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

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. Rühlemann; Williams Turpin; Jee Young Moon; Han Na Kim; Kreete Lüll; 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; Georg Homuth; David A. Hughes; Richard G. Ijzerman; Matthew A. Jackson; Vincent W.V. Jaddoe; Marie Joossens; Torben Jørgensen; Daniel Keszthelyi; Rob Knight; Markku Laakso; Matthias Laudes; Lenore J. Launer; Wolfgang Lieb; Aldons J. Lusis; Ad A.M. Masclee; Henriette A. Moll; Zlatan Mujagic; Qi Qibin; Daphna Rothschild; Hocheol Shin; Søren J. Sørensen; Claire J. Steves; Jonathan Thorsen; Nicholas J. Timpson; Raul Y. Tito; Sara Vieira-Silva; Uwe Völker; Henry Völzke; Urmo Võsa; Kaitlin H. Wade; Susanna Walter; Kyoko Watanabe; Stefan Weiss; Frank U. Weiss; Omer Weissbrod; Harm Jan Westra; Gonneke Willemsen; Haydeh Payami; Daisy M.A.E. Jonkers; Alejandro Arias Vasquez; Eco J.C. de Geus; Katie A. Meyer; Jakob Stokholm; Eran Segal; Elin Org; Cisca Wijmenga; Hyung Lae Kim; Robert C. Kaplan; Tim D. Spector; Andre G. Uitterlinden; Fernando Rivadeneira; Andre Franke; Markus M. Lerch; Lude Franke; Serena Sanna; Mauro D’Amato; Oluf Pedersen; Andrew D. Paterson; Robert Kraaij; Jeroen Raes; Alexandra Zhernakova; MiBioGen Consortium Initiative

doi:10.1038/s41588-020-00763-1

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

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. Rühlemann, Williams Turpin, Jee Young Moon, Han Na Kim, Kreete Lüll, Elad BarkanShiraz 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, Georg Homuth, David A. Hughes, Richard G. Ijzerman, Matthew A. Jackson, Vincent W.V. Jaddoe, Marie Joossens, Torben Jørgensen, Daniel Keszthelyi, Rob Knight, Markku Laakso, Matthias Laudes, Lenore J. Launer, Wolfgang Lieb, Aldons J. Lusis, Ad A.M. Masclee, Henriette A. Moll, Zlatan Mujagic, Qi Qibin, Daphna Rothschild, Hocheol Shin, Søren J. Sørensen, Claire J. Steves, Jonathan Thorsen, Nicholas J. Timpson, Raul Y. Tito, Sara Vieira-Silva, Uwe Völker, Henry Völzke, Urmo Võsa, Kaitlin H. Wade, Susanna Walter, Kyoko Watanabe, Stefan Weiss, Frank U. Weiss, Omer Weissbrod, Harm Jan Westra, Gonneke Willemsen, Haydeh Payami, Daisy M.A.E. Jonkers, Alejandro Arias Vasquez, Eco J.C. de Geus, Katie A. Meyer, Jakob Stokholm, Eran Segal, Elin Org, Cisca Wijmenga, Hyung Lae Kim, Robert C. Kaplan, Tim D. Spector, Andre G. Uitterlinden, Fernando Rivadeneira, Andre Franke, Markus M. Lerch, Lude Franke, Serena Sanna, Mauro D’Amato, Oluf Pedersen, Andrew D. Paterson, Robert Kraaij, Jeroen Raes, Alexandra Zhernakova, MiBioGen Consortium Initiative

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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 × 10⁻⁸) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10⁻²⁰), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10⁻¹⁰ < P < 5 × 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	10
Journal	Nature Genetics
Volume	53
Issue number	2
Early online date	18 Jan 2021
DOIs	https://doi.org/10.1038/s41588-020-00763-1
Publication status	Published - Feb 2021

Funding

Funders	Funder number
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK062370
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	024.004.017

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Largescale association analyses identify host factors influencing human gut microbiome compositionFinal published version, 5.47 MBLicence: Article 25fa Dutch Copyright Act

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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., Rühlemann, M. C., Turpin, W., Moon, J. Y., Kim, H. N., Lüll, K., ... MiBioGen Consortium Initiative (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{a26256d6fb4d4162bbfb284236d25deb,

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 × 10−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10−10 < P < 5 × 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.",

