Molecular and network-level mechanisms explaining individual differences in autism spectrum disorder.
Amanda M BuchPetra E VértesJakob SeidlitzSo Hyun KimLogan GrosenickConor ListonPublished in: Nature neuroscience (2023)
The mechanisms underlying phenotypic heterogeneity in autism spectrum disorder (ASD) are not well understood. Using a large neuroimaging dataset, we identified three latent dimensions of functional brain network connectivity that predicted individual differences in ASD behaviors and were stable in cross-validation. Clustering along these three dimensions revealed four reproducible ASD subgroups with distinct functional connectivity alterations in ASD-related networks and clinical symptom profiles that were reproducible in an independent sample. By integrating neuroimaging data with normative gene expression data from two independent transcriptomic atlases, we found that within each subgroup, ASD-related functional connectivity was explained by regional differences in the expression of distinct ASD-related gene sets. These gene sets were differentially associated with distinct molecular signaling pathways involving immune and synapse function, G-protein-coupled receptor signaling, protein synthesis and other processes. Collectively, our findings delineate atypical connectivity patterns underlying different forms of ASD that implicate distinct molecular signaling mechanisms.
Keyphrases
- autism spectrum disorder
- functional connectivity
- resting state
- attention deficit hyperactivity disorder
- intellectual disability
- gene expression
- single cell
- electronic health record
- signaling pathway
- white matter
- dna methylation
- big data
- genome wide
- rna seq
- copy number
- randomized controlled trial
- artificial intelligence
- long non coding rna
- brain injury
- data analysis
- epithelial mesenchymal transition
- deep learning
- blood brain barrier