Enrichment of the local synaptic translatome for genetic risk associated with schizophrenia and autism spectrum disorder

Abstract

Background: Genes encoding synaptic proteins or mRNA targets of the RNA binding protein, Fragile X mental retardation protein (FMRP), have been linked to schizophrenia and autism spectrum disorder (ASD) through the enrichment of genetic variants conferring risk to these disorders. FMRP binds many transcripts with synaptic functions and is thought to regulate their local translation, a process which enables rapid and compartmentalized protein synthesis required for development and plasticity. Methods: We used summary statistics from large-scale genome-wide association studies of schizophrenia (74,776 cases, 101,023 controls) and ASD (18,381 cases, 27,969 controls) to test the hypothesis that the subset of synaptic genes encoding localized transcripts is more strongly associated with each disorder than non-localized transcripts. We also postulated that this subset of synaptic genes is responsible for associations attributed to FMRP targets. Results: Schizophrenia associations were enriched in genes encoding localized synaptic transcripts compared to the remaining synaptic genes, or to the remaining localized transcripts; this also applied to ASD associations, although only for transcripts observed after stimulation by fear conditioning. The genetic associations with either disorder captured by these gene sets were independent of those derived from FMRP targets. Schizophrenia association was related to FMRP interactions with mRNAs in somata, but not in dendrites, whilst ASD association was related to FMRP binding in either compartment. Conclusions Our data suggest that synaptic transcripts capable of local translation are particularly relevant to the pathogenesis of schizophrenia and ASD, but do not characterize the associations attributed to current sets of FMRP targets.