Pubmed du 17/12/23
1. Clifton NE, Lin JQ, Holt CE, O’Donovan MC, Mill J. Enrichment of the local synaptic translatome for genetic risk associated with schizophrenia and autism spectrum disorder. Biol Psychiatry;2023 (Dec 14)
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.
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2. Ellul P, Maruani A, Peyre H, Vantalon V, Hoareau D, Tiercelin H, Rosenzwajg M, Klatzmann D, Delorme R. Abnormal neutrophil-to-lymphocyte ratio in children with autism spectrum disorder and history of maternal immune activation. Sci Rep;2023 (Dec 16);13(1):22424.
Maternal immune activation (MIA), related to autoimmune/inflammatory diseases or acute infections, during the two first trimesters of pregnancy is a risk factor for autism spectrum disorders (ASD) in offspring. In mice, MIA has a long-term impact on offspring’s immune equilibrium resulting in a pro-inflammatory phenotype. We therefore hypothesized that children with ASD and a history of MIA could display a similar phenotype specifically assessed by a higher neutrophil to lymphocyte ratio (NLR). In this study, we used a retrospective sample of 231 dyads involving children with ASD and their mothers. Among ASD patients, 12% had a history of MIA. The multivariate analysis revealed a significant association between NLR in children with ASD and maternal history of MIA (F = 2.27, p = 0.03). Using a categorical approach, we observed an abnormal NLR (over 3) in 7.4% of children with ASD MIA+ compared to 1.9% for MIA-. Our study supports the hypothesis suggesting an impact of MIA on the risk of ASD. Further studies could contribute to the development of biomarkers in MIA+ ASD and enable the development of targeted immunomodulatory therapies.
