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

Nature Genetics volume 55, pages 796–806 (2023)Cite this article

Subjects

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.

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Fig. 1: Overview of the study design.
Fig. 2: IBD genetic associations.
Fig. 3: Comparative genetic architecture across EAS and EUR.
Fig. 4: Polygenic risk prediction on the Chinese samples.

Data availability

CaVEMaN and DAP-G GTEx v8 fine-mapping cis-eQTL data were retrieved from https://gtexportal.org/home/datasets#filesetFilesDiv15. 1000 Genomes Project Phase 3 is available from https://www.internationalgenome.org/category/phase-3/. TOPMed reference panel R2 is available from https://imputation.biodatacatalyst.nhlbi.nih.gov/#!. Human Genome Diversity Project is available from https://www.internationalgenome.org/data-portal/data-collection/hgdp. Simons Genome Diversity Project is available from https://www.simonsfoundation.org/simons-genome-diversity-project/. Korean Personal Genome Diversity Project is available from http://opengenome.net/Main_Page. NBDC human database (accession ID: JGAS000114) is available from https://humandbs.biosciencedbc.jp/en/. STRING functional protein association networks are available from https://string-db.org/. NFE summary statistics are from ftp://ftp.sanger.ac.uk/pub/project/humgen/summary_statistics/human/2016-11-07/. FIN summary statistics are from FinnGen R7, https://www.finngen.fi/en/access_results. PRS weights and genome-wide summary statistics for the meta-analyzed EAS samples and across all study samples (EAS and EUR) can be downloaded from https://www.ibdgenetics.org. Individual-level genotype data for EAS samples are available upon request: SHA1, Z.L. (zhanjuliu@tongji.edu.cn); KOR1, K.S. (kysong@amc.seoul.kr); JPN1, Y. Kakuta (ykakuta@med.tohoku.ac.jp) and ICH1, IIBDGC (ibdgc-dcc@mssm.edu). Access to individual-level genotypes from samples recruited within mainland China is subject to the policies and approvals from the Human Genetic Resource Administration, Ministry of Science and Technology of the People’s Republic of China.

Code availability

Computer code relating to this study includes:

RICOPILI v2019_Jun_25.001: https://sites.google.com/a/broadinstitute.org/ricopili

EIGENSTRAT v6.1.4: PCA, https://github.com/DReichLab/EIG/tree/master/EIGENSTRAT

bcftools v1.11: http://samtools.github.io/bcftools/bcftools.html

LDSC v1.0.1: https://github.com/bulik/ldsc

S-LDXR v0.3-beta: https://huwenboshi.github.io/s-ldxr

HRC-1000G-check-bim v4.3.0: https://www.well.ox.ac.uk/~wrayner/tools/HRC-1000G-check-bim-v4.3.0.zip

VcfCooker v1.1.1: https://genome.sph.umich.edu/wiki/VcfCooker

Eagle2 v2.4.1: https://alkesgroup.broadinstitute.org/Eagle/

Minimac4 v1.0.0: https://genome.sph.umich.edu/wiki/Minimac4

apt software v2.10.2.2: https://www.thermofisher.com/us/en/home/life-science/microarray-analysis/microarray-analysis-partners-programs/affymetrix-developers-network/affymetrix-power-tools.html

SNPolisher v3.0: https://downloads.thermofisher.com/SNPolisher_3.0.zip

BEAGLE v5.1: https://faculty.washington.edu/browning/beagle/b5_1.html

PLINK2 v2.00a3.6: https://www.cog-genomics.org/plink/2.0

METAL v2011-03-25: https://genome.sph.umich.edu/wiki/METAL

MANTRA v1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460225/

COJO v1.92.2beta: https://yanglab.westlake.edu.cn/software/gcta/#COJO

PRS-CS v1.0.0: https://github.com/getian107/PRScs

PRS-CSx v1.0.0: https://github.com/getian107/PRScsx

Python implementation for SuSiE: https://github.com/getian107/SuSiEx

FinnGen QC and Association analysis: https://finngen.gitbook.io/documentation/methods/genotype-imputation/genotype-data

