Pubmed du 14/04/24
1. Chen Y, Li W, Lv L, Yue W. Shared Genetic Determinants of Schizophrenia and Autism Spectrum Disorder Implicate Opposite Risk Patterns: A Genome-Wide Analysis of Common Variants. Schizophr Bull;2024 (Apr 14)
BACKGROUND AND HYPOTHESIS: The synaptic pruning hypothesis posits that schizophrenia (SCZ) and autism spectrum disorder (ASD) may represent opposite ends of neurodevelopmental disorders: individuals with ASD exhibit an overabundance of synapses and connections while SCZ was characterized by excessive pruning of synapses and a reduction. Given the strong genetic predisposition of both disorders, we propose a shared genetic component, with certain loci having differential regulatory impacts. STUDY DESIGN: Genome-Wide single nucleotide polymorphism (SNP) data of European descent from SCZ (N cases = 53 386, N controls = 77 258) and ASD (N cases = 18 381, N controls = 27 969) were analyzed. We used genetic correlation, bivariate causal mixture model, conditional false discovery rate method, colocalization, Transcriptome-Wide Association Study (TWAS), and Phenome-Wide Association Study (PheWAS) to investigate the genetic overlap and gene expression pattern. STUDY RESULTS: We found a positive genetic correlation between SCZ and ASD (rg = .26, SE = 0.01, P = 7.87e-14), with 11 genomic loci jointly influencing both conditions (conjFDR <0.05). Functional analysis highlights a significant enrichment of shared genes during early to mid-fetal developmental stages. A notable genetic region on chromosome 17q21.31 (lead SNP rs2696609) showed strong evidence of colocalization (PP.H4.abf = 0.85). This SNP rs2696609 is linked to many imaging-derived brain phenotypes. TWAS indicated opposing gene expression patterns (primarily pseudogenes and long noncoding RNAs [lncRNAs]) for ASD and SCZ in the 17q21.31 region and some genes (LRRC37A4P, LINC02210, and DND1P1) exhibit considerable variation in the cerebellum across the lifespan. CONCLUSIONS: Our findings support a shared genetic basis for SCZ and ASD. A common genetic variant, rs2696609, located in the Chr17q21.31 locus, may exert differential risk regulation on SCZ and ASD by altering brain structure. Future studies should focus on the role of pseudogenes, lncRNAs, and cerebellum in synaptic pruning and neurodevelopmental disorders.
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2. Tseng CJ, Canales C, Marcus RE, Parmar AJ, Hightower BG, Mullett JE, Makary MM, Tassone AU, Saro HK, Townsend PH, Birtwell K, Nowinski L, Thom RP, Palumbo ML, Keary C, Catana C, McDougle CJ, Hooker JM, Zürcher NR. In vivo translocator protein in females with autism spectrum disorder: a pilot study. Neuropsychopharmacology;2024 (Apr 13)
Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)-a mitochondrial protein-in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [(11)C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [(11)C]PBR28 PET-MRI scans. Females with ASD exhibited elevated [(11)C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [(11)C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [(11)C]PBR28 SUVR across time in both groups. Elevated regional [(11)C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [(11)C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD.
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3. Yi T, Ji C, Wei W, Wu G, Jin K, Jiang G. Cortical-cerebellar circuits changes in preschool ASD children by multimodal MRI. Cereb Cortex;2024 (Apr 1);34(4)
OBJECTIVE: To investigate the alterations in cortical-cerebellar circuits and assess their diagnostic potential in preschool children with autism spectrum disorder using multimodal magnetic resonance imaging. METHODS: We utilized diffusion basis spectrum imaging approaches, namely DBSI_20 and DBSI_combine, alongside 3D structural imaging to examine 31 autism spectrum disorder diagnosed patients and 30 healthy controls. The participants’ brains were segmented into 120 anatomical regions for this analysis, and a multimodal strategy was adopted to assess the brain networks using a multi-kernel support vector machine for classification. RESULTS: The results revealed consensus connections in the cortical-cerebellar and subcortical-cerebellar circuits, notably in the thalamus and basal ganglia. These connections were predominantly positive in the frontoparietal and subcortical pathways, whereas negative consensus connections were mainly observed in frontotemporal and subcortical pathways. Among the models tested, DBSI_20 showed the highest accuracy rate of 86.88%. In addition, further analysis indicated that combining the 3 models resulted in the most effective performance. CONCLUSION: The connectivity network analysis of the multimodal brain data identified significant abnormalities in the cortical-cerebellar circuits in autism spectrum disorder patients. The DBSI_20 model not only provided the highest accuracy but also demonstrated efficiency, suggesting its potential for clinical application in autism spectrum disorder diagnosis.
