Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

Rees, Elliott; Carrera, Noa; Morgan, Joanne; Hambridge, Kirsty; Escott‐Price, Valentina; Pocklington, Andrew; Richards, Alexander; Pardiñas, Antonio F.; McDonald, Colm; Donohoe, Gary; Morris, Derek W.; Kenny, Elaine; Kelleher, Eric; Gill, Michael; Corvin, Aiden; Kirov, George; Walters, James; Holmans, Peter Alan; O'Donovan, Michael Conlon; Alizadeh, Behrooz Z.; Amelsvoort, Thérèse van; Bartels-Velthuis, Agna A.; Beveren, Nico J. van; Bruggeman, Richard; Cahn, Wiepke; Haan, Lieuwe de; Delespaul, Philippe; Meijer, Carin J.; Myin‐Germeys, Inez; Kahn, René S.; Schirmbeck, Frederike; Simons, Claudia; Haren, Neeltje E. van; Os, Jim van; Winkel, Ruud van; Luykx, Jurjen J.

doi:10.1016/j.biopsych.2018.08.022

Cited by 41 publications

(33 citation statements)

References 38 publications

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“…An enrichment for genetic association in genes encoding voltage-gated calcium channel subunits has been reported in primary GWAS of schizophrenia, BD and MDD, on which this study was based (17,21,22). There has been consistent evidence supporting their involvement in these psychiatric disorders from common variant studies (34) and in schizophrenia from rare variants (19,50). The voltage-gated calcium channel family (consisting of L, T, P/Q, N and R subtypes)…”

Section: Partitioning Association By Developmental Expression Trajectorymentioning

confidence: 68%

“…It is notable that the VG-cation GO term examined here does not include subsets related to the activity of sodium channels. Voltage-gated sodium channels have been linked to schizophrenia and autism in sequencing studies (50,61,62) and are involved in the pharmacodynamics of several mood stabilizers used in the treatment of bipolar disorder, including valproic acid (63).…”

Section: Discussionmentioning

confidence: 99%

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Developmental profile of psychiatric risk associated with voltage-gated cation channel activity

Clifton

Torres

Burke

et al. 2020

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Recent 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. We 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. We observed relationships between the expression of genes involved in voltage-gated cation channel activity during 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. Our 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.

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Section: Partitioning Association By Developmental Expression Trajectorymentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Developmental profile of psychiatric risk associated with voltage-gated cation channel activity

Clifton

Torres

Burke

et al. 2020

Preprint

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“…Clearly more research is required to discern a role for tau protein phosphorylation in oscillatory systems processes, however, other potential mechanisms by which GSK-3β may influence neural oscillations should also be considered. For instance, GSK-3β regulates the activity of voltage-gated ion channels such as sodium [63,64], potassium [65,66] and calcium channels [67] and irregular expression and/or function of various channels have been linked to schizophrenia [68][69][70], AD [71][72][73][74], as well as with aberrant gamma oscillations [71,75,76]. Ligand-gated ion channels, critical to neuronal plasticity and long-term potentiation, and functionally relevant to cognitive disorders including AD [77,78] and schizophrenia [79,80], are also regulated by GSK-3β.…”

Section: Discussionmentioning

confidence: 99%

GSK-3β disrupts neural oscillatory function to inhibit learning and memory in rats

Albeely

Williams

Perreault³

2019

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Background. Alterations in glycogen synthase kinase-3β (GSK-3β) activity have been implicated in disorders of cognitive impairment including Alzheimer’s disease and schizophrenia. Another characteristic of cognitive impairment is the dysregulation of neural oscillatory activity, macroscopic electrical rhythms in brain critical to systems communication. A direct functional relationship between GSK-3β and neural oscillations has not been elucidated.Methods. In the present study, the impact of increasing GSK-3β activity in prefrontal cortex (PFC) or hippocampus (HIP) on the regulation of neural oscillations in rats was investigated using an adeno-associated viral vector containing a persistently active mutant of GSK-3β (S9A), and changes in learning and memory and tau phosphorylation assessed.Results. Increasing GSK-3β activity in either region had similar effects on oscillatory spectral power, enhancing theta and/or gamma oscillatory power recorded from one or both regions. Increasing PFC GSK-3β activity additionally suppressed high gamma PFC-HIP coherence. These oscillatory changes were accompanied by deficits in recognition memory, spatial learning and/or reversal learning. Increased pathogenic tau phosphorylation was also evident in regions where GSK-3β activity was elevated. Conclusions. These findings indicate that increased GSK-3β activity in PFC or HIP dysregulates neural oscillatory function in, and between, these regions. This suggests that GSK-3β may not only play an early role in cognitive decline in Alzheimer’s disease but may also play a more central role in disorders of cognitive dysfunction through the regulation of neurophysiological network function.