FinnGen GWAS: https://finngen.gitbook.io/documentation/methods/phewas

IEU open GWAS project: https://gwas.mrcieu.ac.uk/phewas/

VEP v104.3: https://useast.ensembl.org/info/docs/tools/vep/index.html

Cytoscape v3.9.1: https://cytoscape.org/

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Acknowledgements

Z.L. acknowledges support from the National Natural Science Foundation of China (91942312, 81630017). H.H. acknowledges support from NIDDK K01DK114379, NIDDK R01DK129364 and the Stanley Center for Psychiatric Research. M.L. acknowledges support from the National Natural Science Foundation of China (81870389, 82070565). Y. Kakuta and Y. Kinouchi acknowledge support from JSPS KAKENHI (21K07884, 21K07955), the Japan Agency for Medical Research and Development (AMED) (JP18kk0305002) and Labour Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan. Y. Kakuta, Y. Kawai, K.T. and M.N. acknowledge support from AMED (JP19km0405501). K.S. acknowledges support from the National Research Foundation of Korea (2017R1A2A1A05001119, 2020R1A2C2003275). J.C. acknowledges support from NIDDK U24DK062429 and NIDDK U01DK062422. D.P.B.M. acknowledges the Leona M. and Harry B. Helmsley Charitable Trust and NIDDK U01DK062413. K.T. and M.N. acknowledge support from AMED (JP19km0405205). Part of the computations on JPN1 was performed on the NIG supercomputer at the ROIS National Institute of Genetics. Computations on SHA1 were performed in a supercomputing environment at the Digital Health China Technologies Corp. Ltd. We want to acknowledge the participants and investigators of the FinnGen study. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd., Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme Corp, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc., Novartis AG and Boehringer Ingelheim. The following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta) and Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). Finnish Biobank Cooperative-FINBB (https://finbb.fi/) is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious services (https://site.fingenious.fi/en/) managed by FINBB.

Author information

Author notes

  1. These authors contributed equally: Zhanju Liu, Ruize Liu, Han Gao.

  2. These authors jointly supervised this work: Zhanju Liu, Kyuyoung Song, Yoichi Kakuta, Mingsong Li, Hailiang Huang.

  3. A full list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China

    Zhanju Liu, Han Gao, Xiang Gao & Ruicong Sun

  2. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Ruize Liu, Kai Yuan, Aarno Palotie, Mark J. Daly & Hailiang Huang

  3. Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Ruize Liu, Zhenglin Guo, Kai Yuan, Aarno Palotie & Hailiang Huang

  4. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea

    Seulgi Jung, Yongjae Kim, Ho-Su Lee & Kyuyoung Song

  5. Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Xiaoming Liu & Mingsong Li

  6. Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan

    Yosuke Kawai & Katsushi Tokunaga

  7. Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan

    Masao Nagasaki

  8. Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Masao Nagasaki

  9. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Junji Umeno

  10. Student Healthcare Center, Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan

    Yoshitaka Kinouchi

  11. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Atsushi Masamune & Yoichi Kakuta

  12. Digital Health China Technologies Corp Ltd., Beijing, China

    Wenzhao Shi & Chengguo Shen

  13. 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

    Shu Zhu

  14. Widjaja Inflammatory Bowel Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Dalin Li & Dermot P. B. McGovern

  15. Genome Institute of Singapore, Singapore, Singapore

    Jianjun Liu

  16. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Jianjun Liu

  17. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Tian Ge

  18. Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Tian Ge

  19. Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Tian Ge

  20. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Judy Cho

  21. Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland

    Aarno Palotie & Mark J. Daly

  22. Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Mark J. Daly

  23. Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

    Byong Duk Ye

  24. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Hailiang Huang

  25. Division of Gastroenterology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA

    Maria Abreu

  26. Cleveland Clinic, Cleveland, OH, USA

    Jean-Paul Achkar

  27. Focused Research Unit for Molecular Diagnostic and Clinical Research, Hospital of Southern Jutland, Aabenraa, Denmark

