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Publication Information
Affiliation
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Genetics, Yale University, New Haven, CT, USA.; The Charles Bronfman Institute for Personalized Medicine, 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.; Translational Genomics Unit, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA.; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Immunology Institute, Graduate School, 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.; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pathology, Albert Einstein College of Medicine, New York, NY, USA.; Division of Medicine, University College London (UCL), London, UK.; Division of Medicine, University College London (UCL), London, UK.; Division of Medicine, University College London (UCL), London, UK.; Department of Pediatrics, Emory University, Atlanta, GA, USA.; Institute of Medical Genetics, Cardiff University, Cardiff, UK.; Institute of Medical Genetics, Cardiff University, Cardiff, UK.; Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.; Division of Gastroenterology, Hepatology and Nutrition, Oncology Boston Children's Hospital, Boston, MA, USA.; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.; Translational Genomics Unit, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada.; Research Center, Montreal Heart Institute, Montréal, Québec, Canada.; Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.; Translational Genomics Unit, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. yuval.itan@mssm.edu.
Authors
Wu Yiming, Gettler Kyle, Kars Meltem Ece, Giri Mamta, Li Dalin, Bayrak Cigdem Sevim, Zhang Peng, Jain Aayushee, Maffucci Patrick, Sabic Ksenija, Van Vleck Tielman, Nadkarni Girish, Denson Lee A., Ostrer Harry, Levine Adam P., Schiff Elena R., Segal Anthony W., Kugathasan Subra, Stenson Peter D., Cooper David N., Philip Schumm L., Snapper Scott, Daly Mark J., Haritunians Talin, Duerr Richard H., Silverberg Mark S., Rioux John D., Brant Steven R., McGovern Dermot P. B., Cho Judy H., Itan Yuval
Studies
Abstract
Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.