title: Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism.
abstract: Genetic studies have identified dozens of autism spectrum disorder (ASD) susceptibility genes, raising two critical questions: (1) do these genetic loci converge on specific biological processes, and (2) where does the phenotypic specificity of ASD arise, given its genetic overlap with intellectual disability (ID)? To address this, we mapped ASD and ID risk genes onto coexpression networks representing developmental trajectories and transcriptional profiles representing fetal and adult cortical laminae. ASD genes tightly coalesce in modules that implicate distinct biological functions during human cortical development, including early transcriptional regulation and synaptic development. Bioinformatic analyses suggest that translational regulation by FMRP and transcriptional coregulation by common transcription factors connect these processes. At a circuit level, ASD genes are enriched in superficial cortical layers and glutamatergic projection neurons. Furthermore, we show that the patterns of ASD and ID risk genes are distinct, providing a biological framework for further investigating the pathophysiology of ASD.
authors.affiliation: Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Interdepartmental Program in Neuroscience, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Neelroop N
authors.initials: NN
authors.lastname: Parikshak
authors.forename: Rui
authors.initials: R
authors.lastname: Luo
authors.forename: Alice
authors.initials: A
authors.lastname: Zhang
authors.forename: Hyejung
authors.initials: H
authors.lastname: Won
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lowe
authors.forename: Vijayendran
authors.initials: V
authors.lastname: Chandran
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D001921:Brain / Q000196:embryology* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000503:physiopathology; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D009474:Neurons / Q000378:metabolism; D014158:Transcription, Genetic