Rare structural variation of synapse and neurotransmission genes in autism.

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TitleRare structural variation of synapse and neurotransmission genes in autism.
Publication TypeJournal Article
Year of Publication2012
AuthorsGai, X, Xie, HM, Perin, JC, Takahashi, N, Murphy, K, Wenocur, AS, D'arcy, M, O'Hara, RJ, Goldmuntz, E, Grice, DE, Shaikh, TH, Hakonarson, H, Buxbaum, JD, Elia, J, White, PS
JournalMol Psychiatry
Date Published2012 Apr
KeywordsAdolescent, Adult, Animals, Case-Control Studies, Child, Child Development Disorders, Pervasive, Child, Preschool, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, Male, Mice, Nerve Tissue Proteins, Phenotype, Synapses, Synaptic Transmission

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.

Alternate JournalMol. Psychiatry
PubMed ID21358714
PubMed Central IDPMC3314176
Grant ListU24 MH081810 / MH / NIMH NIH HHS / United States
P30 HD026979 / HD / NICHD NIH HHS / United States
1U24MH081810 / MH / NIMH NIH HHS / United States
P30HD026979 / HD / NICHD NIH HHS / United States
GM081519 / GM / NIGMS NIH HHS / United States
R01 GM081519 / GM / NIGMS NIH HHS / United States
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