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Genetic association of FMRP targets with psychiatric disorders

Clifton, Nicholas, Rees, Elliott, Holmans, Peter, Pardiñas, Antonio, Harwood, Janet, Di Florio, Arianna, Kirov, George, Walters, James, O’Donovan, Michael, Owen, Michael, Hall, Jeremy and Pocklington, Andrew 2020. Genetic association of FMRP targets with psychiatric disorders. Molecular Psychiatry 10.1038/s41380-020-00912-2

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Abstract

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.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Springer Nature
ISSN: 1359-4184
Funders: Wellcome Trust
Date of First Compliant Deposit: 14 October 2020
Date of Acceptance: 28 September 2020
Last Modified: 05 Nov 2020 14:41
URI: http://orca-mwe.cf.ac.uk/id/eprint/135545

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