Inherited and de novo genetic risk for autism impacts shared networks
Open accessAbstract
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.
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These results are consistent with previous studies in post-mortem brain that identified dysregulation of gene expression in microglia but enriched expression of ASD risk genes only in neuronal cells.
“These results are consistent with previous studies in post-mortem brain that identified dysregulation of gene expression in microglia but enriched expression of ASD risk genes only in neuronal cells (Ruzzo et al., 2019; Gandal et al., 2018a, 2018b; Voineagu et al., 2011).”
From Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020) · cites this paper as Ruzzo et al., 2019
The Results section (“Biological insights from known and novel ASD genes”; page not provided) reports enrichment of ASD-risk genes in mid-gestation and adult glutamatergic projection neurons. It does not report microglial gene-expression dysregulation in post-mortem brain or establish that enrichment occurs only in neuronal cells. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAn analysis of genome sequencing data from 2,308 individuals in 493 multiplex ASD families from the Autism Genetic Resource Exchange conducted through TADA mega-analysis identified NCKAP1 among 69 genes associated with an ASD risk.
“An analysis of genome sequencing data from 2,308 individuals in 493 multiplex ASD families from the Autism Genetic Resource Exchange (AGRE) conducted through TADA (Transmitted And De novo Association) mega-analysis identified NCKAP1 among 69 genes associated with an ASD risk128.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [128]
The Results section reports whole-genome sequencing of 2,308 individuals in 493 AGRE multiplex ASD families and identifies 69 ASD-associated genes in a TADA mega-analysis. Our copy does not identify NCKAP1 as one of those genes. The Methods also clarify that the mega-analysis combined the AGRE cohort’s variants with data from other cohorts, rather than analyzing only the 2,308 individuals. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPrevious work indicates neurons as the central cell type harboring genetic risk for the majority of psychiatric disorders.
“In contrast to AD in which multiple glial cells are implicated, previous work has indicated neurons as the central cell-type harboring genetic risk for the majority of psychiatric disorders3,22,46,58–61.”
From Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders (2021) · cites this paper as [60]
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Self-citation
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“These results are consistent with previous studies in post-mortem brain that identified dysregulation of gene expression in microglia but enriched expression of ASD risk genes only in neuronal cells (Ruzzo et al., 2019; Gandal et al., 2018a, 2018b; Voineagu et al., 2011).”
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- Authors
- Ruzzo, E. K., Pérez-Cano, L., Jung, J.-Y., Wang, L.-K., Kashef-Haghighi, D., Hartl, C., Singh, C., Xu, J., Hoekstra, J. N., Leventhal, O., Leppä, V. M., Gandal, M. J., Paskov, K., Stockham, N., Polioudakis, D., Lowe, J. K., Prober, D. A., Geschwind, D. H., & Wall, D. P.
- Affiliations
- University of California, Los Angeles (US)
- Stanford Medicine (US)
- California Institute of Technology (US)
- Corresponding author
- Geschwind, Daniel H.
- Wall, Dennis P.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 178
- Issue
- 4
- Pages
- 850-866.e26
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7102900
- OpenAlex
- W2969167159
- Cited by
- 457
- References
- 115
- Citations by year
- 2026: 40 · 2025: 41 · 2024: 67 · 2023: 69 · 2022: 90 · 2021: 83 · 2020: 61 · 2019: 5 · 2018: 1
- FWCI
- 35.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Hartwell Foundation
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- autism spectrum disorder, de novo mutations, ASD risk genes, multiplex families, protein-protein interaction network, structural variants, promoter deletion, DLG2, mineralocorticoid receptor, corticosteroid receptors, cytoskeletal organization, ion transport, whole genome sequencing
- MeSH terms
- Autism Spectrum Disorder, Machine Learning, Whole Genome Sequencing, Animals, Child, Disease Models, Animal, Female, Humans, Male, Nuclear Family, Pedigree, Promoter Regions, Genetic, Risk Factors, Zebrafish, Gene Deletion, Receptors, Mineralocorticoid, Genetic Predisposition to Disease, Tumor Suppressor Proteins, Databases, Genetic, Inheritance Patterns, Guanylate Kinases, Protein Interaction Maps
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