Key links between peripheral protein dysregulation and neuronal function and behavior are revealed, offering new insights into systemic contributions to ASD pathophysiology and highlighting potential therapeutic targets for mitigating symptom severity.
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a multifactorial etiology involving both genetic and environmental factors. Although previous studies have identified altered levels of circulating proteins in individuals with ASD, the functional significance of these peripheral biomarkers remains largely unclear. In this study, we recruited a well-characterized cohort of young Arab children with ASD (n = 100) and matched controls (n = 60), aged 2-4 years, in Qatar. We used a multimodal approach, integrating data from proteomics, transcriptomics, induced pluripotent stem cell (iPSC)-derived cortical neurons, cellular imaging, functional assays using microelectrode recordings, and behavioral assays in Drosophila models. High-throughput screening of plasma samples revealed considerable heterogeneity in circulating proteomic profiles across different Arab subpopulations; therefore, we focused our subsequent analyses on Qatari children. We identified elevated levels of several neuronal proteins in the peripheral circulation of individuals with severe, but not mild, ASD symptoms. Furthermore, we found that neurons derived from the severe ASD group showed increased MAP2+/DCX+ cell counts, upregulated expression of genes associated with neuronal activity, and increased neuronal hyperexcitability in functional assays. Moreover, targeted overexpression of these proteins specifically in the blood of Drosophila models was sufficient to induce ASD-relevant behaviors. Together, our findings reveal key links between peripheral protein dysregulation and neuronal function and behavior, offering new insights into systemic contributions to ASD pathophysiology and highlighting potential therapeutic targets for mitigating symptom severity.
RNA-sequencing, 3-dimensional protein-centric chromatin conformation, and whole genome DNA methylation sequencing approaches are used to investigate hippocampal tissue from an ASD mouse model to determine if multi-omic data integration improves the resolution of key molecular pathways contributing to the complex ASD phenotype.
Carolina D Alberca, Kwangmoon Park, L. Papale et al.· Molecular Psychiatry· 0 citations
The heterogeneity in both the neurobiological mechanisms and the phenotypic presentations of autism spectrum disorder (ASD) poses a major challenge to clinical and translational research. Alterations in functional connectivity (FC) have been associated with ASD, yet it remains unclear whether and how divergent brain network properties may account for individual differences across ASD-related symptomatology and behaviors. We applied source-level reconstruction to rest-like non-task-related high-density EEG data in a cohort of 104 young children (38 with ASD) to identify global and local alterations of cortical network connectivity. We subsequently used regularized canonical correlation analysis (rCCA) to characterize specific FC patterns linked to variation in cognitive, social and sensory dimensions derived from standard clinical instruments. We found increased low-frequency FC in frontotemporal cross-hemispheric networks and lateral-occipital regions of young ASD children versus healthy peers. RCCA revealed three distinct FC patterns in recurrent ASD-related networks, each contributing to predict individual differences in cognitive, social and sensory features. These linked FC-behavior dimensions may shed light on atypical brain network topology associated with specific phenotypic manifestations of ASD, which might implicate unique underlying neurobiological mechanisms.
B. Rodríguez-Herreros, A. Mheich, J. A. Osório et al.· Autism Research· 0 citations
How human cellular models have advanced basic and translational research in ASD is examined and key cellular and molecular convergent phenotypes that have emerged are identified.
Sudha R. Guttikonda, Christopher D. Makinson· Biological Psychiatry· 0 citations
The study provides an integrated framework linking genetic variation to molecular dysfunction and clinical outcomes, offering valuable insights for future research and therapeutic development in pediatric neurology.
Varada Vidya Rani, Suryanarayana Reddy Kovvuri, D. Arya· Genetics and Molecular Resea...· 0 citations
Attention-deficit/hyperactivity disorder (ADHD) is heterogeneous in the age at which symptoms first lead to clinical diagnosis. Recent genomic analyses of a large Danish population-based cohort showed that individuals diagnosed in childhood differ from those diagnosed in adulthood in polygenic risk scores, rare-variant burden, and patterns of genetic correlation with other psychiatric traits [1]. Childhood cases exhibited stronger overlap with autism and higher rates of rare protein-truncating variants in constrained genes, whereas late-diagnosed cases showed greater genetic overlap with depression. The functional transcriptomic mechanisms underlying these differences have remained unclear.We performed a transcriptome-wide association study (TWAS) using S-PrediXcan and GTEx v8 MASHR models from six adult brain tissues: amygdala, anterior cingulate cortex, caudate, frontal cortex, hippocampus, and nucleus accumbens. Analyses were based on GWAS summary statistics from the iPSYCH study for childhood ADHD (N = 14,878) and late-diagnosed ADHD (N = 6,961). Thirteen curated gene sets were examined, spanning synaptic plasticity, immune function, glial markers, and housekeeping controls.The transcriptomic profiles of the two subgroups showed substantial overall similarity (Spearman ρ = 0.77 across 13,580 genes), with near-perfect directional concordance among nominally significant associations; because the two GWAS contrasted different case groups against the same 38,303 population controls, these similarity estimates should be interpreted as upper bounds rather than unbiased estimates of aetiological overlap. Despite this shared architecture, gene-set analyses suggested biologically interpretable divergences: late-diagnosed ADHD displayed stronger enrichment in long-term potentiation (enrichment ratio = 1.34, Mann-Whitney p = 1.42 × 10⁻⁸) and complement cascade pathways (1.22, p = 5.14 × 10⁻⁵), whereas childhood ADHD showed only nominally greater signals in microglia marker and MHC genes. Eighty-two genes differed in association strength between groups after FDR correction, although this delta-Z comparison should be read cautiously because the shared-control design violates the independence assumption of the test.These findings provide a functional explanation for previously reported genetic and comorbidity differences by age at diagnosis and identify an 82-gene differential list for follow-up. The enrichment patterns generate cautious, hypothesis-level questions regarding potential variation in stimulant response and tolerability, but no direct treatment, adherence, or pharmacogenomic data were analysed. This represents the first TWAS to dissect ADHD subtypes by age at first diagnosis and offers a bridge between statistical genetic associations and biologically interpretable pathways relevant to clinical heterogeneity.
Autism Spectrum Disorder (ASD) is associated with atypical large-scale brain network organization, yet how spatial-functional dependencies relate to clinical features and molecular reference maps remains incompletely understood. To quantify spatial functional heterogeneity (Sill) and coherence persistence (Range), we analyzed resting-state fMRI data from 162 ASD and 175 TD adolescents, all aged 12–18. Compared with TD, adolescents with ASD exhibited significantly increased Sill within higher-order association networks, including the left Language and right Posterior Multimodal networks, whereas no group differences in Range survived multiple-comparison correction. Within the ASD group, elevated Sill was selectively associated with greater social-affective symptom severity but not restricted and repetitive behaviors. To explore potential biological correlates, we integrated cortical gene expression reference data and identified transcriptomic patterns associated with regional Sill differences. These genes showed enrichment for synaptic signaling, mitochondrial processes, and glial-related functions, highlighting multiscale correspondence between spatial-functional organization and molecular reference maps. Together, these results demonstrate statistical associations among altered spatial-functional properties, clinical severity, and transcriptomic profiles related to synaptic signaling, mitochondrial processes, and glial-related functions in ASD, providing a complementary spatial perspective on large-scale functional organization.
Jun Pan, Heng Zhang, Yiran Zhai et al.· Frontiers in Neuroscience· 0 citations