Your browser doesn't support javascript.
loading
Rare coding variation provides insight into the genetic architecture and phenotypic context of autism.
Fu, Jack M; Satterstrom, F Kyle; Peng, Minshi; Brand, Harrison; Collins, Ryan L; Dong, Shan; Wamsley, Brie; Klei, Lambertus; Wang, Lily; Hao, Stephanie P; Stevens, Christine R; Cusick, Caroline; Babadi, Mehrtash; Banks, Eric; Collins, Brett; Dodge, Sheila; Gabriel, Stacey B; Gauthier, Laura; Lee, Samuel K; Liang, Lindsay; Ljungdahl, Alicia; Mahjani, Behrang; Sloofman, Laura; Smirnov, Andrey N; Barbosa, Mafalda; Betancur, Catalina; Brusco, Alfredo; Chung, Brian H Y; Cook, Edwin H; Cuccaro, Michael L; Domenici, Enrico; Ferrero, Giovanni Battista; Gargus, J Jay; Herman, Gail E; Hertz-Picciotto, Irva; Maciel, Patricia; Manoach, Dara S; Passos-Bueno, Maria Rita; Persico, Antonio M; Renieri, Alessandra; Sutcliffe, James S; Tassone, Flora; Trabetti, Elisabetta; Campos, Gabriele; Cardaropoli, Simona; Carli, Diana; Chan, Marcus C Y; Fallerini, Chiara; Giorgio, Elisa; Girardi, Ana Cristina.
Affiliation
  • Fu JM; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Satterstrom FK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Peng M; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Brand H; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Collins RL; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Dong S; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Wamsley B; Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA.
  • Klei L; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Wang L; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Hao SP; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Stevens CR; Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Cusick C; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Babadi M; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Banks E; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Collins B; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
  • Dodge S; Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
  • Gabriel SB; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
  • Gauthier L; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Lee SK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Liang L; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
  • Ljungdahl A; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Mahjani B; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Sloofman L; Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Smirnov AN; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Barbosa M; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Betancur C; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Brusco A; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Chung BHY; Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Cook EH; Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Cuccaro ML; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Domenici E; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Ferrero GB; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Gargus JJ; Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Herman GE; Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Hertz-Picciotto I; Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Maciel P; Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Manoach DS; Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
  • Passos-Bueno MR; Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
  • Persico AM; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Renieri A; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Sutcliffe JS; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Tassone F; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Trabetti E; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Campos G; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Cardaropoli S; Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Carli D; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Chan MCY; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Fallerini C; Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, Paris, France.
  • Giorgio E; Department of Medical Sciences, University of Torino, Turin, Italy.
  • Girardi AC; Medical Genetics Unit, 'Città della Salute e della Scienza' University Hospital, Turin, Italy.
Nat Genet ; 54(9): 1320-1331, 2022 09.
Article in En | MEDLINE | ID: mdl-35982160
ABSTRACT
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.
Subject(s)
Fulltext
Add to My VHL
Print
XML
PubMed Links
Search on Google

Full text: 1 Database: MEDLINE Main subject: Autistic Disorder / Autism Spectrum Disorder Type of study: Etiology_studies / Systematic_reviews Limits: Humans Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2022 Type: Article Affiliation country: United States
Fulltext
Add to My VHL
Print
XML
PubMed Links
Search on Google

Full text: 1 Database: MEDLINE Main subject: Autistic Disorder / Autism Spectrum Disorder Type of study: Etiology_studies / Systematic_reviews Limits: Humans Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2022 Type: Article Affiliation country: United States