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“…Mutations in Nav1.2 (SCN2A) lead to a wide spectrum of epileptic disorders, ID and ASD (Wolff et al, 2017). An excess of rare variants in Nav genes has also recently been reported for SZ (Rees et al, 2019a). Mutations in Cav1.2 (CACNA1C) lead to Timothy syndrome (Splawski et al, 2004) and Brugada syndrome (Watanabe and Minamino, 2016); both CACNA1C and CACNA1I are located in single-gene GWS SZ loci (Pardiñas et al, 2018).…”

Section: Disruption Of Neurogenic Transcriptional Programs In Neurodementioning

confidence: 99%

DLG2 knockout reveals neurogenic transcriptional programs underlying neuropsychiatric disorders and cognition

Sanders

D’Andrea

Collins³

et al. 2020

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Genetic studies robustly implicate perturbation of DLG2-scaffolded mature postsynaptic signalling complexes in schizophrenia. Here we study in vitro cortical differentiation of DLG2 -/human embryonic stem cells via integrated phenotypic, gene expression and disease genetic analyses. This uncovers a developmental role for DLG2 in the regulation of neural stem cell proliferation and adhesion, and the activation of transcriptional programs during early excitatory corticoneurogenesis. Down-regulation of these programs in DLG2 -/lines delays expression of cell-type identity and causes marked deficits in neuronal migration, morphology and active properties. Genetic risk factors for neuropsychiatric and neurodevelopmental disorders converge on these neurogenic programs, each disorder displaying a distinct pattern of enrichment. These data unveil an intimate link between neurodevelopmental and mature signalling deficits contributing to disease -suggesting a dual role for known synaptic risk genes -and reveal a common pathophysiological framework for studying the neurodevelopmental origins of Mendelian and genetically complex mental disorders. Results Knockout generation and validationTwo DLG2 -/lines were created from H7 hESCs using the CRISPR/Cas9-D10A nickase system targeting the first PDZ domain ( Figure S1). Sequencing revealed no off-target mutations (see Methods, Figure S2 & Table S1). A significant decrease in DLG2 mRNA was observed for exons spanning the first PDZ domain, with a similar decrease inferred for PDZ-containing transcripts, indicating degradation of DLG2 -/transcripts via nonsense-mediated decay ( Figure S3A, B). Quantitative mass spectrometry-based proteomic analysis of peptide-affinity pulldowns using the NMDA receptor NR2 subunit PDZ peptide ligand (Husi and Grant, 2001) confirmed the presence of DLG2 in pulldowns from WT but not DLG2 -/lines ( Figure S3C-F & Table S2). Genotyping revealed no CNVs in either DLG2 -/line relative to WT ( Figure S4A). Both DLG2 -/lines expressed pluripotency markers OCT4, SOX2 and NANOG at 100% of WT levels ( Figure S4B-E). Cells were extensively characterised for their cortical identity using western blotting and immunocytochemistry from day 20 to 60 ( Figure S5). Over 90% of day 20 cells were positive for FOXG1, PAX6 and SOX2 confirming their dorsal forebrain fate ( Figure S5A-B). DLG2 regulates neural stem-cell proliferation and adhesionRNA was extracted in triplicate from each line at 4 timepoints spanning cortical excitatory neuron development (Figure 1A, B) and gene expression quantified. To robustly identify genes dysregulated by DLG2 knockout, expression data from the 2 DLG2 -/lines were pooled and compared to a WT sister line at each timepoint (see Methods). Disruption of DLG2 had a profound effect: of the >13,000 protein-coding genes expressed at each timepoint, ~7% were differentially expressed between DLG2 -/and WT at day 15, rising to 40-60% between days 20 and 30 then decreasing to ~25% by day 60 ( Figure 1C). Strikingly, the 3 genes with the strongest ...

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Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

Cited by 41 publications

References 38 publications

Developmental profile of psychiatric risk associated with voltage-gated cation channel activity

Developmental profile of psychiatric risk associated with voltage-gated cation channel activity

GSK-3β disrupts neural oscillatory function to inhibit learning and memory in rats

DLG2 knockout reveals neurogenic transcriptional programs underlying neuropsychiatric disorders and cognition

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