    Vibeke Andersen

  28. University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada

    Charles Bernstein

  29. Rutgers University, New Brunswick, NJ, USA

    Steven R. Brant

  30. Osakidetza-Basque Health Service, Bilbao, Spain

    Luis Bujanda

  31. The Chinese University of Hong Kong, Hong Kong, China

    Siew Chien Ng

  32. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Lee A. Denson

  33. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Richard H. Duerr

  34. The University of Auckland, Auckland, New Zealand

    Lynnette R. Ferguson

  35. Department of Gastroenterology, Erasme Hospital, Free University of Brussels, Brussels, Belgium

    Denis Franchimont

  36. Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Kiel, Germany

    Andre Franke

  37. Department of Medicine, University of Otago, Christchurch, New Zealand

    Richard Gearry

  38. Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Hakon Hakonarson & Judith Kelsen

  39. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden

    Jonas Halfvarson

  40. Crohn’s & Colitis Foundation, New York, NY, USA

    Caren Heller

  41. Rheumatology Research Group, Vall d’Hebron University Hospital, Barcelona, Spain

    Antonio Julià

  42. Massachusetts General Hospital Gastroenterology Unit, Boston, MA, USA

    Hamed Khalili

  43. Emory University, Atlanta, GA, USA

    Subramaniam Kugathasan & David Okou

  44. Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania

    Juozas Kupcinskas

  45. Fondazione IRCCS Casa Sollievo della Sofferenza, Gastroenterology Unit, San Giovanni Rotondo, Foggia, Italy

    Anna Latiano

  46. University of Liège, ULG, Liège, Belgium

    Edouard Louis

  47. DDRI, Tehran University of Medical Sciences, Tehran, Iran

    Reza Malekzadeh

  48. John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA

    Jacob L. McCauley

  49. MassGeneral Hospital for Children, Boston, MA, USA

    Christopher Moran

  50. Imperial College London, London, UK

    Tim Orchard

  51. Addenborookes Hospital, Cambridge, UK

    Miles Parkes

  52. University of Chicago, Chicago, IL, USA

    Joel Pekow

  53. Faculty of Medicine, Center for Human Molecular Genetics and Pharmacogenomics, University of Maribor, Maribor, Slovenia

    Uroš Potočnik

  54. QIMR Berghofer MRI, Herston, Queensland, Australia

    Graham Radford-Smith

  55. Montreal Heart InstituteResearch Center, Montreal, Quebec, Canada

    John D. Rioux

  56. Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland

    Gerhard Rogler

  57. Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Bruce Sands

  58. Mount Sinai Hospital, Toronto, Ontario, Canada

    Mark Silverberg

  59. St Antoine Hospital, APHP, Paris, France

    Harry Sokol

  60. Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium

    Séverine Vermeire

  61. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands

    Rinse K. Weersma

  62. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Ramnik J. Xavier

  63. Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

    Naizhong Hu

  64. Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Qian Cao

  65. Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China

    Yufang Wang & Hu Zhang

  66. Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, China

    Yinglei Miao

  67. Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Hongjie Zhang

  68. Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China

    Xiaoping Lv

  69. Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Xiang Gao

  70. Department of Gastroenterology, Affiliated Zhongshan Hospital of Xiamen University, Xiamen, China

    Jingling Su

  71. Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Baisui Feng

  72. Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Ye Zhao

  73. Department of Gastroenterology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China

    Liangru Zhu

  74. Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yan Chen

  75. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China

    Lanxiang Zhu

  76. Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Chunxiao Chen

  77. Department of Gastroenterology, Datong Third People’s Hospital, Datong, China

    Yali Wang

  78. Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, China

    Yingde Wang

  79. Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China

    Zhi Pang

  80. Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Yingxuan Chen

  81. Department of Gastroenterology, The East Branch of the Second Hospital of Hebei Medical University, Shijiazhuang, China

