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Nat Neurosci. 2016 Nov;19(11):1454-1462. doi: 10.1038/nn.4353. Epub 2016 Aug 1.

Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder.

Author information

  • 1Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
  • 2Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
  • 3Department of Computer Science, Princeton University, Princeton, New Jersey, USA.
  • 4Simons Foundation, New York, New York, USA.
  • 5Flatiron Institute, Simons Foundation, New York, New York, USA.

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic basis. Yet, only a small fraction of potentially causal genes-about 65 genes out of an estimated several hundred-are known with strong genetic evidence from sequencing studies. We developed a complementary machine-learning approach based on a human brain-specific gene network to present a genome-wide prediction of autism risk genes, including hundreds of candidates for which there is minimal or no prior genetic evidence. Our approach was validated in a large independent case-control sequencing study. Leveraging these genome-wide predictions and the brain-specific network, we demonstrated that the large set of ASD genes converges on a smaller number of key pathways and developmental stages of the brain. Finally, we identified likely pathogenic genes within frequent autism-associated copy-number variants and proposed genes and pathways that are likely mediators of ASD across multiple copy-number variants. All predictions and functional insights are available at http://asd.princeton.edu.

PMID:
27479844
DOI:
10.1038/nn.4353
[PubMed - in process]
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