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Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility.
Sazonovs, Aleksejs; Stevens, Christine R; Venkataraman, Guhan R; Yuan, Kai; Avila, Brandon; Abreu, Maria T; Ahmad, Tariq; Allez, Matthieu; Ananthakrishnan, Ashwin N; Atzmon, Gil; Baras, Aris; Barrett, Jeffrey C; Barzilai, Nir; Beaugerie, Laurent; Beecham, Ashley; Bernstein, Charles N; Bitton, Alain; Bokemeyer, Bernd; Chan, Andrew; Chung, Daniel; Cleynen, Isabelle; Cosnes, Jacques; Cutler, David J; Daly, Allan; Damas, Oriana M; Datta, Lisa W; Dawany, Noor; Devoto, Marcella; Dodge, Sheila; Ellinghaus, Eva; Fachal, Laura; Farkkila, Martti; Faubion, William; Ferreira, Manuel; Franchimont, Denis; Gabriel, Stacey B; Ge, Tian; Georges, Michel; Gettler, Kyle; Giri, Mamta; Glaser, Benjamin; Goerg, Siegfried; Goyette, Philippe; Graham, Daniel; Hämäläinen, Eija; Haritunians, Talin; Heap, Graham A; Hiltunen, Mikko; Hoeppner, Marc; Horowitz, Julie E.
Afiliação
  • Sazonovs A; Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Stevens CR; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Venkataraman GR; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Yuan K; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Avila B; Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
  • Abreu MT; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ahmad T; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Allez M; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ananthakrishnan AN; Crohn's and Colitis Center, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
  • Atzmon G; Royal Devon and Exeter Hospital, Exeter, UK.
  • Baras A; Hopital Saint-Louis, APHP, Universite de Paris, INSERM U1160, Paris, France.
  • Barrett JC; Division of Gastroenterology, Crohn's and Colitis Center, Massachusetts General Hospital, Boston, MA, USA.
  • Barzilai N; Department for Human Biology, University of Haifa, Haifa, Israel.
  • Beaugerie L; Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Beecham A; Regeneron Genetics Center, Tarrytown, NY, USA.
  • Bernstein CN; Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Bitton A; Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Bokemeyer B; The Institute for Aging Research, The Nathan Shock Center of Excellence in the Basic Biology of Aging and the Paul F. Glenn Center for the Biology of Human Aging Research at Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA.
  • Chan A; Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France.
  • Chung D; John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
  • Cleynen I; The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
  • Cosnes J; University of Manitoba, Winnipeg, Manitoba, Canada.
  • Cutler DJ; McGill University and McGill University Health Centre, Montreal, Quebec, Canada.
  • Daly A; Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany.
  • Damas OM; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Datta LW; Channing Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital, Boston, MA, USA.
  • Dawany N; Massachusetts General Hospital, Boston, MA, USA.
  • Devoto M; Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • Dodge S; Professeur Chef de Service chez APHP and Universite Paris-6, Paris, France.
  • Ellinghaus E; Department of Human Genetics, Emory University, Atlanta, GA, USA.
  • Fachal L; Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.
  • Farkkila M; Human Genetics Informatics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Faubion W; University of Miami, Miami, FL, USA.
  • Ferreira M; Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Franchimont D; Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
  • Gabriel SB; Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
  • Ge T; University of Rome Sapienza, Rome, Italy.
  • Georges M; IRGB - CNR, Cagliari, Italy.
  • Gettler K; Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
  • Giri M; Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Glaser B; Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
  • Goerg S; Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • Goyette P; Helsinki University Central Hospital, Helsinki, Finland.
  • Graham D; Mayo Clinic, Rochester, Rochester, MN, USA.
  • Hämäläinen E; Regeneron Genetics Center, Tarrytown, NY, USA.
  • Haritunians T; Erasme Hospital, ULB, Brussels, Belgium.
  • Heap GA; Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Hiltunen M; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Hoeppner M; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Horowitz JE; Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Nat Genet ; 54(9): 1275-1283, 2022 09.
Article em En | MEDLINE | ID: mdl-36038634
Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article