    Xiaolan Zhang

  82. Department of Gastroenterology, The Second Hospital of Harbin Medical University, Harbin, China

    Hui Li

  83. Department of Gastroenterology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China

    Qin Yu

  84. Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Mei Ye

  85. Department of Colorectal Surgery, Nanjing Hospital of TCM Affiliated to Nanjing University of Chinese Medicine, Nanjing, China

    Sumin Zhang

  86. Department of Gastroenterology, The Second Hospital of Soochow University, Suzhou, China

    Wen Tang

  87. Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, China

    Mei Wang

  88. Department of Gastroenterology, General Hospital, Tianjin Medical University, Tianjin, China

    Xiaocang Cao

  89. Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China

    Ruixin Zhu

  90. Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining, China

    Guangxi Zhou

  91. Department of Gastroenterology, Nantong Third People’s Hospital, Nantong University, Nantong, China

    Zhaolian Bian

  92. Department of Gastroenterology, Shanxi Provincial People’s Hospital, Taiyuan, China

    Xiaofeng Guo

  93. Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Xiaoli Wu

  94. Department of Gastroenterology, First Hospital of Shanxi Medical University, Taiyuan, China

    Jinchun Liu

  95. Department of Colorectal Surgery, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, China

    Wei Xu

  96. Department of Gastroenterology, Bethune First Affiliated Hospital of Jilin University, Changchun, China

    Yuqin Li

  97. Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, China

    Qin Guo

  98. Department of Gastroenterology, Suzhou Hospital of Anhui Medical University, Suzhou, China

    Zhiguo Guo

Authors
  1. Zhanju Liu
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  2. Ruize Liu
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  3. Han Gao
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  4. Seulgi Jung
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  5. Xiang Gao
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  6. Ruicong Sun
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  7. Xiaoming Liu
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  8. Yongjae Kim
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  9. Ho-Su Lee
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  10. Yosuke Kawai
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  11. Masao Nagasaki
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  12. Junji Umeno
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  13. Katsushi Tokunaga
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  14. Yoshitaka Kinouchi
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  15. Atsushi Masamune
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  16. Wenzhao Shi
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  17. Chengguo Shen
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  18. Zhenglin Guo
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  19. Kai Yuan
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  20. Shu Zhu
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  21. Dalin Li
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  22. Jianjun Liu
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  23. Tian Ge
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  24. Judy Cho
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  26. Dermot P. B. McGovern
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  27. Byong Duk Ye
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  28. Kyuyoung Song
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  29. Yoichi Kakuta
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  30. Mingsong Li
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  31. Hailiang Huang
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Consortia

FinnGen

  • Mark J. Daly

International Inflammatory Bowel Disease Genetics Consortium

  • Maria Abreu
  • , Jean-Paul Achkar
  • , Vibeke Andersen
  • , Charles Bernstein
  • , Steven R. Brant
  • , Luis Bujanda
  • , Siew Chien Ng
  • , Judy Cho
  • , Mark J. Daly
  • , Lee A. Denson
  • , Richard H. Duerr
  • , Lynnette R. Ferguson
  • , Denis Franchimont
  • , Andre Franke
  • , Richard Gearry
  • , Hakon Hakonarson
  • , Jonas Halfvarson
  • , Caren Heller
  • , Hailiang Huang
  • , Antonio Julià
  • , Judith Kelsen
  • , Hamed Khalili
  • , Subramaniam Kugathasan
  • , Juozas Kupcinskas
  • , Anna Latiano
  • , Edouard Louis
  • , Reza Malekzadeh
  • , Jacob L. McCauley
  • , Dermot P. B. McGovern
  • , 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

