Advancing the understanding of autism disease mechanisms through genetics
Open accessAbstract
Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.
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Genetic syndromes are rare in ASD (found in 5% of the total ASD population), but many syndromic forms of ASD share a hypermobile phenotype (e.g., Fragile X syndrome).
“Whilst genetic syndromes are rare in ASD (only found in 5% of the total ASD population (35), many syndromic forms of ASD share a hypermobile phenotype (e.g., Fragile X syndrome) (14, 36).”
From The Relationship Between Generalised Joint Hypermobility and Autism Spectrum Disorder in Adults: A Large, Cross-Sectional, Case Control Comparison (2022) · cites this paper as [35]
Cortical abnormalities are a prominent feature of autism spectrum disorder.
“Cortical abnormalities are a prominent feature of ASD8,20.”
From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [8]
Developmental stages 5 and 6 represent mid-gestation, when upper layer neurons are generated and neuronal differentiation including axonogenesis and dendritic arborization occurs.
“Developmental stages 5 and 6 represent mid-gestation, the period during which upper layer neurons are generated and neuronal differentiation including axonogenesis and dendritic arborization takes place12,13.”
From A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles (2020) · cites this paper as [13]
Fetus-linked genes were highly expressed in adult neurons, whereas adult-linked ones were preferentially expressed in glia.
“They were also highly expressed in adult neurons, whereas the adult-linked ones were preferentially expressed in glia, reflecting known cell-type composition (Fig. 5, D and F) (42).”
From Comprehensive functional genomic resource and integrative model for the human brain (2018) · cites this paper as [42]
Most known pathogenic copy number variants increase risk for multiple disorders.
“Most known pathogenic CNVs increase risk for multiple disorders (de la Torre-Ubieta et al., 2016; Kirov, 2015; Lowther et al., 2017; Malhotra and Sebat, 2012).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as de la Torre-Ubieta et al., 2016
The genetic contributions to ASD are highly heterogeneous but may converge on common pathways that are not yet well understood.
“These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood1–3.”
From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [3]
Autism spectrum disorder has a substantial genetic component.
“Autism spectrum disorder (ASD) involves substantial genetic contributions.”
From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [3]
The observed transcriptome changes are consistent with an ongoing process triggered largely by genetic and prenatal factors but evolving during the first decade of brain development.
“In this regard, it is notable that the observed transcriptome changes are consistent with an ongoing process that is triggered largely by genetic and prenatal factors3,9,10,23, but that evolves during the first decade of brain development.”
From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [3]
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Inherited risk for autism through maternal and paternal lineage
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A phenotype of childhood autism is associated with preexisting maternal anxiety and depression
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- Authors
- de la Torre-Ubieta, L., Won, H., Stein, J. L., & Geschwind, D. H.
- Affiliations
- University of California, Los Angeles (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Geschwind, Daniel H
- Venue
- Nature Medicine
- Published
- 2016-04
- Volume
- 22
- Issue
- 4
- Pages
- 345-361
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5072455
- OpenAlex
- W2316811866
- Cited by
- 827
- References
- 305
- Citations by year
- 2026: 35 · 2025: 61 · 2024: 61 · 2023: 80 · 2022: 86 · 2021: 110 · 2020: 98 · 2019: 102 · 2018: 86 · 2017: 79 · 2016: 26
- FWCI
- 10.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- UNC Libraries
- Funders
- California Institute for Regenerative Medicine (TG2-01169)
- National Institutes of Health (TG2-01169, 5r01mh094714-04, MH060233)
- National Institute of Mental Health (K99MH102357, 5R01MH094714, R01-MH094714, R00MH102357, R37MH060233)
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Keywords
- autism spectrum disorder, genetic etiology, genetic architecture, neurobiological mechanisms, ASD pathophysiology, neuropathology, animal models of autism, causal heterogeneity, targeted therapy
- MeSH terms
- Autism Spectrum Disorder, Animals, Child Development Disorders, Pervasive, Disease Models, Animal, Humans, Genetic Predisposition to Disease, Molecular Targeted Therapy
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