Genetic association of FMRP targets with psychiatric disorders

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.

FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

“…Gene ontology analyses of brain-derived FMRP targets confirm an overrepresentation of genes involved in functions related to synaptic activity, plasticity, development, and anatomy [19, 52, 58], consistent with studies of FMRP function. The proteins they encode include both presynaptic and postsynaptic components.…”

“…A set of FMRP target mRNAs derived from a study of mouse cortical polyribosomes [19] have been recurrently highlighted in the literature due to their enrichment for genes associated with an array of psychiatric disorders. Through large-scale genome-wide association studies, these 842 FMRP targets have been shown to be genetically associated with schizophrenia [161, 162], autism [166], major depressive disorder [167], and bipolar disorder [58]. In addition to the risk conferred from common variation, this gene set is enriched for rare variants from patients with schizophrenia [168-171], autism [172], and bipolar disorder [173]; de novo variants from patients with schizophrenia [174] and autism [175-177]; and to a lesser extent copy number variants from patients with schizophrenia [178-180].…”

“…Brain FMRP targets overlap considerably with other gene sets associated with psychiatric disorders, such as genes encoding PSD proteins and those involved in calcium signalling, synaptic plasticity, learning, and memory [19, 52, 58, 181]. However, despite these overlaps, the enrichment of brain FMRP targets for association with psychiatric disorders is independent [58, 162, 168] and proportional to the confidence of binding by FMRP [58]. Moreover, in many instances, it appears that FMRP targets capture subsets of these other gene sets in which genetic association is concentrated [58].…”

“…However, despite these overlaps, the enrichment of brain FMRP targets for association with psychiatric disorders is independent [58, 162, 168] and proportional to the confidence of binding by FMRP [58]. Moreover, in many instances, it appears that FMRP targets capture subsets of these other gene sets in which genetic association is concentrated [58]. Hence, this set of genes locally regulated by FMRP during plasticity and development at the synapse may represent a collection of biological pathways important for the manifestation of a range of psychiatric disorders.…”

A Neurodevelopment Approach for a Transitional Model of Early Onset Schizophrenia

“…A more recent meta-analytic GWAS of common variants in schizophrenia included an additional 5220 schizophrenia cases and 18,823 controls and identified 145 independent loci significantly associated with schizophrenia [ 7 ]. Schizophrenia-associated SNPs were enriched for genes that are intolerant to mutation, genes involved in synaptic transmission, and genes that are targets of the fragile X mental retardation protein (FMRP), which is known to regulate the protein-level expression of genes involved in brain development and synaptic plasticity [ 8 ]. Together, these seminal studies provided compelling evidence that common risk variants for schizophrenia converge onto neuronal and synaptic gene-sets.…”