Whole-genome deep-learning analysis identifies contribution of noncoding mutations to autism risk.

Journal: Nature genetics
Published Date: Jun 1, 2019

Abstract

We address the challenge of detecting the contribution of noncoding mutations to disease with a deep-learning-based framework that predicts the specific regulatory effects and the deleterious impact of genetic variants. Applying this framework to 1,790 autism spectrum disorder (ASD) simplex families reveals a role in disease for noncoding mutations-ASD probands harbor both transcriptional- and post-transcriptional-regulation-disrupting de novo mutations of significantly higher functional impact than those in unaffected siblings. Further analysis suggests involvement of noncoding mutations in synaptic transmission and neuronal development and, taken together with previous studies, reveals a convergent genetic landscape of coding and noncoding mutations in ASD. We demonstrate that sequences carrying prioritized mutations identified in probands possess allele-specific regulatory activity, and we highlight a link between noncoding mutations and heterogeneity in the IQ of ASD probands. Our predictive genomics framework illuminates the role of noncoding mutations in ASD and prioritizes mutations with high impact for further study, and is broadly applicable to complex human diseases.

Authors

  • Jian Zhou
    CTIQ, Canon Medical Research USA, Inc., Vernon Hills, 60061, USA.
  • Christopher Y Park
    Flatiron Institute, Simons Foundation, New York, NY, USA.
  • Chandra L Theesfeld
    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • Aaron K Wong
    Flatiron Institute, Simons Foundation, New York, NY, USA.
  • Yuan Yuan
    Department of Geriatrics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China.
  • Claudia Scheckel
    Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
  • John J Fak
    Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
  • Julien Funk
    Flatiron Institute, Simons Foundation, New York, NY, USA.
  • Kevin Yao
    Flatiron Institute, Simons Foundation, New York, NY, USA.
  • Yoko Tajima
    Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
  • Alan Packer
    Simons Foundation, New York, NY, USA.
  • Robert B Darnell
    The Rockefeller University and New York Genome Center, New York, New York.
  • Olga G Troyanskaya
    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA. ogt@cs.princeton.edu.

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