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Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Research output: Contribution to journalArticlepeer-review

Belgium IBD Consortium

Original languageEnglish
Pages (from-to)1275-1283
Number of pages9
JournalNature genetics
Volume54
Issue number9
Early online date29 Aug 2022
DOIs
Accepted/In press12 Jul 2022
E-pub ahead of print29 Aug 2022
PublishedSep 2022

Bibliographical note

Funding Information: We thank all of the principal investigators, local staff from individual cohorts and all of the patients who kindly donated samples used in the study for making possible this global collaboration and resource to advance IBD genetics research. This research was funded in whole, or in part, by the US National Institutes of Health grants no. U54HG003067 and no. 5UM1HG008895, the Wellcome Trust grants no. 206194 and no. 108413/A/15/D, and The Leona M. & Harry B. Helmsley Charitable Trust grant no. 2015PG-IBD001. We thank the Broad Institute Genomics Platform for genomic data generation efforts and the Stanley Center for Psychiatric Research at the Broad Institute for supporting control sample aggregation. M.A.R. is in part supported by the NHGRI of the NIH under award no. R01HG010140 and an NIH Center for Multi- and Trans-ethnic Mapping of Mendelian and Complex Diseases grant (no. 5U01HG009080). H.H. acknowledges support from NIDDK grant no. K01DK114379, grant no. P30DK043351 and the Stanley Center for Psychiatric Research. H.S.W. receives philanthropic support from Martin Schlaff, James Brooks and the B. Hasso Family Foundation. H.H.U. and A. Sazonovs. are supported by the NIHR Oxford Biomedical Research Centre and by The Leona M. and Harry B. Helmsley Charitable Trust. A.P. is in part supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics grants no. 312074 and no. 336824. Individual studies contributing to this meta-analysis acknowledge support from NIH grants no. DK062431, no. DK062432, no. DK087694, no. K23DK117054, no. R01DK111843, no. P01DK094779, no. R01HG010140, no. 5U01HG009080 and no. DK062420, and NIDDK grants no. P01DK046763, no. U01DK062413 and no. R01DK104844. Funding Information: We thank all of the principal investigators, local staff from individual cohorts and all of the patients who kindly donated samples used in the study for making possible this global collaboration and resource to advance IBD genetics research. This research was funded in whole, or in part, by the US National Institutes of Health grants no. U54HG003067 and no. 5UM1HG008895, the Wellcome Trust grants no. 206194 and no. 108413/A/15/D, and The Leona M. & Harry B. Helmsley Charitable Trust grant no. 2015PG-IBD001. We thank the Broad Institute Genomics Platform for genomic data generation efforts and the Stanley Center for Psychiatric Research at the Broad Institute for supporting control sample aggregation. M.A.R. is in part supported by the NHGRI of the NIH under award no. R01HG010140 and an NIH Center for Multi- and Trans-ethnic Mapping of Mendelian and Complex Diseases grant (no. 5U01HG009080). H.H. acknowledges support from NIDDK grant no. K01DK114379, grant no. P30DK043351 and the Stanley Center for Psychiatric Research. H.S.W. receives philanthropic support from Martin Schlaff, James Brooks and the B. Hasso Family Foundation. H.H.U. and A. Sazonovs. are supported by the NIHR Oxford Biomedical Research Centre and by The Leona M. and Harry B. Helmsley Charitable Trust. A.P. is in part supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics grants no. 312074 and no. 336824. Individual studies contributing to this meta-analysis acknowledge support from NIH grants no. DK062431, no. DK062432, no. DK087694, no. K23DK117054, no. R01DK111843, no. P01DK094779, no. R01HG010140, no. 5U01HG009080 and no. DK062420, and NIDDK grants no. P01DK046763, no. U01DK062413 and no. R01DK104844. Funding Information: A. Baras., M. Ferreira., J.E.H. and D.S are current or former employees and/or stockholders of Regeneron Genetics Center or Regeneron Pharmaceuticals. M.A. is consulting for or part of the advisory board for AbbVie Inc., Bellatrix Pharmaceuticals, Bristol Myers Squibb, Eli Lilly Pharmaceuticals, Gilead, Janssen Ortho, LLC, and Prometheus Biosciences; and teaching, lecturing or speaking at Alimentiv, Arena Pharmaceuticals, Janssen, Prime CME, Takeda Pharmaceuticals. A.B. is an employee of Regeneron and owns stock in Regeneron. O.M.D. has served in the IBD fellowship funding committee for Pfizer and has a funded research project by Pfizer. H.K. receives grant funding from Takeda and Pfizer and has received consulting fees from Takeda. A.P. is a member of Astra Zenecas Genomics Advisory Board. M.A.R. is on the SAB of 54gene and has advised BioMarin, Third Rock Ventures, MazeTx and Related Sciences. G.A.H. is an employee of Takeda, former employee of AbbVie and owns stock in Takeda and AbbVie. C.A.L. reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma and grants from AstraZeneca, outside the submitted work. H.H.U. reports research collaboration or consultancy with Janssen, Eli Lilly, UCB Pharma, Celgene, MiroBio, OMass and Mestag. D.P.B.M. has consulted for Takeda, Boehringer Ingelheim, Palatin Technologies, Bridge Biotherapeutics, Pfizer and Gilead. M.P. received an unrestricted research grant from Pfizer UK and speaker fees from Janssen. P.I. received lecture fees from AbbVie, BMS, Celgene, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire and Warner Chilcott; financial support for research from Celltrion, MSD, Pfizer and Takeda; advisory fees from AbbVie, Arena, Boehringer Ingelheim, BMS, Celgene, Celltrion, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma and Warner Chilcott. Cedars-Sinai and D.P.B.M. have financial interests in Prometheus Biosciences, a company which has access to the data and specimens in Cedars-Sinais MIRIAD Biobank (including the Cedars-Sinai data and specimens used in this study) and seeks to develop commercial products. H.H. has received consultancy fees from Ono Pharmaceutical and honoraria from Xian Janssen Pharmaceutical. C.A.A. has received consultancy fees from Genomics plc and BridgeBio Inc. and lecture fees from GSK. M.J.D. is a founder of Maze Therapeutics. The remaining authors declare no competing interests. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

King's Authors

Abstract

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

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