author = "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 R{\"u}hlemann, {Malte C.} and Williams Turpin and Moon, {Jee Young} and Kim, {Han Na} and Kreete L{\"u}ll 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 Georg Homuth and Hughes, {David A.} and Ijzerman, {Richard G.} and Jackson, {Matthew A.} and Jaddoe, {Vincent W.V.} and Marie Joossens and Torben J{\o}rgensen and Daniel Keszthelyi and Rob Knight and Markku Laakso and Matthias Laudes and Launer, {Lenore J.} and Wolfgang Lieb and Lusis, {Aldons J.} and Masclee, {Ad A.M.} and Moll, {Henriette A.} and Zlatan Mujagic and Qi Qibin and Daphna Rothschild and Hocheol Shin and S{\o}rensen, {S{\o}ren J.} and Steves, {Claire J.} and Jonathan Thorsen and Timpson, {Nicholas J.} and Tito, {Raul Y.} and Sara Vieira-Silva and Uwe V{\"o}lker and Henry V{\"o}lzke and Urmo V{\~o}sa and Wade, {Kaitlin H.} and Susanna Walter and Kyoko Watanabe and Stefan Weiss and Weiss, {Frank U.} and Omer Weissbrod and Westra, {Harm Jan} and Gonneke Willemsen and Haydeh Payami and Jonkers, {Daisy M.A.E.} and {Arias Vasquez}, Alejandro and {de Geus}, {Eco J.C.} and Meyer, {Katie A.} and Jakob Stokholm and Eran Segal and Elin Org and Cisca Wijmenga and Kim, {Hyung Lae} and Kaplan, {Robert C.} and Spector, {Tim D.} and Uitterlinden, {Andre G.} and Fernando Rivadeneira and Andre Franke and Lerch, {Markus M.} and Lude Franke and Serena Sanna and Mauro D{\textquoteright}Amato and Oluf Pedersen and Paterson, {Andrew D.} and Robert Kraaij and Jeroen Raes and Alexandra Zhernakova and {MiBioGen Consortium Initiative}",

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 Publishing Group",

number = "2",

}

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, Rühlemann, MC, Turpin, W, Moon, JY, Kim, HN, Lüll, 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, Homuth, G, Hughes, DA, Ijzerman, RG, Jackson, MA, Jaddoe, VWV, Joossens, M, Jørgensen, T, Keszthelyi, D, Knight, R, Laakso, M, Laudes, M, Launer, LJ, Lieb, W, Lusis, AJ, Masclee, AAM, Moll, HA, Mujagic, Z, Qibin, Q, Rothschild, D, Shin, H, Sørensen, SJ, Steves, CJ, Thorsen, J, Timpson, NJ, Tito, RY, Vieira-Silva, S, Völker, U, Völzke, H, Võsa, U, Wade, KH, Walter, S, Watanabe, K, Weiss, S, Weiss, FU, Weissbrod, O, Westra, HJ, Willemsen, G, Payami, H, Jonkers, DMAE, Arias Vasquez, A, de Geus, EJC, Meyer, KA, Stokholm, J, Segal, E, Org, E, Wijmenga, C, Kim, HL, Kaplan, RC, Spector, TD, Uitterlinden, AG, Rivadeneira, F, Franke, A, Lerch, MM, Franke, L, Sanna, S, D’Amato, M, Pedersen, O, Paterson, AD, Kraaij, R, Raes, J, Zhernakova, A & MiBioGen Consortium Initiative 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, 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 - Rühlemann, Malte C.

AU - Turpin, Williams

AU - Moon, Jee Young

AU - Kim, Han Na

AU - Lüll, 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 - Homuth, Georg

AU - Hughes, David A.

AU - Ijzerman, Richard G.

AU - Jackson, Matthew A.

AU - Jaddoe, Vincent W.V.

AU - Joossens, Marie

AU - Jørgensen, Torben

AU - Keszthelyi, Daniel

AU - Knight, Rob

AU - Laakso, Markku

AU - Laudes, Matthias

AU - Launer, Lenore J.

AU - Lieb, Wolfgang

AU - Lusis, Aldons J.

AU - Masclee, Ad A.M.

AU - Moll, Henriette A.

AU - Mujagic, Zlatan

AU - Qibin, Qi

AU - Rothschild, Daphna

AU - Shin, Hocheol

AU - Sørensen, Søren J.

AU - Steves, Claire J.

AU - Thorsen, Jonathan

AU - Timpson, Nicholas J.

AU - Tito, Raul Y.

AU - Vieira-Silva, Sara

AU - Völker, Uwe

AU - Völzke, Henry

AU - Võsa, Urmo

AU - Wade, Kaitlin H.

AU - Walter, Susanna

AU - Watanabe, Kyoko

AU - Weiss, Stefan

AU - Weiss, Frank U.

AU - Weissbrod, Omer

AU - Westra, Harm Jan

AU - Willemsen, Gonneke

AU - Payami, Haydeh

AU - Jonkers, Daisy M.A.E.

AU - Arias Vasquez, Alejandro

AU - de Geus, Eco J.C.

AU - Meyer, Katie A.

AU - Stokholm, Jakob

AU - Segal, Eran

AU - Org, Elin

AU - Wijmenga, Cisca

AU - Kim, Hyung Lae

AU - Kaplan, Robert C.

AU - Spector, Tim D.

AU - Uitterlinden, Andre G.

AU - Rivadeneira, Fernando

AU - Franke, Andre

AU - Lerch, Markus M.

AU - Franke, Lude

AU - Sanna, Serena

AU - D’Amato, Mauro

AU - Pedersen, Oluf

AU - Paterson, Andrew D.

AU - Kraaij, Robert

AU - Raes, Jeroen

AU - Zhernakova, Alexandra

AU - MiBioGen Consortium Initiative

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 × 10−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10−10 < P < 5 × 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 × 10−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10−20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10−10 < P < 5 × 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85100210047&partnerID=8YFLogxK

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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