Large-scale association analyses identify host factors influencing human gut microbiome composition

A. Kurilshikov; C. Medina-Gomez; R. Bacigalupe; D. Radjabzadeh; J. Wang; A. Demirkan; C.I. Le Roy; J.A.R. Garay; C.T. Finnicum; X.R. Liu; D.V. Zhernakova; M.J. Bonder; T.H. Hansen; F. Frost; M.C. Ruhlemann; W. Turpin; J.Y. Moon; H.N. Kim; K. Lull; E. Barkan; S.A. Shah; M. Fornage; J. Szopinska-Tokov; Z.D. Wallen; D. Borisevich; L. Agreus; A. Andreasson; C. Bang; L. Bedrani; J.T. Bell; H. Bisgaard; M. Boehnke; D.I. Boomsma; R.D. Burk; A. Claringbould; K. Croitoru; G.E. Davies; C.M. van Duijn; L. Duijts; G. Falony; J.Y. Fu; A. van der Graaf; T. Hansen; G. Homuth; D.A. Hughes; R.G. Ijzerman; M.A. Jackson; V.W.V. Jaddoe; M. Joossens; T. Jorgensen; Daniel Keszthelyi; Ad Masclee; Zlatan Mujagic; Daisy Jonkers

doi:10.1038/s41588-020-00763-1

Large-scale association analyses identify host factors influencing human gut microbiome composition

A. Kurilshikov^*, C. Medina-Gomez, R. Bacigalupe, D. Radjabzadeh, J. Wang, A. Demirkan, C.I. Le Roy, J.A.R. Garay, C.T. Finnicum, X.R. Liu, D.V. Zhernakova^*, M.J. Bonder, T.H. Hansen, F. Frost, M.C. Ruhlemann, W. Turpin, J.Y. Moon, H.N. Kim, K. Lull, E. BarkanS.A. Shah, M. Fornage, J. Szopinska-Tokov, Z.D. Wallen, D. Borisevich, L. Agreus, A. Andreasson, C. Bang, L. Bedrani, J.T. Bell, H. Bisgaard, M. Boehnke, D.I. Boomsma, R.D. Burk, A. Claringbould, K. Croitoru, G.E. Davies, C.M. van Duijn, L. Duijts, G. Falony, J.Y. Fu, A. van der Graaf, T. Hansen, G. Homuth, D.A. Hughes, R.G. Ijzerman, M.A. Jackson, V.W.V. Jaddoe, M. Joossens, T. Jorgensen, Daniel Keszthelyi, Ad Masclee, Zlatan Mujagic, Daisy Jonkers

^*Corresponding author for this work

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Abstract

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

Original language	English
Pages (from-to)	156-165
Number of pages	19
Journal	Nature Genetics
Volume	53
Issue number	2
DOIs	https://doi.org/10.1038/s41588-020-00763-1
Publication status	Published - Feb 2021

Keywords

diseases
ecosystem
environment
framework
genetics
genome-wide association
genotype imputation
identification
mendelian randomization
metagenome
METAGENOME
ENVIRONMENT
MENDELIAN RANDOMIZATION
IDENTIFICATION
DISEASES
GENOTYPE IMPUTATION
GENETICS
FRAMEWORK
ECOSYSTEM
GENOME-WIDE ASSOCIATION

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Kurilshikov, A., Medina-Gomez, C., Bacigalupe, R., Radjabzadeh, D., Wang, J., Demirkan, A., Le Roy, C. I., Garay, J. A. R., Finnicum, C. T., Liu, X. R., Zhernakova, D. V., Bonder, M. J., Hansen, T. H., Frost, F., Ruhlemann, M. C., Turpin, W., Moon, J. Y., Kim, H. N., Lull, K., ... Jonkers, D. (2021). Large-scale association analyses identify host factors influencing human gut microbiome composition. Nature Genetics, 53(2), 156-165. https://doi.org/10.1038/s41588-020-00763-1

@article{62050c8684854fe095088e11c94548ba,

title = "Large-scale association analyses identify host factors influencing human gut microbiome composition",

abstract = "To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.",

keywords = "diseases, ecosystem, environment, framework, genetics, genome-wide association, genotype imputation, identification, mendelian randomization, metagenome, METAGENOME, ENVIRONMENT, MENDELIAN RANDOMIZATION, IDENTIFICATION, DISEASES, GENOTYPE IMPUTATION, GENETICS, FRAMEWORK, ECOSYSTEM, GENOME-WIDE ASSOCIATION",

