Autism genes converge on three functional programs organized by neuronal subclass, developmental timing, and cortical patterning
Year: 2026
Type: preprint
Abstract: Summary Our companion sequencing study uncovered 253 genes robustly associated with autism spectrum disorder (ASD), yet the biological programs they impact, and the cellular, developmental, and spatial contexts in which they converge, remain unresolved. Here we systematically contextualize genes associated with ASD across neurodevelopment and cortical areas, integrating developmental single-cell and spatial atlases with gene- and isoform co-expression, regulatory, proteomic, and synaptic networks. Genetic burden concentrates within temporally-resolved neuronal subclasses: newborn excitatory neurons, immature interneurons, and maturing intratelencephalic lineages. Genes associated with ASD converge on three functional programs—gene regulation, neuronal morphogenesis, and synaptic transmembrane signaling machinery—resolved from 28 ASD-associated networks, several of which are directly regulated by ASD genes including MEF2C , SOX11 , and FOXP2 . These programs are spatially patterned, with risk genes exhibiting an increasing anterior-to-posterior cortical expression gradient, anchored in the primary visual cortex and driven by excitatory neuron gene-regulatory programs. Finally, ASD risk genes associated with more severe developmental phenotypes show broader excitatory neuron enrichment and less interneuron involvement. Together, these findings anchor ASD genetic vulnerability to specific neurodevelopmental lineages, epochs, and molecular substrates, and delineate the features that distinguish ASD from comorbidities with broader developmental impacts.
Authors: Rachel L. Smith, Yundan Liao, Lambertus Klei, Lujing Zhang, Yunlong Ma, Miao Tang, F. Kyle Satterstrom, Chiara Auwerx, Jack M. Fu, Joseph D. Buxbaum, Mark J. Daly, Michael E. Talkowski, Luis de la Torre-Ubieta, Yevgenia Kozorovitskiy, Matthew L. MacDonald, Kathryn Roeder, Bernie Devlin, Michael J. Gandal
Institutions: Children's Hospital of Philadelphia, University of Pennsylvania Health System, University of Pennsylvania, University of Pittsburgh, Carnegie Mellon University, Broad Institute, Massachusetts General Hospital, Stanley Center for Psychiatric Research, Harvard University, Icahn School of Medicine at Mount Sinai, University of Helsinki, Institute for Molecular Medicine Finland, University of California, Los Angeles, Northwestern University
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Isoform-level probabilistic transcriptome-wide association to undercover neurogenetic mechanisms underlying complex psychiatric traits, RECODE: Spatial engineering of morphogens for the reproducible formation of cortical organoids with arealization, Population-level and mechanistic dissection of 17q21 structural variant association with psychiatric traits, Methods for single-cell CRISPR screens and multiomic data: constructing powerful well-calibrated tests, circumventing unmeasured confounding, and accounting for denoising and imputation
OpenAlex ID: W7214128648