title: Genotype to phenotype relationships in autism spectrum disorders.
abstract: Autism spectrum disorders (ASDs) are characterized by phenotypic and genetic heterogeneity. Our analysis of functional networks perturbed in ASD suggests that both truncating and nontruncating de novo mutations contribute to autism, with a bias against truncating mutations in early embryonic development. We find that functional mutations are preferentially observed in genes likely to be haploinsufficient. Multiple cell types and brain areas are affected, but the impact of ASD mutations appears to be strongest in cortical interneurons, pyramidal neurons and the medium spiny neurons of the striatum, implicating cortical and corticostriatal brain circuits. In females, truncating ASD mutations on average affect genes with 50-100% higher brain expression than in males. Our results also suggest that truncating de novo mutations play a smaller role in the etiology of high-functioning ASD cases. Overall, we find that stronger functional insults usually lead to more severe intellectual, social and behavioral ASD phenotypes.
authors.affiliation: 1] Department of Biomedical Informatics, Columbia University, New York, New York, USA. [2] Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chang
authors.affiliation: 1] Department of Biomedical Informatics, Columbia University, New York, New York, USA. [2] Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Gilman
authors.affiliation: 1] Department of Biomedical Informatics, Columbia University, New York, New York, USA. [2] Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Chiang
authors.affiliation: 1] Department of Psychiatry, University of California, San Francisco, California, USA. [2] Department of Psychiatry, Department of Genetics, Yale University, New Haven, Connecticut, USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: 1] Department of Biomedical Informatics, Columbia University, New York, New York, USA. [2] Department of Systems Biology, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Vitkup
mesh_terms: D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype