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

MiBioGen Consortium Initiative; Alexander Kurilshikov; Carolina Medina-Gomez; Rodrigo Bacigalupe; Djawad Radjabzadeh; Jun Wang; Ayse Demirkan; Caroline I. Le Roy; Juan Antonio Raygoza Garay; Casey T. Finnicum; Xingrong Liu; Daria V. Zhernakova; Marc Jan Bonder; Tue H. Hansen; Fabian Frost; Malte C. Ruehlemann; Williams Turpin; Jee-Young Moon; Han-Na Kim; Kreete Lull; Elad Barkan; Shiraz A. Shah; Myriam Fornage; Joanna Szopinska-Tokov; Zachary D. Wallen; Dmitrii Borisevich; Lars Agreus; Anna Andreasson; Corinna Bang; Larbi Bedrani; Jordana T. Bell; Hans Bisgaard; Michael Boehnke; Dorret I. Boomsma; Robert D. Burk; Annique Claringbould; Kenneth Croitoru; Gareth E. Davies; Cornelia M. van Duijn; Liesbeth Duijts; Gwen Falony; Jingyuan Fu; Adriaan van der Graaf; Torben Hansen; Urmo Vosa; Harm-Jan Westra; Cisca Wijmenga; Markus M. Lerch; Lude Franke; Serena Sanna; Alexandra Zhernakova

doi:10.1038/s41588-020-00763-1

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

MiBioGen Consortium Initiative, Alexander Kurilshikov^*, Carolina Medina-Gomez, Rodrigo Bacigalupe, Djawad Radjabzadeh, Jun Wang, Ayse Demirkan, Caroline I. Le Roy, Juan Antonio Raygoza Garay, Casey T. Finnicum, Xingrong Liu, Daria V. Zhernakova, Marc Jan Bonder, Tue H. Hansen, Fabian Frost, Malte C. Ruehlemann, Williams Turpin, Jee-Young Moon, Han-Na Kim, Kreete LullElad Barkan, Shiraz A. Shah, Myriam Fornage, Joanna Szopinska-Tokov, Zachary D. Wallen, Dmitrii Borisevich, Lars Agreus, Anna Andreasson, Corinna Bang, Larbi Bedrani, Jordana T. Bell, Hans Bisgaard, Michael Boehnke, Dorret I. Boomsma, Robert D. Burk, Annique Claringbould, Kenneth Croitoru, Gareth E. Davies, Cornelia M. van Duijn, Liesbeth Duijts, Gwen Falony, Jingyuan Fu, Adriaan van der Graaf, Torben Hansen, Urmo Vosa, Harm-Jan Westra, Cisca Wijmenga, Markus M. Lerch, Lude Franke, Serena Sanna, Alexandra Zhernakova^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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
DOIs	https://doi.org/10.1038/s41588-020-00763-1
Publication status	Published - 18-Jan-2021

Keywords

GENOME-WIDE ASSOCIATION
MENDELIAN RANDOMIZATION
GENOTYPE IMPUTATION
GENETICS
IDENTIFICATION
ENVIRONMENT
METAGENOME
FRAMEWORK
ECOSYSTEM
DISEASES

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Large-scale association analyses identify host factors influencing human gut microbiome compositionFinal publisher's version, 5.47 MBLicence: Taverne

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

@article{79358c5fe4a5460b8703b681bdf8da4a,

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 = "GENOME-WIDE ASSOCIATION, MENDELIAN RANDOMIZATION, GENOTYPE IMPUTATION, GENETICS, IDENTIFICATION, ENVIRONMENT, METAGENOME, FRAMEWORK, ECOSYSTEM, DISEASES",

