TY - JOUR
T1 - Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism
AU - Parikshak, Neelroop N.
AU - Swarup, Vivek
AU - Belgard, T. Grant
AU - Irimia, Manuel
AU - Ramaswami, Gokul
AU - Gandal, Michael J.
AU - Hartl, Christopher
AU - Leppa, Virpi
AU - Ubieta, Luis De La Torre
AU - Huang, Jerry
AU - Lowe, Jennifer K.
AU - Blencowe, Benjamin J.
AU - Horvath, Steve
AU - Geschwind, Daniel H.
N1 - Publisher Copyright:
© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2016/12/15
Y1 - 2016/12/15
N2 - Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2-13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.
AB - Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2-13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.
UR - http://www.scopus.com/inward/record.url?scp=85016140982&partnerID=8YFLogxK
U2 - 10.1038/nature20612
DO - 10.1038/nature20612
M3 - Article
C2 - 27919067
AN - SCOPUS:85016140982
SN - 0028-0836
VL - 540
SP - 423
EP - 427
JO - Nature
JF - Nature
IS - 7633
ER -