Rare structural variation of synapse and neurotransmission genes in autism

• Published in: Molecular psychiatry Vol. 17; no. 4; pp. 402 - 411
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2012; Nature Publishing Group
• Subjects: Adolescent; Adult; Animals; Autism; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Case-Control Studies; Child; Child clinical studies; Child Development Disorders, Pervasive - genetics; Child, Preschool; Developmental disorders; DNA Copy Number Variations - genetics; Female; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic variation; Genome-Wide Association Study - methods; Genome-Wide Association Study - statistics & numerical data; Genotyping Techniques - methods; Genotyping Techniques - psychology; Health aspects; Humans; Infantile autism; Male; Medical sciences; Medicine; Medicine & Public Health; Mice; Nerve Tissue Proteins - genetics; Neural transmission; Neurosciences; Original; original-article; Pharmacotherapy; Phenotype; Physiological aspects; Psychiatry; Psychological aspects; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Synapses; Synapses - genetics; Synaptic Transmission - genetics; United States; structural variation; synaptic transmission; neurotransmission; glutamatergic signaling; autism; copy-number variation; Copy number; Developmental disorder; Genetic determinism; Autism; Signal transduction; Synapse; Gene; Synaptic transmission; Genetics; Neurotransmission; Polymorphism
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2011.10

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.