ADAP1 protein, human; GIT2 protein, human; NOD2 protein, human; TNFSF15 protein, human; Tumor Necrosis Factor Ligand Superfamily Member 15; Humans; Colitis, Ulcerative/genetics; Crohn Disease/genetics; East Asian People; European People; Genetic Predisposition to Disease; Genome-Wide Association Study; Inflammatory Bowel Diseases/genetics; Polymorphism, Single Nucleotide/genetics; Tumor Necrosis Factor Ligand Superfamily Member 15/genetics
Abstract :
[en] 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.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Liu, Zhanju ; Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. zhanjuliu@tongji.edu.cn.
Liu, Ruize; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. ; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Gao, Han; Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Jung, Seulgi ; Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
Gao, Xiang; Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Sun, Ruicong; Center for IBD Research, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Liu, Xiaoming; Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Kim, Yongjae; Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
Lee, Ho-Su; Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
Kawai, Yosuke ; Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan.
Nagasaki, Masao ; Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan. ; Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Umeno, Junji ; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Tokunaga, Katsushi ; Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan.
Kinouchi, Yoshitaka; Student Healthcare Center, Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan.
Masamune, Atsushi ; Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Shi, Wenzhao; Digital Health China Technologies Corp Ltd., Beijing, China.
Shen, Chengguo; Digital Health China Technologies Corp Ltd., Beijing, China.
Guo, Zhenglin; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Yuan, Kai ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. ; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
FinnGen
International Inflammatory Bowel Disease Genetics, Consortium
Chinese Inflammatory Bowel Disease Genetics, Consortium
Zhu, Shu ; 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.
Li, Dalin ; Widjaja Inflammatory Bowel Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Liu, Jianjun ; Genome Institute of Singapore, Singapore, Singapore. ; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Ge, Tian; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. ; Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Cho, Judy ; Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Daly, Mark J; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. ; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland. ; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
McGovern, Dermot P B; Widjaja Inflammatory Bowel Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Ye, Byong Duk ; Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Song, Kyuyoung ; Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea. kysong@amc.seoul.kr.
Kakuta, Yoichi ; Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. ykakuta@med.tohoku.ac.jp.
Li, Mingsong ; Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. lims661216@163.com.
Huang, Hailiang ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. hhuang@broadinstitute.org. ; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. hhuang@broadinstitute.org. ; Department of Medicine, Harvard Medical School, Boston, MA, USA. hhuang@broadinstitute.org.
Chaney, A. F ast Facts About GI and Liver Diseases for Nurses (Springer Publishing Company, 2016).
GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. Hepatol. 5, 17–30 (2020).
M’Koma, A. E. Inflammatory bowel disease: an expanding global health problem. Clin. Med. Insights Gastroenterol. 6, 33–47 (2013).
de Lange, K. M. et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 49, 256–261 (2017).
Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).
Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015).
Jung, S. et al. Identification of three novel susceptibility loci for inflammatory bowel disease in Koreans in an extended genome-wide association study. J. Crohns Colitis 15, 1898–1907 (2021).
Yang, S.-K. et al. Identification of loci at 1q21 and 16q23 that affect susceptibility to inflammatory bowel disease in Koreans. Gastroenterology 151, 1096–1099 (2016).
Brant, S. R. et al. Genome-wide association study identifies African-specific susceptibility loci in African Americans with inflammatory bowel disease. Gastroenterology 152, 206–217 (2017).
Goyette, P. et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat. Genet. 47, 172–179 (2015).
Cleynen, I. et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387, 156–167 (2016).
Huang, H. et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547, 173–178 (2017).
Lam, M. et al. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat. Genet. 51, 1670–1678 (2018).
Tang, C. S. et al. Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese. Nat. Commun. 6, 10206 (2015).
Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411, 599–603 (2001).
Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411, 603–606 (2001).
Martin, A. R. et al. Clinical use of current polygenic risk scores may exacerbate health disparities. Nat. Genet. 51, 584–591 (2019).
Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023).
Sazonovs, A. et al. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility. Nat. Genet. 54, 1275–1283 (2022).
Kanai, M. et al. Meta-analysis fine-mapping is often miscalibrated at single-variant resolution. Cell Genom. 2, 100210 (2022).
Rivas, M. A. et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat. Genet. 43, 1066–1073 (2011).
Rivas, M. A. et al. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nat. Commun. 7, 12342 (2016).
Lassen, K. G. et al. Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk. Immunity 44, 1392–1405 (2016).
Lavoie, S. et al. The Crohn’s disease polymorphism, ATG16L1 T300A, alters the gut microbiota and enhances the local Th1/Th17 response. eLife 8, e39982 (2019).
Varma, M. et al. Cell type- and stimulation-dependent transcriptional programs regulated by Atg16L1 and its Crohn’s disease risk variant T300A. J. Immunol. 205, 414–424 (2020).
Morris, A. P. Transethnic meta-analysis of genomewide association studies. Genet. Epidemiol. 35, 809–822 (2011).
Festen, E. A. M. et al. Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut 58, 799–804 (2009).
Aoki, C. A. et al. Transforming growth factor beta (TGF-beta) and autoimmunity. Autoimmun. Rev. 4, 450–459 (2005).