author = "{MiBioGen Consortium Initiative} and Alexander Kurilshikov and Carolina Medina-Gomez and Rodrigo Bacigalupe and Djawad Radjabzadeh and Jun Wang and Ayse Demirkan and {Le Roy}, {Caroline I.} and {Raygoza Garay}, {Juan Antonio} and Finnicum, {Casey T.} and Xingrong Liu and Zhernakova, {Daria V.} and Bonder, {Marc Jan} and Hansen, {Tue H.} and Fabian Frost and Ruehlemann, {Malte C.} and Williams Turpin and Jee-Young Moon and Han-Na Kim and Kreete Lull and Elad Barkan and Shah, {Shiraz A.} and Myriam Fornage and Joanna Szopinska-Tokov and Wallen, {Zachary D.} and Dmitrii Borisevich and Lars Agreus and Anna Andreasson and Corinna Bang and Larbi Bedrani and Bell, {Jordana T.} and Hans Bisgaard and Michael Boehnke and Boomsma, {Dorret I.} and Burk, {Robert D.} and Annique Claringbould and Kenneth Croitoru and Davies, {Gareth E.} and {van Duijn}, {Cornelia M.} and Liesbeth Duijts and Gwen Falony and Jingyuan Fu and {van der Graaf}, Adriaan and Torben Hansen and Urmo Vosa and Harm-Jan Westra and Cisca Wijmenga and Lerch, {Markus M.} and Lude Franke and Serena Sanna and Alexandra Zhernakova",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = jan,

day = "18",

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

language = "English",

volume = "53",

pages = "156--165",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

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MiBioGen Consortium Initiative, Kurilshikov, A, Medina-Gomez, C, Bacigalupe, R, Radjabzadeh, D, Wang, J, Demirkan, A, Le Roy, CI, Raygoza Garay, JA, Finnicum, CT, Liu, X, Zhernakova, DV , Bonder, MJ, Hansen, TH, Frost, F, Ruehlemann, MC, Turpin, W, Moon, J-Y, Kim, H-N, 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, J , van der Graaf, A, Hansen, T, Vosa, U , Westra, H-J , Wijmenga, C, Lerch, MM, Franke, L , Sanna, S & Zhernakova, A 2021, 'Large-scale association analyses identify host factors influencing human gut microbiome composition', Nature Genetics, vol. 53, 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 - MiBioGen Consortium Initiative

AU - Kurilshikov, Alexander

AU - Medina-Gomez, Carolina

AU - Bacigalupe, Rodrigo

AU - Radjabzadeh, Djawad

AU - Wang, Jun

AU - Demirkan, Ayse

AU - Le Roy, Caroline I.

AU - Raygoza Garay, Juan Antonio

AU - Finnicum, Casey T.

AU - Liu, Xingrong

AU - Zhernakova, Daria V.

AU - Bonder, Marc Jan

AU - Hansen, Tue H.

AU - Frost, Fabian

AU - Ruehlemann, Malte C.

AU - Turpin, Williams

AU - Moon, Jee-Young

AU - Kim, Han-Na

AU - Lull, Kreete

AU - Barkan, Elad

AU - Shah, Shiraz A.

AU - Fornage, Myriam

AU - Szopinska-Tokov, Joanna

AU - Wallen, Zachary D.

AU - Borisevich, Dmitrii

AU - Agreus, Lars

AU - Andreasson, Anna

AU - Bang, Corinna

AU - Bedrani, Larbi

AU - Bell, Jordana T.

AU - Bisgaard, Hans

AU - Boehnke, Michael

AU - Boomsma, Dorret I.

AU - Burk, Robert D.

AU - Claringbould, Annique

AU - Croitoru, Kenneth

AU - Davies, Gareth E.

AU - van Duijn, Cornelia M.

AU - Duijts, Liesbeth

AU - Falony, Gwen

AU - Fu, Jingyuan

AU - van der Graaf, Adriaan

AU - Hansen, Torben

AU - Vosa, Urmo

AU - Westra, Harm-Jan

AU - Wijmenga, Cisca

AU - Lerch, Markus M.

AU - Franke, Lude

AU - Sanna, Serena

AU - Zhernakova, Alexandra

PY - 2021/1/18

Y1 - 2021/1/18

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 - GENOME-WIDE ASSOCIATION

KW - MENDELIAN RANDOMIZATION

KW - GENOTYPE IMPUTATION

KW - GENETICS

KW - IDENTIFICATION

KW - ENVIRONMENT

KW - METAGENOME

KW - FRAMEWORK

KW - ECOSYSTEM

KW - DISEASES

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

ER -