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 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 and Yuval Itan ()
Additional contact information
Yiming Wu: Icahn School of Medicine at Mount Sinai
Kyle Gettler: Yale University
Meltem Ece Kars: Icahn School of Medicine at Mount Sinai
Mamta Giri: Icahn School of Medicine at Mount Sinai
Dalin Li: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
Cigdem Sevim Bayrak: Icahn School of Medicine at Mount Sinai
Peng Zhang: The Rockefeller University
Aayushee Jain: Icahn School of Medicine at Mount Sinai
Patrick Maffucci: Icahn School of Medicine at Mount Sinai
Ksenija Sabic: Icahn School of Medicine at Mount Sinai
Tielman Vleck: Icahn School of Medicine at Mount Sinai
Girish Nadkarni: Icahn School of Medicine at Mount Sinai
Lee A. Denson: Cincinnati Children’s Hospital Medical Center
Harry Ostrer: Albert Einstein College of Medicine
Adam P. Levine: University College London (UCL)
Elena R. Schiff: University College London (UCL)
Anthony W. Segal: University College London (UCL)
Subra Kugathasan: Emory University
Peter D. Stenson: Cardiff University
David N. Cooper: Cardiff University
L. Philip Schumm: University of Chicago
Scott Snapper: Hepatology and Nutrition, Oncology Boston Children’s Hospital
Mark J. Daly: University of Helsinki
Talin Haritunians: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
Richard H. Duerr: University of Pittsburgh School of Medicine
Mark S. Silverberg: Mount Sinai Hospital
John D. Rioux: Research Center, Montreal Heart Institute
Steven R. Brant: Rutgers Robert Wood Johnson Medical School
Dermot P. B. McGovern: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
Judy H. Cho: Icahn School of Medicine at Mount Sinai
Yuval Itan: Icahn School of Medicine at Mount Sinai

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-37849-3

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