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

Clifton, Nicholas E., Collado-Torres, Leonardo, Burke, Emily E., Pardinas, Antonio F., Harwood, Janet C., Di Florio, Arianna, Walters, James T. R., Owen, Michael J., O'Donovan, Michael C., Weinberger, Daniel R., Holmans, Peter A., Jaffe, Andrew E. and Hall, Jeremy 2021. Developmental profile of psychiatric risk associated with voltage-gated cation channel activity. Biological Psychiatry 10.1016/j.biopsych.2021.03.009

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Abstract

Background 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. Methods 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 prenatal and postnatal timepoints, with 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, then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage. Results 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. Conclusions 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 timepoints and potential targets for disorder-specific therapeutic interventions.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information: Creative Commons Attribution (CC BY 4.0)
Publisher: Elsevier
ISSN: 0006-3223
Funders: Wellcome Trust; MRC
Date of First Compliant Deposit: 19 March 2021
Date of Acceptance: 4 March 2021
Last Modified: 19 Mar 2021 10:45
URI: http://orca.cardiff.ac.uk/id/eprint/139894

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