title: Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder.
abstract: A universal challenge in genetic studies of autism spectrum disorders (ASDs) is determining whether a given DNA sequence alteration will manifest as disease. Among different population controls, we observed, for specific exons, an inverse correlation between exon expression level in brain and burden of rare missense mutations. For genes that harbor de novo mutations predicted to be deleterious, we found that specific critical exons were significantly enriched in individuals with ASD relative to their siblings without ASD (P < 1.13 × 10(-38); odds ratio (OR) = 2.40). Furthermore, our analysis of genes with high exonic expression in brain and low burden of rare mutations demonstrated enrichment for known ASD-associated genes (P < 3.40 × 10(-11); OR = 6.08) and ASD-relevant fragile-X protein targets (P < 2.91 × 10(-157); OR = 9.52). Our results suggest that brain-expressed exons under purifying selection should be prioritized in genotype-phenotype studies for ASD and related neurodevelopmental conditions.
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Uddin
authors.affiliation: 1] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Center of Neurodevelopmental Disorders (KIND), Neuropsychiatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Tammimies
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pellecchia
authors.affiliation: Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Babak
authors.initials: B
authors.lastname: Alipanahi
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Zhuozhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 1] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Lynette
authors.initials: L
authors.lastname: Lau
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nalpathamkalam
authors.affiliation: 1] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: 1] Donnelly Centre, University of Toronto, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.affiliation: 1] Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada. [2] Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Frey
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ryan K C
authors.initials: RK
authors.lastname: Yuen
authors.affiliation: 1] The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada. [3] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002675:Child, Preschool; D005091:Exons / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger