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Association of host genome with intestinal microbial composition in a large healthy cohort

Nature Genetics volume 48, pages 1413–1417 (2016)Cite this article

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Abstract

Intestinal microbiota is known to be important in health and disease. Its composition is influenced by both environmental and host factors. Few large-scale studies have evaluated the association between host genetic variation and the composition of microbiota. We recruited a cohort of 1,561 healthy individuals, of whom 270 belong in 123 families, and found that almost one-third of fecal bacterial taxa were heritable. In addition, we identified 58 SNPs associated with the relative abundance of 33 taxa in 1,098 discovery subjects. Among these, four loci were replicated in a second cohort of 463 subjects: rs62171178 (nearest gene UBR3) associated with Rikenellaceae, rs1394174 (CNTN6) associated with Faecalibacterium, rs59846192 (DMRTB1) associated with Lachnospira, and rs28473221 (SALL3) associated with Eubacterium. After correction for multiple testing, 6 of the 58 associations remained significant, one of which replicated. These results identify associations between specific genetic variants and the gut microbiome.

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Figure 1: Taxonomic representation of heritable or SNP-associated taxa.
Figure 2: Beeswarm plots of replicated taxon–SNP associations.
Figure 3: Regional association plot of rs62171178 with Rikenellaceae.

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Acknowledgements

We thank the members of the GEM Global Project Office, C. Bravi, D. Couchman, N. Ganeswaren, A. Keludjian, K. Ow, R. Caplan, M. Greaves, A. Craig-Neil, A. Olteanu, N. Allam, A. Garrioch, D. Ng, V. Onay, and I. Yeadon, for administrative support. We thank D. Cvitkovitch for his helpful scientific discussion of the project. All authors disclose no potential conflicts (financial, professional, or personal) that are relevant to the manuscript. This study was supported by grants from Crohn's and Colitis Canada, Canadian Institutes of Health Research (CIHR) grant CMF108031 and the Helmsley Charitable Trust. W.T. is the recipient of a Postdoctoral Fellowship Research Award from CIHR Fellowship/Canadian Association of Gastroenterology (CAG)/Ferring Pharmaceuticals, Inc., and a fellowship from the Department of Medicine, Mount Sinai Hospital, Toronto. M.S.S. is supported in part by the Gale and Graham Wright Chair in Digestive Diseases. D.K. is the recipient of a CIHR/CAG/Abbvie IBD Fellowship Award. L.X. is the recipient of a CIHR STAGE fellowship. K.S. is the recipient of an Ontario Graduate Scholarship.

Author information

Author notes

  1. Denis O Krause and David Mack: Deceased.

Authors and Affiliations

  1. Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada

    Williams Turpin, Mark S Silverberg, David Kevans, Michelle I Smith, Hillary Steinhart & Kenneth Croitoru

  2. Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Williams Turpin, Mark S Silverberg, David Kevans & Kenneth Croitoru

  3. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada

    Osvaldo Espin-Garcia, Mark S Silverberg, Michelle I Smith & Kenneth Croitoru

  4. Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    Osvaldo Espin-Garcia, Wei Xu, Lizhen Xu, Konstantin Shestopaloff & Andrew D Paterson

