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Nature. 2016 Dec 15;540(7633):423-427. doi: 10.1038/nature20612. Epub 2016 Dec 5.

Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism.

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Center for Autism Research and Treatment and Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA.
Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), 88 Dr. Aiguader, Barcelona 08003, Spain.
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
Department of Biostatistics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.


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.

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