), 2025-2037.
Author URL.
2020
Clifton NE, Thomas KL, Wilkinson LS, Hall J, Trent S (2020). FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability. Complex Psychiatry, 6(1-2), 5-19.
2019
Morgan SE, Seidlitz J, Whitaker KJ, Romero-Garcia R, Clifton NE, Scarpazza C, van Amelsvoort T, Marcelis M, van Os J, Donohoe G, et al (2019). Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia-related genes.
Proc Natl Acad Sci U S A,
116(19), 9604-9609.
Abstract:
Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia-related genes.
Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case-control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case-control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia.
Abstract.
Author URL.
Clifton NE, Hannon E, Harwood JC, Di Florio A, Thomas KL, Holmans PA, Walters JTR, O’Donovan MC, Owen MJ, Pocklington AJ, et al (2019). Dynamic expression of genes associated with schizophrenia and bipolar disorder across development.
Translational Psychiatry,
9(1).
Abstract:
Dynamic expression of genes associated with schizophrenia and bipolar disorder across development
Common genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between the two disorders. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome-wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genetic association with schizophrenia is positively correlated with expression in the prefrontal cortex during early midfetal development and early infancy, and negatively correlated with expression during late childhood, which stabilises in adolescence. In contrast, risk-associated genes for bipolar disorder did not exhibit a bias towards expression at any prenatal stage, although the pattern of postnatal expression was similar to that of schizophrenia. These results highlight the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the hypothesis that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.
Abstract.
Clifton NE, Trent S, Thomas KL, Hall J (2019). Regulation and Function of Activity-Dependent Homer in Synaptic Plasticity.
Complex Psychiatry,
5(3), 147-161.
Abstract:
Regulation and Function of Activity-Dependent Homer in Synaptic Plasticity
Alterations in synaptic signaling and plasticity occur during the refinement of neural circuits over the course of development and the adult processes of learning and memory. Synaptic plasticity requires the rearrangement of protein complexes in the postsynaptic density (PSD), trafficking of receptors and ion channels and the synthesis of new proteins. Activity-induced short Homer proteins, Homer1a and Ania-3, are recruited to active excitatory synapses, where they act as dominant negative regulators of constitutively expressed, longer Homer isoforms. The expression of Homer1a and Ania-3 initiates critical processes of PSD remodeling, the modulation of glutamate receptor-mediated functions, and the regulation of calcium signaling. Together, available data support the view that Homer1a and Ania-3 are responsible for the selective, transient destabilization of postsynaptic signaling complexes to facilitate plasticity of the excitatory synapse. The interruption of activity-dependent Homer proteins disrupts disease-relevant processes and leads to memory impairments, reflecting their likely contribution to neurological disorders.
Abstract.
2018
Morgan SE, Seidlitz J, Whitaker K, Romero-Garcia R, Clifton NE, Scarpazza C, van Amelsvoort T, Marcelis M, van Os J, Donohoe G, et al (2018). Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia related genes.
Clifton NE, Hannon E, Di Florio A, Thomas KL, Holmans PA, Walters JT, O’Donovan MC, Owen MJ, Pocklington AJ, Hall J, et al (2018). Dynamic expression of risk genes for schizophrenia and bipolar disorder across development.
Sykes L, Clifton NE, Hall J, Thomas KL (2018). Regulation of the Expression of the Psychiatric Risk Gene <b><i>Cacna1c</i></b> during Associative Learning.
Complex Psychiatry,
4(3), 149-157.
Abstract:
Regulation of the Expression of the Psychiatric Risk Gene <b><i>Cacna1c</i></b> during Associative Learning
<i>CACNA1C</i>encodes the Ca<sub>v</sub>1.2 L-type voltage-gated calcium channel. Generic variation in CACNA1C has been consistently identified as associated with risk for psychiatric disorders including schizophrenia, bipolar disorder, major depressive disorder and autism. Psychiatric risk loci are also enriched for genes involved in the regulation of synaptic plasticity. Here, we show that the expression of <i>Cacna1c</i> is regulated in the rat hippocampus after context exposure, contextual fear conditioning and fear memory retrieval in a manner that correlates to specific memory processes. Using quantitative in situ hybridisation, the expression was down-regulated in CA1 by brief exposure to a novel context and to a conditioned context, and up-regulated in the dentate gyrus after contextual fear conditioning. No changes were measured after prolonged context exposure followed by conditioning, a procedure that retards fear conditioning (latent inhibition), nor with fear memory recall leading to extinction. These results are consistent with a selective role for Ca<sub>v</sub>1.2 in the consolidation of context memory and contextual fear memory, and with processes associated with the maintenance of the fear memory after recall. The dysregulation of <i>CACNA1C</i> may thus be related to associative memory dysfunction in schizophrenia and other psychiatric disorders.
Abstract.
Clifton NE, Thomas KL, Hall J (2018). The effect of ketamine on the consolidation and extinction of contextual fear memory.
JOURNAL OF PSYCHOPHARMACOLOGY,
32(2), 156-162.
Author URL.
2017
Clifton NE, Cameron D, Trent S, Sykes LH, Thomas KL, Hall J (2017). Hippocampal Regulation of Postsynaptic Density Homer1 by Associative Learning.
NEURAL PLASTICITY,
2017 Author URL.
Clifton NE, Pocklington AJ, Scholz B, Rees E, Walters JTR, Kirov G, O'Donovan MC, Owen MJ, Wilkinson LS, Thomas KL, et al (2017). Schizophrenia copy number variants and associative learning.
Molecular Psychiatry,
22(2), 178-182.
Abstract:
Schizophrenia copy number variants and associative learning
Large-scale genomic studies have made major progress in identifying genetic risk variants for schizophrenia. A key finding from these studies is that there is an increased burden of genomic copy number variants (CNVs) in schizophrenia cases compared with controls. The mechanism through which these CNVs confer risk for the symptoms of schizophrenia, however, remains unclear. One possibility is that schizophrenia risk CNVs impact basic associative learning processes, abnormalities of which have long been associated with the disorder. To investigate whether genes in schizophrenia CNVs impact on specific phases of associative learning we combined human genetics with experimental gene expression studies in animals. In a sample of 11 917 schizophrenia cases and 16 416 controls, we investigated whether CNVs from patients with schizophrenia are enriched for genes expressed during the consolidation, retrieval or extinction of associative memories. We show that CNVs from cases are enriched for genes expressed during fear extinction in the hippocampus, but not genes expressed following consolidation or retrieval. These results suggest that CNVs act to impair inhibitory learning in schizophrenia, potentially contributing to the development of core symptoms of the disorder.
Abstract.
2013
Clifton NE, Morisot N, Girardon S, Millan MJ, Loiseau F (2013). Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine.
PSYCHOPHARMACOLOGY,
225(3), 579-594.
Author URL.