TY - JOUR
T1 - XIntegrative functional genomic analyses implicate specific molecular pathways and circuits in autism
AU - Parikshak, Neelroop N.
AU - Luo, Rui
AU - Zhang, Alice
AU - Won, Hyejung
AU - Lowe, Jennifer K.
AU - Chandran, Vijayendran
AU - Horvath, Steve
AU - Geschwind, Daniel H.
N1 - Funding Information:
We thank the Simons Foundation Autism Research Initiative ( http://www.sfari.org ) and the Autism Genetic Resource Exchange ( http://www.agre.org ) and all families involved for making this work possible. We gratefully acknowledge data resources from the BrainSpan consortium and the Allen Brain Institute ( http://www.brain-map.org ). This work was supported by a NIMH Training and NRSA Fellowship (T32MH073526 and F30MH099886, N.N.P.), NIMH grants (5R37MH060233 and 5R01MH094714, D.H.G.), an Autism Center for Excellence network grant (9R01MH100027), the Simons Foundation (SFARI 206744, D.H.G.), and the Medical Scientist Training Program at UCLA. We thank the NINDS Informatics Center for Neurogenetics and Neurogenomics (funded by grant P30NS062691) at UCLA for computing resources, and we specifically thank Yeongshnn Ong and Giovanni Coppola for making the interactive network available. We thank Jason Chen, Michael Gandal, and Jason Stein for critically reading the manuscript, as well as Willsey et al. (2013) for sharing their findings prior to publication.
PY - 2013/11/21
Y1 - 2013/11/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84889561601&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2013.10.031
DO - 10.1016/j.cell.2013.10.031
M3 - Article
C2 - 24267887
AN - SCOPUS:84889561601
SN - 0092-8674
VL - 155
SP - 1008
JO - Cell
JF - Cell
IS - 5
ER -