Rare coding variation provides insight into the genetic architecture and phenotypic context of autism.

Autor:	Fu JM; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Satterstrom FK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Peng M; Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA., Brand H; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA., Collins RL; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA., Dong S; Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA., Wamsley B; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Klei L; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Wang L; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA., Hao SP; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA., Stevens CR; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Cusick C; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Babadi M; Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Banks E; Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Collins B; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Dodge S; Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Gabriel SB; Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Gauthier L; Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Lee SK; Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Liang L; Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA., Ljungdahl A; Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA., Mahjani B; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Sloofman L; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Smirnov AN; Data Sciences Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA., Barbosa M; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Betancur C; Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, Paris, France., Brusco A; Department of Medical Sciences, University of Torino, Turin, Italy.; Medical Genetics Unit, 'Città della Salute e della Scienza' University Hospital, Turin, Italy., Chung BHY; Department of Pediatrics and Adolescent Medicine, Duchess of Kent Children's Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China., Cook EH; Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA., Cuccaro ML; The John P Hussman Institute for Human Genomics, The University of Miami Miller School of Medicine, Miami, FL, USA., Domenici E; Department of Cellular, Computational and Integrative Biology, , University of Trento, Trento, Italy., Ferrero GB; Department of Public Health and Pediatrics, University of Torino, Turin, Italy., Gargus JJ; Center for Autism Research and Translation, University of California Irvine, Irvine, CA, USA., Herman GE; The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Hertz-Picciotto I; MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, Davis, CA, USA., Maciel P; Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal., Manoach DS; Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Passos-Bueno MR; Centro de Pesquisas sobre o Genoma Humano e Células tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Persico AM; Interdepartmental Program 'Autism 0-90', 'Gaetano Martino' University Hospital, University of Messina, Messina, Italy., Renieri A; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy.; Medical Genetics, , University of Siena, Siena, Italy.; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy., Sutcliffe JS; Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.; Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA., Tassone F; MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, Davis, CA, USA.; Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, Sacramento, CA, USA., Trabetti E; Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biology and Genetics, University of Verona, Verona, Italy., Campos G; Centro de Pesquisas sobre o Genoma Humano e Células tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Cardaropoli S; Department of Public Health and Pediatrics, University of Torino, Turin, Italy., Carli D; Department of Public Health and Pediatrics, University of Torino, Turin, Italy., Chan MCY; Department of Pediatrics and Adolescent Medicine, Duchess of Kent Children's Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China., Fallerini C; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy.; Medical Genetics, , University of Siena, Siena, Italy., Giorgio E; Department of Medical Sciences, University of Torino, Turin, Italy., Girardi AC; Centro de Pesquisas sobre o Genoma Humano e Células tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Hansen-Kiss E; Department of Diagnostic and Biomedical Sciences, University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, USA., Lee SL; Department of Pediatrics and Adolescent Medicine, Duchess of Kent Children's Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China., Lintas C; Service for Neurodevelopmental Disorders, University Campus Bio-medico of Rome, Rome, Italy., Ludena Y; MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, Davis, CA, USA., Nguyen R; Center for Autism Research and Translation, University of California Irvine, Irvine, CA, USA., Pavinato L; Department of Medical Sciences, University of Torino, Turin, Italy., Pericak-Vance M; The John P Hussman Institute for Human Genomics, The University of Miami Miller School of Medicine, Miami, FL, USA., Pessah IN; MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, Davis, CA, USA.; Department of Molecular Biosciences, University of California Davis, School of Veterinary Medicine, Davis, CA, USA., Schmidt RJ; MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, Davis, CA, USA., Smith M; Center for Autism Research and Translation, University of California Irvine, Irvine, CA, USA., Costa CIS; Centro de Pesquisas sobre o Genoma Humano e Células tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Trajkova S; Department of Medical Sciences, University of Torino, Turin, Italy., Wang JYT; Centro de Pesquisas sobre o Genoma Humano e Células tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil., Yu MHC; Department of Pediatrics and Adolescent Medicine, Duchess of Kent Children's Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China., Cutler DJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., De Rubeis S; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Buxbaum JD; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu., Daly MJ; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@atgu.mgh.harvard.edu.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. mjdaly@atgu.mgh.harvard.edu.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu.; Harvard Medical School, Boston, MA, USA. mjdaly@atgu.mgh.harvard.edu.; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. mjdaly@atgu.mgh.harvard.edu., Devlin B; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. devlinbj@upmc.edu., Roeder K; Department of Statistics and Data Science, Carnegie Mellon University, Pittsburgh, PA, USA. roeder@andrew.cmu.edu.; Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA. roeder@andrew.cmu.edu., Sanders SJ; Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. Stephan.Sanders@ucsf.edu., Talkowski ME; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. MTALKOWSKI@mgh.harvard.edu.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. MTALKOWSKI@mgh.harvard.edu.; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. MTALKOWSKI@mgh.harvard.edu.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. MTALKOWSKI@mgh.harvard.edu.; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA. MTALKOWSKI@mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Nature genetics [Nat Genet] 2022 Sep; Vol. 54 (9), pp. 1320-1331. Date of Electronic Publication: 2022 Aug 18.
DOI:	10.1038/s41588-022-01104-0
Abstrakt:	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. (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu Full text from SpringerLink