Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks

Elizabeth K Ruzzo; Laura Pérez-Cano; Jae-Yoon Jung; Lee-Kai Wang; Dorna Kashef-Haghighi; Chris Hartl; Chanpreet Singh; Jin Xu; Jackson N Hoekstra; Olivia Leventhal; Virpi M Leppä; Michael J Gandal; Kelley Paskov; Nate Stockham; Damon Polioudakis; Jennifer K Lowe; David A Prober; Daniel H Geschwind; Dennis P Wall

doi:10.1016/j.cell.2019.07.015

Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks

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

Authors

Elizabeth K Ruzzo¹, Laura Pérez-Cano², Jae-Yoon Jung³, Lee-Kai Wang¹, Dorna Kashef-Haghighi³, Chris Hartl⁴, Chanpreet Singh⁵, Jin Xu⁵, Jackson N Hoekstra¹, Olivia Leventhal¹, Virpi M Leppä², Michael J Gandal¹, Kelley Paskov³, Nate Stockham³, Damon Polioudakis², Jennifer K Lowe¹, David A Prober⁵, Daniel H Geschwind⁶, Dennis P Wall⁷

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autism Spectrum Disorder / genetics*
Child
Databases, Genetic
Disease Models, Animal
Female
Gene Deletion
Genetic Predisposition to Disease / genetics*
Guanylate Kinases / genetics
Humans
Inheritance Patterns / genetics
Machine Learning
Male
Nuclear Family
Pedigree*
Promoter Regions, Genetic / genetics
Protein Interaction Maps / genetics*
Receptors, Mineralocorticoid / genetics
Risk Factors
Tumor Suppressor Proteins / genetics
Whole Genome Sequencing
Zebrafish / genetics

Substances

NR3C2 protein, human
Receptors, Mineralocorticoid
Tumor Suppressor Proteins
DLG2 protein, human
Guanylate Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding