Letter | Published:

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

Nature volume 540, pages 423427 (15 December 2016) | Download Citation

This article has been updated


Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood1,2,3. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge4,5,6,7, 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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Change history

  • 11 July 2018

    In this Letter, the labels for splicing events A3SS and A5SS were swapped in column D of Supplementary Table 3a and b. Supplementary Table 3 has been corrected online.


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Tissue, biological specimens or data used in this research were obtained from the Autism BrainNet (formerly the Autism Tissue Program), which is sponsored by the Simons Foundation, and the University of Maryland Brain and Tissue Bank, which is a component of the NIH NeuroBioBank. We are grateful to the patients and families who participate in the tissue donation programs. The authors acknowledge R. Zielke, J. Cottrell and R. Johnson, who assisted with sample acquisition from the latter brain bank. Funding for this work was provided by grants to D.H.G. (NIMH 5R37 MH060233, 5R01 MH09714 and 5R01 MH100027), N.N.P. (NRSA F30 MH099886, UCLA Medical Scientist Training Program), V.L. (Sigrid Juselius Fellowship) and T.G.B. (training grant 5T32 MH073526). Additional grants supporting this work include those to B.J.B. (CIHR, Alzheimer’s Research Foundation and University of Toronto McLaughlin Centre) and M.I. (ERC-StG-LS2-637591). We also thank D. Polioudakis for assistance with data management and V. Chandran for discussion of transcription factor binding site analysis and providing software.

Author information

Author notes

    • Neelroop N. Parikshak
    • , Vivek Swarup
    •  & T. Grant Belgard

    These authors contributed equally to this work.


  1. 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

    • Neelroop N. Parikshak
    • , Vivek Swarup
    • , T. Grant Belgard
    • , Gokul Ramaswami
    • , Michael J. Gandal
    • , Christopher Hartl
    • , Virpi Leppa
    • , Luis de la Torre Ubieta
    • , Jerry Huang
    • , Jennifer K. Lowe
    •  & Daniel H. Geschwind
  2. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA

    • Neelroop N. Parikshak
    • , Vivek Swarup
    • , T. Grant Belgard
    • , Gokul Ramaswami
    • , Michael J. Gandal
    • , Christopher Hartl
    • , Luis de la Torre Ubieta
    • , Jerry Huang
    •  & Daniel H. Geschwind
  3. Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), 88 Dr. Aiguader, Barcelona 08003, Spain

    • Manuel Irimia
  4. Universitat Pompeu Fabra (UPF), Barcelona, Spain

    • Manuel Irimia
  5. Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada

    • Benjamin J. Blencowe
  6. Department of Molecular Genetics, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada

    • Benjamin J. Blencowe
  7. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA

    • Steve Horvath
    •  & Daniel H. Geschwind
  8. Department of Biostatistics, David Geffen School of Medicine, University of California, Los Angeles, California, USA

    • Steve Horvath


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N.N.P. and D.H.G. planned and directed experiments, guided analyses, and wrote the manuscript with assistance from all authors. N.N.P., V.S. and T.G.B. performed dissections, RNA-seq analysis, and differential gene expression analysis. N.N.P. and V.S. performed splicing analysis. M.I. and B.J.B. provided splicing validation data and assisted with splicing analysis. N.N.P., V.S., S.H., G.R., M.J.G. and C.H. performed co-expression network analysis. N.N.P., T.G.B., V.L. and J.K.L. performed analysis of duplication 15q syndrome samples. V.S. performed RT–PCR validation experiments and V.S., L.d.l.T.U. and J.H. performed SOX5 validation experiments.

Competing interests

D.H.G. is a paid consultant to Ovid Therapeutics. The authors declare no other competing financial interests related to this work.

Corresponding author

Correspondence to Daniel H. Geschwind.

Reviewer Information

Nature thanks K. Mirnics and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Methods, full legends for Supplementary Tables 1-4 and Supplementary References.

Excel files

  1. 1.

    Supplementary Table 1

    Metadata for samples used in the study.

  2. 2.

    Supplementary Table 2

    Differential gene expression changes in cortex and cerebellum, cortical patterning results, and co-expression network module assignments.

  3. 3.

    Supplementary Table 3

    Differential splicing changes in cortex and cerebellum.

  4. 4.

    Supplementary Table 4

    Module preservation analyses and Gene Ontology term enrichment analyses.

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