RT Journal Article
SR Electronic
T1 Genetic association of FMRP targets with psychiatric disorders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.21.952226
DO 10.1101/2020.02.21.952226
A1 Nicholas E Clifton
A1 Elliott Rees
A1 Peter A Holmans
A1 Antonio F. Pardiñas
A1 Janet C Harwood
A1 Arianna Di Florio
A1 George Kirov
A1 James TR Walters
A1 Michael C O’Donovan
A1 Michael J Owen
A1 Jeremy Hall
A1 Andrew J Pocklington
YR 2020
UL http://biorxiv.org/content/early/2020/02/25/2020.02.21.952226.abstract
AB 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.FMRPFragile X mental retardation proteinmRNAMessenger ribonucleic acidMAGMAMulti-marker Analysis of GenoMic AnnotationGWASGenome-wide association studyDNADeoxyribonucleic acidCNVCopy number variantGOGene ontologyMGIMouse genome informaticsMPMammalian phenotypeCYFIP1Cytoplasmic FMR1 interacting protein 1PGCPsychiatric genomics consortium