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Original research
Whole exome sequencing analyses reveal gene–microbiota interactions in the context of IBD
  1. Shixian Hu1,2,
  2. Arnau Vich Vila1,2,
  3. Ranko Gacesa1,2,
  4. Valerie Collij1,2,
  5. Christine Stevens3,
  6. Jack M Fu4,5,6,
  7. Isaac Wong4,5,
  8. Michael E Talkowski4,5,6,7,8,
  9. Manuel A Rivas9,
  10. Floris Imhann1,2,
  11. Laura Bolte1,2,
  12. Hendrik van Dullemen1,
  13. Gerard Dijkstra1,
  14. Marijn C Visschedijk1,
  15. Eleonora A Festen1,
  16. Ramnik J Xavier10,11,
  17. Jingyuan Fu2,12,
  18. Mark J Daly3,
  19. Cisca Wijmenga2,
  20. Alexandra Zhernakova2,
  21. Alexander Kurilshikov2,
  22. Rinse K Weersma1
  1. 1 Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
  2. 2 Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
  3. 3 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  4. 4 Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
  5. 5 Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  6. 6 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  7. 7 Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA
  8. 8 Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  9. 9 Department of Biomedical Data Science, Stanford University, Stanford, California, USA
  10. 10 Center for Microbiome Informatics and Therapeutic, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  11. 11 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
  12. 12 Department of Pediatrics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
  1. Correspondence to Professor Rinse K Weersma; r.k.weersma{at}mdl.umcg.nl

Abstract

Objective Both the gut microbiome and host genetics are known to play significant roles in the pathogenesis of IBD. However, the interaction between these two factors and its implications in the aetiology of IBD remain underexplored. Here, we report on the influence of host genetics on the gut microbiome in IBD.

Design To evaluate the impact of host genetics on the gut microbiota of patients with IBD, we combined whole exome sequencing of the host genome and whole genome shotgun sequencing of 1464 faecal samples from 525 patients with IBD and 939 population-based controls. We followed a four-step analysis: (1) exome-wide microbial quantitative trait loci (mbQTL) analyses, (2) a targeted approach focusing on IBD-associated genomic regions and protein truncating variants (PTVs, minor allele frequency (MAF) >5%), (3) gene-based burden tests on PTVs with MAF <5% and exome copy number variations (CNVs) with site frequency <1%, (4) joint analysis of both cohorts to identify the interactions between disease and host genetics.

Results We identified 12 mbQTLs, including variants in the IBD-associated genes IL17REL, MYRF, SEC16A and WDR78. For example, the decrease of the pathway acetyl-coenzyme A biosynthesis, which is involved in short chain fatty acids production, was associated with variants in the gene MYRF (false discovery rate <0.05). Changes in functional pathways involved in the metabolic potential were also observed in participants carrying rare PTVs or CNVs in CYP2D6, GPR151 and CD160 genes. These genes are known for their function in the immune system. Moreover, interaction analyses confirmed previously known IBD disease-specific mbQTLs in TNFSF15.

Conclusion This study highlights that both common and rare genetic variants affecting the immune system are key factors in shaping the gut microbiota in the context of IBD and pinpoints towards potential mechanisms for disease treatment.

  • inflammatory bowel disease
  • genetics
  • intestinal microbiology
https://creativecommons.org/licenses/by/4.0/

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Footnotes

  • SH, AVV, RG and VC are joint first authors.

  • AZ, AK and RKW are joint senior authors.

  • Contributors Study supervision: RKW and AK. Analysis and drafting: SH, AVV, RG and VC. Data support: CS, MR, RX, MJD, JMF, IW and MET. Critical revision: RKW, AK, AZ, JF, CW, FI, EAF, HMvD, GD, MCV and LB. Shared last authors: AZ, AK and RKW.

  • Funding MR is supported by a National Institute of Health Center for Multi- and Trans-Ethnic Mapping of Mendelian and Complex Diseases grant (5U01 HG009080) and by the National Human Genome Research Institute of the National Institutes of Health (NIH) under award R01HG010140. CW is supported by a European Research Council (ERC) Advanced grant (FP/2007-2013/ERC grant 2012-322698), a Netherlands Organization for Scientific Research (NWO) Spinoza prize grant (NWO SPI 92-266) and the Gravitation Netherlands Organ-on-Chip Initiative (024.003.001). JF is supported by grants from NWO (NWO-VIDI 864.13.013) and CardioVasculair Onderzoek Nederland (CVON 2018-27). AZ is supported by an NWO Vidi grant (NWO-VIDI 016.178.056), an ERC Starting Grant (715772), CVON 2018-27 and a Rosalind Franklin Fellowship from the University of Groningen. Copy number variant analyses were supported by NIH MH115957 to MET.

  • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. The data for the LifeLines DEEP cohort available upon request from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/) at accession number EGAS00001001704. The data for the Groningen IBD cohort can be requested with the accession number EGAS00001002702.

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