| Title: |
Synaptic, transcriptional and chromatin genes disrupted in autism |
| Authors: |
De Rubeis, Silvia; He, Xin; Goldberg, Arthur P; Poultney, Christopher S; Samocha, Kaitlin; Ercument Cicek, A; Kou, Yan; Liu, Li; Fromer, Menachem; Walker, Susan; Singh, Tarjinder; Klei, Lambertus; Kosmicki, Jack; Fu, Shih-Chen; Aleksic, Branko; Biscaldi, Monica; Bolton, Patrick F; Brownfeld, Jessica M; Cai, Jinlu; Campbell, Nicholas G; Carracedo, Angel; Chahrour, Maria H; Chiocchetti, Andreas G; Coon, Hilary; Crawford, Emily L; Crooks, Lucy; Curran, Sarah R; Dawson, Geraldine; Duketis, Eftichia; Fernandez, Bridget A; Gallagher, Louise; Geller, Evan; Guter, Stephen J; Sean Hill, R; Ionita-Laza, Iuliana; Jimenez Gonzalez, Patricia; Kilpinen, Helena; Klauck, Sabine M; Kolevzon, Alexander; Lee, Irene; Lei, Jing; Lehtimäki, Terho; Lin, Chiao-Feng; Ma’ayan, Avi; Marshall, Christian R; McInnes, Alison L; Neale, Benjamin; Owen, Michael J; Ozaki, Norio; Parellada, Mara; Parr, Jeremy R; Purcell, Shaun; Puura, Kaija; Rajagopalan, Deepthi; Rehnström, Karola; Reichenberg, Abraham; Sabo, Aniko; Sachse, Michael; Sanders, Stephan J; Schafer, Chad; Schulte-Rüther, Martin; Skuse, David; Stevens, Christine; Szatmari, Peter; Tammimies, Kristiina; Valladares, Otto; Voran, Annette; Wang, Li-San; Weiss, Lauren A; Jeremy Willsey, A; Yu, Timothy W; Yuen, Ryan KC; Cook, Edwin H; Freitag, Christine M; Gill, Michael; Hultman, Christina M; Lehner, Thomas; Palotie, Aarno; Schellenberg, Gerard D; Sklar, Pamela; State, Matthew W; Sutcliffe, James S; Walsh, Christopher A; Scherer, Stephen W; Zwick, Michael E; Barrett, Jeffrey C; Cutler, David J; Roeder, Kathryn; Devlin, Bernie; Daly, Mark J; Buxbaum, Joseph D; Eapen, Valsamma |
| Source: |
urn:ISSN:0028-0836 ; urn:ISSN:1476-4687 ; Nature, 515, 7526, 209-215 |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2014 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
31 Biological Sciences; 3102 Bioinformatics and Computational Biology; 32 Biomedical and Clinical Sciences; 3105 Genetics; Genetics; Brain Disorders; Intellectual and Developmental Disabilities (IDD); Pediatric; Mental Health; Human Genome; Autism; Neurosciences; 1.1 Normal biological development and functioning; 2.1 Biological and endogenous factors; Amino Acid Sequence; Child Development Disorders; Pervasive; Chromatin; Chromatin Assembly and Disassembly; Exome; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Male; Molecular Sequence Data; Mutation; Missense; Nerve Net; Odds Ratio |
| Description: |
The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability–transcription coupling, as well as histone-modifying enzymes and chromatin remodellers—most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_43745; https://doi.org/10.1038/nature13772 |
| DOI: |
10.1038/nature13772 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_43745; https://unsworks.unsw.edu.au/bitstreams/9f50d6eb-470c-4712-a120-d771d31336c5/download; https://doi.org/10.1038/nature13772 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC-BY-NC-ND ; https://creativecommons.org/licenses/by-nc-nd/4.0/ ; free_to_read |
| Accession Number: |
edsbas.30F4413C |
| Database: |
BASE |