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Genetic association of FMRP targets with psychiatric disorders

By Nicholas E Clifton, Elliott Rees, Peter Holmans, Antonio F. PardiƱas, Janet C. Harwood, Arianna Di Florio, Kirov George, James TR Walters, Michael C O'Donovan, Michael J Owen, Jeremy Hall, Andrew J. Pocklington

Posted 24 Feb 2020
bioRxiv DOI: 10.1101/2020.02.21.952226 (published DOI: 10.1038/s41380-020-00912-2)

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. 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 and de novo nonsynonymous 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. * FMRP : Fragile X mental retardation protein mRNA : Messenger ribonucleic acid MAGMA : Multi-marker Analysis of GenoMic Annotation GWAS : Genome-wide association study DNA : Deoxyribonucleic acid CNV : Copy number variant GO : Gene ontology MGI : Mouse genome informatics MP : Mammalian phenotype CYFIP1 : Cytoplasmic FMR1 interacting protein 1 PGC : Psychiatric genomics consortium

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