title: Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.
abstract: Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: A Jeremy
authors.initials: AJ
authors.lastname: Willsey
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Li
authors.forename: Shan
authors.initials: S
authors.lastname: Dong
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Tebbenkamp
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Muhle
authors.forename: Steven K
authors.initials: SK
authors.lastname: Reilly
authors.forename: Leon
authors.initials: L
authors.lastname: Lin
authors.forename: Sofia
authors.initials: S
authors.lastname: Fertuzinhos
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Miller
authors.forename: Michael T
authors.initials: MT
authors.lastname: Murtha
authors.forename: Candace
authors.initials: C
authors.lastname: Bichsel
authors.forename: Wei
authors.initials: W
authors.lastname: Niu
authors.forename: Justin
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authors.lastname: Cotney
authors.forename: A Gulhan
authors.initials: AG
authors.lastname: Ercan-Sencicek
authors.forename: Jake
authors.initials: J
authors.lastname: Gockley
authors.forename: Abha R
authors.initials: AR
authors.lastname: Gupta
authors.forename: Wenqi
authors.initials: W
authors.lastname: Han
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Hoffman
authors.forename: Lambertus
authors.initials: L
authors.lastname: Klei
authors.forename: Jing
authors.initials: J
authors.lastname: Lei
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Cong
authors.initials: C
authors.lastname: Lu
authors.forename: Xuming
authors.initials: X
authors.lastname: Xu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.forename: Ed S
authors.initials: ES
authors.lastname: Lein
authors.forename: Liping
authors.initials: L
authors.lastname: Wei
authors.forename: James P
authors.initials: JP
authors.lastname: Noonan
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.forename: Nenad
authors.initials: N
authors.lastname: Sestan
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D059472:Exome; D005260:Female; D005333:Fetus / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D017422:Sequence Analysis, DNA