Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries

Zhanju Liu; Ruize Liu; Han Gao; Seulgi Jung; Xiang Gao; Ruicong Sun; Xiaoming Liu; Yongjae Kim; Ho-Su Lee; Yosuke Kawai; Masao Nagasaki; Junji Umeno; Katsushi Tokunaga; Yoshitaka Kinouchi; Atsushi Masamune; Wenzhao Shi; Chengguo Shen; Zhenglin Guo; Kai Yuan; FinnGen; International Inflammatory Bowel Disease Genetics Consortium; Chinese Inflammatory Bowel Disease Genetics Consortium; Shu Zhu; Dalin Li; Jianjun Liu; Tian Ge; Judy Cho; Mark J Daly; Dermot P B McGovern; Byong Duk Ye; Kyuyoung Song; Yoichi Kakuta; Mingsong Li; Hailiang Huang

doi:10.1038/s41588-023-01384-0

Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries

Nat Genet. 2023 May;55(5):796-806. doi: 10.1038/s41588-023-01384-0. Epub 2023 May 8.

Authors

Zhanju Liu^#¹, Ruize Liu^#^{2

3}, Han Gao^#⁴, Seulgi Jung⁵, Xiang Gao⁴, Ruicong Sun⁴, Xiaoming Liu⁶, Yongjae Kim⁵, Ho-Su Lee⁵, Yosuke Kawai⁷, Masao Nagasaki^{8

9}, Junji Umeno¹⁰, Katsushi Tokunaga⁷, Yoshitaka Kinouchi¹¹, Atsushi Masamune¹², Wenzhao Shi¹³, Chengguo Shen¹³, Zhenglin Guo³, Kai Yuan^{2

3}; FinnGen; International Inflammatory Bowel Disease Genetics Consortium; Chinese Inflammatory Bowel Disease Genetics Consortium; Shu Zhu¹⁴, Dalin Li¹⁵, Jianjun Liu^{16

17}, Tian Ge^{18

19

20}, Judy Cho²¹, Mark J Daly^{2

22

23}, Dermot P B McGovern¹⁵, Byong Duk Ye²⁴, Kyuyoung Song²⁵, Yoichi Kakuta²⁶, Mingsong Li²⁷, Hailiang Huang^{28

29

30}

Collaborators

Maria Abreu, Jean-Paul Achkar, Vibeke Andersen, Charles Bernstein, Steven R Brant, Luis Bujanda, Siew Chien Ng, Lee A Denson, Richard H Duerr, Lynnette R Ferguson, Denis Franchimont, Andre Franke, Richard Gearry, Hakon Hakonarson, Jonas Halfvarson, Caren Heller, Antonio Julià, Judith Kelsen, Hamed Khalili, Subramaniam Kugathasan, Juozas Kupcinskas, Anna Latiano, Edouard Louis, Reza Malekzadeh, Jacob L McCauley, Christopher Moran, David Okou, Tim Orchard, Aarno Palotie, Miles Parkes, Joel Pekow, Uroš Potočnik, Graham Radford-Smith, John D Rioux, Gerhard Rogler, Bruce Sands, Mark Silverberg, Harry Sokol, Séverine Vermeire, Rinse K Weersma, Ramnik J Xavier, Naizhong Hu, Qian Cao, Yufang Wang, Yinglei Miao, Hongjie Zhang, Xiaoping Lv, Xiang Gao, Hu Zhang, Jingling Su, Baisui Feng, Ye Zhao, Liangru Zhu, Yan Chen, Lanxiang Zhu, Chunxiao Chen, Yali Wang, Yingde Wang, Zhi Pang, Yingxuan Chen, Xiaolan Zhang, Hui Li, Qin Yu, Mei Ye, Sumin Zhang, Wen Tang, Mei Wang, Xiaocang Cao, Ruixin Zhu, Guangxi Zhou, Zhaolian Bian, Xiaofeng Guo, Xiaoli Wu, Jinchun Liu, Wei Xu, Yuqin Li, Qin Guo, Zhiguo Guo

Affiliations

¹ Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. zhanjuliu@tongji.edu.cn.
² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
⁵ Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
⁶ Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁷ Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan.
⁸ Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan.
⁹ Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁰ Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
¹¹ Student Healthcare Center, Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan.
¹² Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
¹³ Digital Health China Technologies Corp Ltd., Beijing, China.
¹⁴ Institute of Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
¹⁵ Widjaja Inflammatory Bowel Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁶ Genome Institute of Singapore, Singapore, Singapore.
¹⁷ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹⁸ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁰ Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
²¹ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²² Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
²³ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁴ Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
²⁵ Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea. kysong@amc.seoul.kr.
²⁶ Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. ykakuta@med.tohoku.ac.jp.
²⁷ Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. lims661216@163.com.
²⁸ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. hhuang@broadinstitute.org.
²⁹ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. hhuang@broadinstitute.org.
³⁰ Department of Medicine, Harvard Medical School, Boston, MA, USA. hhuang@broadinstitute.org.

^# Contributed equally.

Abstract

Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2. Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency (NOD2) and effect (TNFSF15). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Colitis, Ulcerative* / genetics
Crohn Disease* / genetics
East Asian People
European People
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Inflammatory Bowel Diseases* / genetics
Polymorphism, Single Nucleotide / genetics
Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics

Substances

ADAP1 protein, human
GIT2 protein, human
NOD2 protein, human
TNFSF15 protein, human
Tumor Necrosis Factor Ligand Superfamily Member 15

Abstract

Publication types

MeSH terms

Substances

Grants and funding