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Cell. 2019 Aug 8;178(4):850-866.e26. doi: 10.1016/j.cell.2019.07.015.

Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.

Author information

1
Department of Psychiatry and Biobehavioral Sciences, Semel Institue, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
2
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
3
Department of Pediatrics, Division of Systems Medicine, Stanford University, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
4
Bioinformatics IDP, University of California, Los Angeles, Los Angeles, CA, USA.
5
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
6
Department of Psychiatry and Biobehavioral Sciences, Semel Institue, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. Electronic address: dhg@mednet.ucla.edu.
7
Department of Pediatrics, Division of Systems Medicine, Stanford University, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. Electronic address: dpwall@stanford.edu.

Abstract

We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

KEYWORDS:

ASD; autism; de novo; genetics; inherited; machine learning; multiplex families

PMID:
31398340
DOI:
10.1016/j.cell.2019.07.015
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