Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
In: ISSN: 1061-4036, 2022
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International audience ; Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.
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Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
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| Autor/in / Beteiligte Person: | Fu, Jack ; Satterstrom, F. Kyle ; Peng, Minshi ; Brand, Harrison ; Collins, Ryan ; Dong, Shan ; Wamsley, Brie ; Klei, Lambertus ; Wang, Lily ; Hao, Stephanie ; Stevens, Christine ; Cusick, Caroline ; Babadi, Mehrtash ; Banks, Eric ; Collins, Brett ; Dodge, Sheila ; Gabriel, Stacey ; Gauthier, Laura ; Lee, Samuel ; Liang, Lindsay ; Ljungdahl, Alicia ; Mahjani, Behrang ; Sloofman, Laura ; Smirnov, Andrey ; Barbosa, Mafalda ; Betancur, Catalina ; Brusco, Alfredo ; Chung, Brian ; Cook, Edwin ; Cuccaro, Michael ; Domenici, Enrico ; Ferrero, Giovanni Battista ; Gargus, J. Jay ; Herman, Gail ; Hertz-Picciotto, Irva ; Maciel, Patricia ; Manoach, Dara ; Passos-Bueno, Maria Rita ; Persico, Antonio ; Renieri, Alessandra ; Sutcliffe, James ; Tassone, Flora ; Trabetti, Elisabetta ; Campos, Gabriele ; Cardaropoli, Simona ; Carli, Diana ; Chan, Marcus ; Fallerini, Chiara ; Giorgio, Elisa ; Girardi, Ana Cristina ; Hansen-Kiss, Emily ; Lee, So Lun ; Lintas, Carla ; Ludena, Yunin ; Nguyen, Rachel ; Pavinato, Lisa ; Pericak-Vance, Margaret ; Pessah, Isaac ; Schmidt, Rebecca ; Smith, Moyra ; Costa, Claudia ; Trajkova, Slavica ; Wang, Jaqueline ; Yu, Mullin ; Cutler, David ; de Rubeis, Silvia ; Buxbaum, Joseph ; Daly, Mark ; Devlin, Bernie ; Roeder, Kathryn ; Sanders, Stephan ; Talkowski, Michael ; Massachusetts General Hospital Boston ; Broad Institute of MIT and Harvard (BROAD INSTITUTE) ; Harvard Medical School Boston (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital Boston ; Carnegie Mellon University Pittsburgh (CMU) ; Harvard Medical School Boston (HMS) ; University of California San Francisco (UC San Francisco) ; University of California (UC) ; University of California Los Angeles (UCLA) ; University of Pittsburgh School of Medicine ; Pennsylvania Commonwealth System of Higher Education (PCSHE) ; Icahn School of Medicine at Mount Sinai New York (MSSM) ; Neuroscience Paris Seine (NPS) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) ; Università degli studi di Torino = University of Turin (UNITO) ; Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino ; The University of Hong Kong (HKU) ; University of Illinois Chicago (UIC) ; University of Illinois System ; University of Miami Leonard M. Miller School of Medicine (UMMSM) ; Università degli Studi di Trento = University of Trento (UNITN) ; University of California Irvine (UC Irvine) ; Nationwide Children's Hospital ; University of California Davis (UC Davis) ; Universidade do Minho = University of Minho Braga ; Massachusetts General Hospital Boston, MA, USA ; Escola Politecnica da Universidade de Sao Paulo Sao Paulo ; Università degli Studi di Messina = University of Messina (UniMe) ; Università degli Studi di Siena = University of Siena (UNISI) ; Azienda Ospedaliera Universitaria Senese ; Vanderbilt University Nashville ; Vanderbilt University School of Medicine Nashville ; Università degli studi di Verona = University of Verona (UNIVR) ; University of Texas Health Science Center ; The University of Texas Health Science Center at Houston (UTHealth) ; Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM) ; Emory University School of Medicine ; Emory University Atlanta, GA ; Helsingin yliopisto = Helsingfors universitet = University of Helsinki ; Autism Sequencing Consortium (ASC) ; Broad Institute Center for Common Disease Genomics (Broad-CCDG) ; iPSYCH-BROAD Consortium : Branko Aleksic, Mykyta Artomov, Elisa Benetti, Monica Biscaldi-Schafer, Anders D Børglum, Angel Carracedo, Andreas G Chiocchetti, Hilary Coon, Ryan N Doan, Montserrat Fernández-Prieto, Christine M Freitag, Sherif Gerges, Stephen Guter, David M Hougaard, Christina M Hultman, Suma Jacob, Miia Kaartinen, Alexander Kolevzon, Itaru Kushima, Terho Lehtimäki, Caterina Lo Rizzo, Nell Maltman, Marianna Manara, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Matthew Mosconi, Norio Ozaki, Aarno Palotie, Mara Parellada, Kaija Puura, Abraham Reichenberg, Sven Sandin, Stephen W Scherer, Sabine Schlitt, Lauren Schmitt, Katja Schneider-Momm, Paige M Siper, Pål Suren, John A Sweeney, Karoline Teufel, Maria Del Pilar Trelles, Lauren A Weiss, Ryan Yuen. |
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| Zeitschrift: | ISSN: 1061-4036, 2022 |
| Veröffentlichung: | HAL CCSD ; Nature Publishing Group, 2022 |
| Medientyp: | academicJournal |
| DOI: | 10.1038/s41588-022-01104-0 |
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