Rare structural variation of synapse and neurotransmission genes in autism
Open accessAbstract
Autism spectrum disorders (ASDs) comprise a constellation of highly heritable neuropsychiatric disorders. Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but few common variants, suggesting a complex genetic model with many contributing loci. To assess commonality of biological function among rare risk alleles, we compared functional knowledge of genes overlapping inherited structural variants in idiopathic ASD subjects relative to healthy controls. In this study we show that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls. Analysis of phenotypes observed for mouse models of copy-variant genes established significant and replicated enrichment of observable phenotypes consistent with ASD behaviors. Most functional terms retained significance after excluding previously reported ASD loci. These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of ASD pathophysiology and suggest a sizable pool of additional potential ASD risk loci.
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Enrichment of synaptic functioning has also been reported among inherited events in the AGRE families and among de novo events in the Simons Simplex Collection.
“Enrichment of synaptic functioning has also been reported among inherited events in the AGRE families47 and among de novo events in the Simons Simplex Collection.36”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [47]
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- Authors
- Gai, X., Xie, H. M., Perin, J. C., Takahashi, N., Murphy, K., Wenocur, A. S., D'arcy, M., O'Hara, R. J., Goldmuntz, E., Grice, D. E., Shaikh, T. H., Hakonarson, H., Buxbaum, J. D., Elia, J., & White, P. S.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Icahn School of Medicine at Mount Sinai (US)
- Columbia University (US)
- University of Colorado Anschutz (US)
- Corresponding author
- White, P S
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2011-03-01
- Volume
- 17
- Issue
- 4
- Pages
- 402-411
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3314176
- OpenAlex
- W1970741708
- Cited by
- 177
- References
- 46
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 8 · 2023: 8 · 2022: 13 · 2021: 5 · 2020: 10 · 2019: 8 · 2018: 11 · 2017: 14 · 2016: 18 · 2015: 17 · 2014: 16 · 2013: 14 · 2012: 17
- FWCI
- 9.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Autism Speaks
- Pennsylvania Department of Health (SAP 4100037707)
- Children's Hospital of Philadelphia
- National Institutes of Health (GM081519)
- National Institute of Mental Health (U24MH081810)
- National Institute of General Medical Sciences (R01GM081519, GM081519)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD026979)
- 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, structural variants, copy number variation, rare variants, synaptic function, neurotransmission, glutamatergic signaling, mouse model, functional enrichment
- MeSH terms
- Adolescent, Adult, Animals, Child, Child Development Disorders, Pervasive, Child, Preschool, Female, Humans, Male, Nerve Tissue Proteins, Synaptic Transmission, Phenotype, Synapses, Case-Control Studies, Genetic Predisposition to Disease, Mice, Genome-Wide Association Study, DNA Copy Number Variations, Genotyping Techniques
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