RT Journal Article
SR Electronic
T1 Genome-wide changes in lncRNA, alternative splicing, and cortical patterning in autism
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 077057
DO 10.1101/077057
A1 Neelroop N. Parikshak
A1 Vivek Swarup
A1 T. Grant Belgard
A1 Manuel Irimia
A1 Gokul Ramaswami
A1 Michael J. Gandal
A1 Christopher Hartl
A1 Virpi Leppa
A1 Luis de la Torre Ubieta
A1 Jerry Huang
A1 Jennifer K. Lowe
A1 Benjamin J. Blencowe
A1 Steve Horvath
A1 Daniel H. Geschwind
YR 2016
UL http://biorxiv.org/content/early/2016/09/23/077057.abstract
AB Summary Paragraph The genetic contributions to autism spectrum disorder (ASD) are substantial and profoundly heterogeneous, potentially converging on common molecular and cellular pathways that still are not well understood1–3. Here, through genome-wide transcriptome analysis in the largest cohort of postmortem ASD brains analyzed to date4–7, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analyses reveal dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuronal exons, and attenuation of normal gene expression differences between frontal and temporal lobes in ASD. We further demonstrate that a genetically defined subtype of ASD, Duplication 15q Syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals age related changes in microglial and synaptic function that plateau after the first decade of life, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our work implicates SOX5, a transcription factor involved in neuron fate specification, in contributing to these diminished regional differences. These data and analyses show how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.