Nature Communications (Apr 2023)
Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients
- Yiming Wu,
- Kyle Gettler,
- Meltem Ece Kars,
- Mamta Giri,
- Dalin Li,
- Cigdem Sevim Bayrak,
- Peng Zhang,
- Aayushee Jain,
- Patrick Maffucci,
- Ksenija Sabic,
- Tielman Van Vleck,
- Girish Nadkarni,
- Lee A. Denson,
- Harry Ostrer,
- Adam P. Levine,
- Elena R. Schiff,
- Anthony W. Segal,
- Subra Kugathasan,
- Peter D. Stenson,
- David N. Cooper,
- L. Philip Schumm,
- Scott Snapper,
- Mark J. Daly,
- Talin Haritunians,
- Richard H. Duerr,
- Mark S. Silverberg,
- John D. Rioux,
- Steven R. Brant,
- Dermot P. B. McGovern,
- Judy H. Cho,
- Yuval Itan
Affiliations
- Yiming Wu
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Kyle Gettler
- Department of Genetics, Yale University
- Meltem Ece Kars
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Mamta Giri
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
- Dalin Li
- Translational Genomics Unit, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
- Cigdem Sevim Bayrak
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Peng Zhang
- St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University
- Aayushee Jain
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Patrick Maffucci
- Immunology Institute, Graduate School, Icahn School of Medicine at Mount Sinai
- Ksenija Sabic
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
- Tielman Van Vleck
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Girish Nadkarni
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Lee A. Denson
- Department of Pediatrics, Cincinnati Children’s Hospital Medical Center
- Harry Ostrer
- Department of Pathology, Albert Einstein College of Medicine
- Adam P. Levine
- Division of Medicine, University College London (UCL)
- Elena R. Schiff
- Division of Medicine, University College London (UCL)
- Anthony W. Segal
- Division of Medicine, University College London (UCL)
- Subra Kugathasan
- Department of Pediatrics, Emory University
- Peter D. Stenson
- Institute of Medical Genetics, Cardiff University
- David N. Cooper
- Institute of Medical Genetics, Cardiff University
- L. Philip Schumm
- Department of Public Health Sciences, University of Chicago
- Scott Snapper
- Division of Gastroenterology, Hepatology and Nutrition, Oncology Boston Children’s Hospital
- Mark J. Daly
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki
- Talin Haritunians
- Translational Genomics Unit, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
- Richard H. Duerr
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine
- Mark S. Silverberg
- Inflammatory Bowel Disease Centre, Mount Sinai Hospital
- John D. Rioux
- Research Center, Montreal Heart Institute
- Steven R. Brant
- Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School
- Dermot P. B. McGovern
- Translational Genomics Unit, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
- Judy H. Cho
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Yuval Itan
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- DOI
- https://doi.org/10.1038/s41467-023-37849-3
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 12
Abstract
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.
