Enrichment of the local synaptic translatome for genetic risk associated with schizophrenia and autism spectrum disorder
Clifton, NE; Lin, JQ; Holt, CE; et al.O’Donovan, MC; Mill, J
Date: 14 December 2023
Article
Journal
Biological Psychiatry
Publisher
Elsevier / Society of Biological Psychiatry.
Publisher DOI
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 ...
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.
Clinical and Biomedical Sciences
Faculty of Health and Life Sciences
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