Chinese Inflammatory Bowel Disease Genetics Consortium

  • 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
  • , Mingsong Li
  •  & Zhanju Liu

Contributions

Z.L., J.L., K.S., Y. Kakuta, M.L. and H.H. designed the study and supervised the work. Z.L., R.L., H.G., S.J., W.S., C.S., Z.G., K.Y., D.L., T.G., J.C., M.J.D., D.P.B.M., K.S., Y. Kakuta, M.L. and H.H. analyzed the data and helped in study management. Z.L., H.G., S.J., X.G., R.S., X.L., Y. Kim, H.-S.L., Y. Kawai, M.N., J.U., K.T., Y. Kinouchi, A.M., B.D.Y., K.S., Y. Kakuta and M.L. helped in recruitment, clinical phenotyping, analysis and/or leadership on study contribution. Z.L., R.L., H.G., S.Z., D.L., T.G., M.J.D., D.P.B.M., B.D.Y., K.S., Y. Kakuta, M.L. and H.H. wrote the manuscript.

Corresponding authors

Correspondence to Zhanju Liu, Kyuyoung Song, Yoichi Kakuta, Mingsong Li or Hailiang Huang.

Ethics declarations

Competing interests

W.S. and C.S. are employees of Digital Health China Technologies Corp. Ltd. M.J.D. is a founder of Maze Therapeutics. D.P.B.M. has received consultancy fees from Prometheus Biosciences, Prometheus Laboratories, Takeda, Gilead, Pfizer. Stock—Prometheus Biosciences. B.D.Y. has served on advisory boards for AbbVie Korea, Celltrion, Daewoong Pharma, Ferring Korea, Janssen Korea, Pfizer Korea and Takeda Korea; has received research grants from Celltrion and Pfizer Korea; has received consulting fees from Chong Kun Dang Pharm., CJ Red BIO, Cornerstones Health, Daewoong Pharma, IQVIA, Kangstem Biotech, Korea United Pharm. Inc., Medtronic Korea, NanoEntek and Takeda; and has received speaking fees from AbbVie Korea, Celltrion, Ferring Korea, IQVIA, Janssen Korea, Pfizer Korea, Takeda and Takeda Korea. H.H. received consultancy fees from Ono Pharmaceutical and an honorarium from Xian Janssen Pharmaceutical. The remaining authors declare no competing interests.

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Nature Genetics thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Quantile-Quantile plots for IBD genetic associations.

λ, genomic inflation factor; λ1000, scaled inflation factor for an equivalent study of 1,000 cases and 1,000 controls. The dots indicate variants. Shaded area indicates the 95% confidence interval under the null distribution. a-c, SHA1. d-f, ICH1 (only the designated null variants in ImmunoChip were used). g-i, KOR1. j-l, JPN1. m-o, Meta-analysis including all EAS samples (SHA1, ICH1, KOR1, and JPN1). p-r, FIN. a, d, g, j, m, and p are for CD. b, e, h, k, n, and q are for UC. c, f, i, l, o, and r are for IBD.

Extended Data Fig. 2 Index variants in the 16 new IBD loci in EAS.

a, Minor allele frequency (MAF) taken from 1000 Genomes EAS and EUR reference panels, respectively. b, P-value in respective studies.

Extended Data Fig. 3 Comparison between the fixed-effect (FE) meta-analysis and MANTRA.

Index variants in loci identified by either FE or MANTRA were plotted. For FE, we used genome-wide significance threshold of 5 × 10−8, and for MANTRA, we used the Bayes Factor threshold of 106, plotted as the vertical and horizontal lines respectively. P, P-value from FE. BF, Bayes factor from MANTRA.

Extended Data Fig. 4 IBD gene network.