Ihara, S., Hirata, Y. & Koike, K. TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota. J. Gastroenterol. 52, 777–787 (2017).
Kiryluk, K. et al. GWAS defines pathogenic signaling pathways and prioritizes drug targets for IgA nephropathy. Preprint at bioRxiv https://doi.org/10.1101/2021.11.19.21265383 (2021).
Ge, T., Chen, C.-Y., Ni, Y., Feng, Y.-C. A. & Smoller, J. W. Polygenic prediction via Bayesian regression and continuous shrinkage priors. Nat. Commun. 10, 1776 (2019).
Hammer, T. & Langholz, E. The epidemiology of inflammatory bowel disease: balance between East and West? A narrative review. Dig. Med. Res. 3, 48 (2020).
Ruan, Y. et al. Improving polygenic prediction in ancestrally diverse populations. Nat. Genet. 54, 573–580 (2022).
Asano, K. et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat. Genet. 41, 1325–1329 (2009).
Yamazaki, K. et al. A genome-wide association study identifies 2 susceptibility loci for Crohn’s disease in a Japanese population. Gastroenterology 144, 781–788 (2013).
Yang, S.-K. et al. Genome-wide association study of ulcerative colitis in Koreans suggests extensive overlapping of genetic susceptibility with Caucasians. Inflamm. Bowel Dis. 19, 954–966 (2013).
Yang, S.-K. et al. Genome-wide association study of Crohn’s disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations. Gut 63, 80–87 (2014).
Fuyuno, Y. et al. Genetic characteristics of inflammatory bowel disease in a Japanese population. J. Gastroenterol. 51, 672–681 (2016).
Yang, S.-K. et al. Immunochip analysis identification of 6 additional susceptibility loci for Crohn’s disease in Koreans. Inflamm. Bowel Dis. 21, 1–7 (2014).
Lee, H.-S. et al. X chromosome-wide association study identifies a susceptibility locus for inflammatory bowel disease in Koreans. J. Crohns Colitis 11, 820–830 (2017).
Kakuta, Y. et al. A genome-wide association study identifying RAP1A as a novel susceptibility gene for Crohn’s disease in Japanese individuals. J. Crohns Colitis 13, 648–658 (2019).
Okamoto, D. et al. Genetic analysis of ulcerative colitis in Japanese individuals using population-specific SNP array. Inflamm. Bowel Dis. 26, 1177–1187 (2020).
Ye, B. D. et al. Identification of ten additional susceptibility loci for ulcerative colitis through Immunochip analysis in Koreans. Inflamm. Bowel Dis. 22, 13–19 (2016).
Kanai, M. et al. Insights from complex trait fine-mapping across diverse populations. Preprint at bioRxiv https://doi.org/10.1101/2021.09.03.21262975 (2021).
Ye, B. D. et al. Association of FUT2 and ABO with Crohn’s disease in Koreans. J. Gastroenterol. Hepatol. 35, 104–109 (2020).
Magro, F. et al. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders. J. Crohns Colitis 11, 649–670 (2017).
Gomollón, F. et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 1: diagnosis and medical management. J. Crohns Colitis 11, 3–25 (2017).
Sturm, A. et al. ECCO-ESGAR guideline for diagnostic assessment in IBD part 2: IBD scores and general principles and technical aspects. J. Crohns Colitis 13, 273–284 (2019).
Maaser, C. et al. ECCO-ESGAR guideline for diagnostic assessment in IBD part 1: initial diagnosis, monitoring of known IBD, detection of complications. J. Crohns Colitis 13, 144–164 (2019).
Kakuta, Y. et al. NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study. J. Gastroenterol. 53, 1065–1078 (2018).
Kakuta, Y. et al. Crohn’s disease and early exposure to thiopurines are independent risk factors for mosaic chromosomal alterations in patients with inflammatory bowel diseases. J. Crohns Colitis 16, 643–655 (2022).
Cortes, A. & Brown, M. A. Promise and pitfalls of the Immunochip. Arthritis Res. Ther. 13, 101 (2011).
Taliun, D. et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 590, 290–299 (2021).
Kawai, Y. et al. Japonica array: improved genotype imputation by designing a population-specific SNP array with 1070 Japanese individuals. J. Hum. Genet. 60, 581–587 (2015).
Wang, G., Sarkar, A., Carbonetto, P. & Stephens, M. A simple new approach to variable selection in regression, with application to genetic fine mapping. J. R. Stat. Soc. B 82, 1273–1300 (2020).
Yang, J. et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375 (2012).
Bulik-Sullivan, B. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).
Lee, S. H., Wray, N. R., Goddard, M. E. & Visscher, P. M. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 88, 294–305 (2011).
Shi, H. et al. Population-specific causal disease effect sizes in functionally important regions impacted by selection. Nat. Commun. 12, 1098 (2021).
Park, S. H. et al. A 30-year trend analysis in the epidemiology of inflammatory bowel disease in the Songpa-Kangdong district of Seoul, Korea in 1986–2015. J. Crohns Colitis 13, 1410–1417 (2019).
Szklarczyk, D. et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47, D607–D613 (2019).
