title: De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.
abstract: We analyze de novo synonymous mutations identified in autism spectrum disorders (ASDs) and schizophrenia (SCZ) with potential impact on regulatory elements using data from whole-exome sequencing (WESs) studies. Focusing on five types of genetic regulatory functions, we found that de novo near-splice site synonymous mutations changing exonic splicing regulators and those within frontal cortex-derived DNase I hypersensitivity sites are significantly enriched in ASD and SCZ, respectively. These results remained significant, albeit less so, after incorporating two additional ASD datasets. Among the genes identified, several are hit by multiple functional de novo mutations, with RAB2A and SETD1A showing the highest statistical significance in ASD and SCZ, respectively. The estimated contribution of these synonymous mutations to disease liability is comparable to de novo protein-truncating mutations. These findings expand the repertoire of functional de novo mutations to include "functional" synonymous ones and strengthen the role of rare variants in neuropsychiatric disease risk.
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takata
authors.affiliation: Department of Biostatistics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Iuliana
authors.initials: I
authors.lastname: Ionita-Laza
authors.affiliation: Department of Neuroscience, Columbia University Medical Center, New York, NY 10032, USA; Department of Physiology & Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: bx2105@cumc.columbia.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY 10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA. Electronic address: mk2758@cumc.columbia.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D016208:Databases, Factual / Q000706:statistics & numerical data; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D000069550:Machine Learning; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA; D020693:rab2 GTP-Binding Protein / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human; D020693:rab2 GTP-Binding Protein