  5. Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada

    David S Guttman

  6. Centre for the Analysis of Genome Evolution and Function, University of Toronto, Toronto, Ontario, Canada

    David S Guttman

  7. Division of Gastroenterology, Department of Pediatrics, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada

    Anne Griffiths

  8. Division of Gastroenterology and Hepatology, Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, Alberta, Canada

    Remo Panaccione

  9. Departement of Pediatrics, IWK Health Centre, Halifax, Nova Scotia, Canada

    Anthony Otley

  10. Genetics and Genome Biology, The Hospital for Sick Children Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada

    Lizhen Xu & Andrew D Paterson

  11. Department of Biology, Wilfrid Laurier University, Waterloo, Ontario, Canada

    Gabriel Moreno-Hagelsieb

  12. Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    Andrew D Paterson

  13. University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA

    Maria Abreu

  14. Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada

    Paul Beck

  15. University of Manitoba Health Sciences Centre, Winnipeg, Manitoba, Canada

    Charles Bernstein

  16. Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada

    Leo Dieleman & Karen Madsen

  17. Department of Medicine, University of Western Ontario, London, Ontario, Canada

    Brian Feagan

  18. Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada

    Brian Feagan

  19. Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada

    Kevan Jacobson & Bruce Vallance

  20. Department of Medicine, University of Calgary, Calgary, Alberta, Canada

    Gilaad Kaplan

  21. Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

    Gilaad Kaplan

  22. Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada

    Denis O Krause

  23. Department of Medicine, McMaster University, Hamilton, Ontario, Canada

    John Marshall, Paul Moayyedi & Michael Surette

  24. Department of Medicine, Queen's University, Kingston, Ontario, Canada

    Mark Ropeleski

  25. Department of Medicine, McGill University, Montreal, Quebec, Canada

    Ernest Seidman

  26. Department of Pediatrics, McGill University, Montreal, Quebec, Canada

    Ernest Seidman

  27. Gastroenterology, Hepatology and Nutrition Research, Boston Children's Hospital, Boston, Massachusetts, USA

    Scott Snapper

  28. Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada

    Andy Stadnyk

  29. Pediatric Gastroenterology and Nutrition Unit, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel

    Dan Turner

  30. Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada

    Tom Walters

  31. Division of Gastroenterology, Hôpital Maisonneuve Rosemont, Montreal, Quebec, Canada

    Guy Aumais

  32. Division of Gastroenterology, McGill University, Montreal, Quebec, Canada

    Alain Bitton

  33. Division of Gastroenterology, Toronto Western Hospital, Toronto, Ontario, Canada

    Maria Cino

  34. Division of Gastroenterology, Memorial University, St John's, Newfoundland and Labrador, Canada

    Jeff Critch & Jerry McGrath

  35. Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA

    Lee Denson

  36. Division of Gastroenterology, Hôpital Sainte-Justine, Montreal, Quebec, Canada

    Colette Deslandres

  37. Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada

    Wael El-Matary

  38. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Hans Herfarth

  39. Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA

    Peter Higgins

  40. Division of Pediatrics, University of Alberta, Edmonton, Alberta, Canada

    Hien Huynh

  41. Department of Pediatrics, University of Connecticut School of Medicine Hartford, Hartford, Connecticut, USA

    Jeff Hyams

  42. Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada

    David Mack

Authors
  1. Williams Turpin
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  2. Osvaldo Espin-Garcia
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  3. Wei Xu
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  4. Mark S Silverberg
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  5. David Kevans
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  6. Michelle I Smith
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  7. David S Guttman
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  8. Anne Griffiths
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  9. Remo Panaccione
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  10. Anthony Otley
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  11. Lizhen Xu
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  12. Konstantin Shestopaloff
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  13. Gabriel Moreno-Hagelsieb
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  14. Andrew D Paterson
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  15. Kenneth Croitoru
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Consortia

GEM Project Research Consortium

  • Maria Abreu
  • , Paul Beck
  • , Charles Bernstein
  • , Leo Dieleman
  • , Brian Feagan
  • , Kevan Jacobson
  • , Gilaad Kaplan
  • , Denis O Krause
  • , Karen Madsen
  • , John Marshall
  • , Paul Moayyedi
  • , Mark Ropeleski
  • , Ernest Seidman
  • , Scott Snapper
  • , Andy Stadnyk
  • , Hillary Steinhart
  • , Michael Surette
  • , Dan Turner
  • , Tom Walters
  • , Bruce Vallance
  • , Guy Aumais
  • , Alain Bitton
  • , Maria Cino
  • , Jeff Critch
  • , Lee Denson
  • , Colette Deslandres
  • , Wael El-Matary
  • , Hans Herfarth
  • , Peter Higgins
  • , Hien Huynh
  • , Jeff Hyams
  • , David Mack
  •  & Jerry McGrath

Contributions

A.D.P. and K.C. contributed equally. A.D.P. and K.C. jointly supervised research. W.T., M.S.S., A.D.P., K.C., and the GEM Project Steering Committee conceived and designed the experiments. W.T., W.X., L.X., and K.C. performed the experiments. W.T., O.E.-G., W.X., L.X., and A.D.P. performed statistical analysis. W.T., M.S.S., M.I.S., W.X., G.M.-H., D.K., K.S., O.E.-G., D.S.G., L.X., A.D.P., and K.C. analyzed the data. W.X., L.X., A.D.P., A.G., R.P., A.O., and the GEM Project Consortium contributed reagents, materials, and/or analysis tools and contributed significant subject recruitment. W.T., A.D.P., and K.C. wrote the manuscript.

Corresponding authors

Correspondence to Andrew D Paterson or Kenneth Croitoru.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Note. (PDF 3576 kb)

Supplementary Table 1

Geographic origin of individuals in the discovery and replication cohorts. (XLSX 18 kb)

Supplementary Table 2

Heritability assessment of bacterial taxa, choa1, Shannon PD whole-tree α diversity index, and microbial dysbiosis index in 123 independent families. (XLSX 42 kb)

Supplementary Table 3

P values of association of the bacterial α diversity measure with SNPs in the discovery cohort. (XLS 102 kb)

Supplementary Table 4

P values of association of SNPs with the bacterial microbial dysbiosis index in the discovery cohort. (XLSX 18 kb)

Supplementary Table 5

P values of association of the bacterial taxa with 123 IBD-related SNPs in the discovery cohort. (XLS 10046 kb)

Supplementary Table 6

Significant genome-wide associated taxa. (XLSX 55 kb)

Supplementary Table 7

Results of colocalization analysis of rs62171178 with Rikenellaceae relative abundance and PHOSPHO2 expression in the stomach. (XLSX 222 kb)

Supplementary Table 8

P values for association of bacterial COG function with rs62171178. (XLSX 530 kb)

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Turpin, W., Espin-Garcia, O., Xu, W. et al. Association of host genome with intestinal microbial composition in a large healthy cohort. Nat Genet 48, 1413–1417 (2016). https://doi.org/10.1038/ng.3693

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