Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients

• Type of Material: Article
• Authors: Yiming Wu, Icahn School of Medicine at Mount Sinai; Kyle Gettler, Yale University; Meltem Ece Kars, Icahn School of Medicine at Mount Sinai; Mmata Giri, Icahn School of Medicine at Mount Sinai; Dalin Li, Cedars-Sinai Medical Center; Cigdem Sevim Bayrak, Icahn School of Medicine at Mount Sinai; Peng Zhang, 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 Van 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), London; Elena R Schiff, University College London (UCL), London; Anthony W Segal, University College London (UCL), London; Subramaniam Kugathasan, Emory University; Peter D Stenson, Cardiff University; David N Cooper, Cardiff University; Philip L Schumm, University of Chicago; Scott Snapper, Boston Childrens Hosp; Mark J Daly, University of Helsinki; Talin Haritunians, Cedars-Sinai Medical Center, Los Angeles; Richard H Duerr, University of Pittsburgh; Mark S Silverberg, Mount Sinai Hospital, Toronto; John D Rioux, Montreal Heart Inst; Steven R Brant, Rutgers Robert Wood Johnson Med Sch; Dermot PB McGovern, Cedars-Sinai Medical Center, Los Angeles; Judy H Cho, Icahn School of Medicine at Mount Sinai; Yuvak Itan, Icahn School of Medicine at Mount Sinai
• Language: English
• Date: 2023-04-20
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-023-37849-3
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 14
• Issue: 1
• Start Page: 2256
• End Page: 2256
• Keywords: EXPRESSION; ASSOCIATION; SUSCEPTIBILITY; CROHNS-DISEASE; INFERENCE; Science & Technology - Other Topics; POWERFUL; Science & Technology; Multidisciplinary Sciences; POPULATION-STRUCTURE; RISK; METAANALYSIS; GENOME
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery

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.