author = "A. Kurilshikov and C. Medina-Gomez and R. Bacigalupe and D. Radjabzadeh and J. Wang and A. Demirkan and {Le Roy}, C.I. and J.A.R. Garay and C.T. Finnicum and X.R. Liu and D.V. Zhernakova and M.J. Bonder and T.H. Hansen and F. Frost and M.C. Ruhlemann and W. Turpin and J.Y. Moon and H.N. Kim and K. Lull and E. Barkan and S.A. Shah and M. Fornage and J. Szopinska-Tokov and Z.D. Wallen and D. Borisevich and L. Agreus and A. Andreasson and C. Bang and L. Bedrani and J.T. Bell and H. Bisgaard and M. Boehnke and D.I. Boomsma and R.D. Burk and A. Claringbould and K. Croitoru and G.E. Davies and {van Duijn}, C.M. and L. Duijts and G. Falony and J.Y. Fu and {van der Graaf}, A. and T. Hansen and G. Homuth and D.A. Hughes and R.G. Ijzerman and M.A. Jackson and V.W.V. Jaddoe and M. Joossens and T. Jorgensen and Daniel Keszthelyi and Ad Masclee and Zlatan Mujagic and Daisy Jonkers",

year = "2021",

month = feb,

doi = "10.1038/s41588-020-00763-1",

language = "English",

volume = "53",

pages = "156--165",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "2",

}

Kurilshikov, A, Medina-Gomez, C, Bacigalupe, R, Radjabzadeh, D, Wang, J, Demirkan, A, Le Roy, CI, Garay, JAR, Finnicum, CT, Liu, XR, Zhernakova, DV, Bonder, MJ, Hansen, TH, Frost, F, Ruhlemann, MC, Turpin, W, Moon, JY, Kim, HN, Lull, K, Barkan, E, Shah, SA, Fornage, M, Szopinska-Tokov, J, Wallen, ZD, Borisevich, D, Agreus, L, Andreasson, A, Bang, C, Bedrani, L, Bell, JT, Bisgaard, H, Boehnke, M, Boomsma, DI, Burk, RD, Claringbould, A, Croitoru, K, Davies, GE, van Duijn, CM, Duijts, L, Falony, G, Fu, JY, van der Graaf, A, Hansen, T, Homuth, G, Hughes, DA, Ijzerman, RG, Jackson, MA, Jaddoe, VWV, Joossens, M, Jorgensen, T, Keszthelyi, D, Masclee, A, Mujagic, Z & Jonkers, D 2021, 'Large-scale association analyses identify host factors influencing human gut microbiome composition', Nature Genetics, vol. 53, no. 2, pp. 156-165. https://doi.org/10.1038/s41588-020-00763-1

TY - JOUR

T1 - Large-scale association analyses identify host factors influencing human gut microbiome composition

AU - Kurilshikov, A.

AU - Medina-Gomez, C.

AU - Bacigalupe, R.

AU - Radjabzadeh, D.

AU - Wang, J.

AU - Demirkan, A.

AU - Le Roy, C.I.

AU - Garay, J.A.R.

AU - Finnicum, C.T.

AU - Liu, X.R.

AU - Zhernakova, D.V.

AU - Bonder, M.J.

AU - Hansen, T.H.

AU - Frost, F.

AU - Ruhlemann, M.C.

AU - Turpin, W.

AU - Moon, J.Y.

AU - Kim, H.N.

AU - Lull, K.

AU - Barkan, E.

AU - Shah, S.A.

AU - Fornage, M.

AU - Szopinska-Tokov, J.

AU - Wallen, Z.D.

AU - Borisevich, D.

AU - Agreus, L.

AU - Andreasson, A.

AU - Bang, C.

AU - Bedrani, L.

AU - Bell, J.T.

AU - Bisgaard, H.

AU - Boehnke, M.

AU - Boomsma, D.I.

AU - Burk, R.D.

AU - Claringbould, A.

AU - Croitoru, K.

AU - Davies, G.E.

AU - van Duijn, C.M.

AU - Duijts, L.

AU - Falony, G.

AU - Fu, J.Y.

AU - van der Graaf, A.

AU - Hansen, T.

AU - Homuth, G.

AU - Hughes, D.A.

AU - Ijzerman, R.G.

AU - Jackson, M.A.

AU - Jaddoe, V.W.V.

AU - Joossens, M.

AU - Jorgensen, T.

AU - Keszthelyi, Daniel

AU - Masclee, Ad

AU - Mujagic, Zlatan

AU - Jonkers, Daisy

PY - 2021/2

Y1 - 2021/2

N2 - To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

AB - To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

KW - diseases

KW - ecosystem

KW - environment

KW - framework

KW - genetics

KW - genome-wide association

KW - genotype imputation

KW - identification

KW - mendelian randomization

KW - metagenome

KW - METAGENOME

KW - ENVIRONMENT

KW - MENDELIAN RANDOMIZATION

KW - IDENTIFICATION

KW - DISEASES

KW - GENOTYPE IMPUTATION

KW - GENETICS

KW - FRAMEWORK

KW - ECOSYSTEM

KW - GENOME-WIDE ASSOCIATION

U2 - 10.1038/s41588-020-00763-1

DO - 10.1038/s41588-020-00763-1

M3 - Article

C2 - 33462485

SN - 1061-4036

VL - 53

SP - 156

EP - 165

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Large-scale association analyses identify host factors influencing human gut microbiome composition

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Keywords

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