IBD gene network was created using the STRING functional protein association networks and clustered using Community Clustering Glay (Methods). For clusters with more than two genes or with new IBD genes, the top three significantly enriched pathways were shown if false-discovery rate (FDR) < 0.05. New, nearest genes to the index variants in new IBD loci or new genes in Table 2 (boldfaced). Known, nearest genes to the index variants in known IBD loci. Index, nearest genes to the index variants in IBD loci except for those in Table 2. Tier, genes in Table 2.

Extended Data Fig. 5 Comparative genetic architecture within EAS.

a, SNP-based heritability in the liability scale with the prevalence in its respective population or the European population. b, Genetic correlation (rg). For a and b, the sample size used to derive SHA1, KOR1 and JPN1 h2 and their rg were 8,831, 6,038 and 2,624 for CD, and 8,679, 5,988 and 2,803 for UC, respectively. Results are plotted as mean value ± 95% confidence interval (error bar).

Extended Data Fig. 6 Quantile-Quantile plots for the heterogeneity test within EAS.

a, b, CD. c, d, UC. e, f, IBD. a, c, e, Genome-wide variants including the MHC locus. b, d, f, Genome-wide variants excluding the MHC locus. Cochran’s Q-test, two-sided, was used for the heterogeneity test. The dots indicate variants. Shaded area indicates the 95% confidence interval under the null distribution.

Extended Data Fig. 7 Enrichment of squared genetic correlation stratified across genomic annotations.

No significant enrichment or depletion (deviation from 1) was observed after Bonferroni corrections. Results are plotted as mean value ± 95% confidence interval before multiple testing corrections (error bar).

Extended Data Fig. 8 Variance explained for IBD associations across EUR and EAS.

We included all loci from Supplementary Table 8. For loci with fine-mapping analyses performed, we used the conditional OR (using COJO, Methods) for variants with the highest PIP in each credible set to account for multiple independent associations. We took fine-mapping results from ref. 12 for EUR and from this study for EAS. For loci with no fine-mapping results, we used the index variant (variant with the most significant P-value) as the proxy for the loci. We only plotted associations that have variance explained > 0.3% in either EAS or EUR. Different MAF is defined as Fst > 0.01, and different OR is defined as heterogeneity test P-value < 0.05 after Bonferroni correction. Because the heterogeneity test was corrected using a higher multiple testing burden, the significance for a handful of loci, for example, RNF186, can be different from Fig. 3c. Nearest genes to the associations were used as labels for associations when the text space is available.

Extended Data Fig. 9 Difference between variance explained for CD and UC across EUR and EAS.

Index variants from Supplementary Table 8 were plotted. Difference between variance explained was calculated as variance explained of CD − variance explained of UC.

Extended Data Fig. 10 Polygenic risk prediction on Chinese, Korean and Japanese study participants.

a, Leave-one-country-out strategy was performed to test the performance of PRS on SHA1 (Chinese), KOR1 (Korean), and JPN1 (Japanese) individuals, respectively. The prediction accuracy was measured as R2 on the liability scale using the population prevalence (Methods). For the testing cohort, we randomly split study participants into validation and testing 100 times (Methods). All other EAS cohorts were used as discovery. Results are plotted as mean value ± 95% confidence interval of R2 across the 100 replicates (error bar). b, Effective sample size of training datasets calculated as 4/(1/ncase + 1/ncontrol).

Supplementary information

Supplementary Information

Supplementary Note.

Reporting Summary

Peer Review File

Supplementary Tables

Supplementary Tables 1–13.

Supplementary Data 1

Manhattan plot for IBD genetic associations.

Supplementary Data 2

Regional association plot for IBD-associated loci in EAS.

Supplementary Data 3

Forest plot for index variants in IBD-associated loci.

Supplementary Data 4

Forest plot for putative causal variants identified in EAS and in EUR.

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Liu, Z., Liu, R., Gao, H. et al. Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries. Nat Genet 55, 796–806 (2023). https://doi.org/10.1038/s41588-023-01384-0

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