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

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.

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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.

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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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