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

A Kurilshikov; Maria Medina Gomez; R Bacigalupe; Djawad Radjabzadeh; J Wang; A Demirkan; CI Le Roy; JAR Garay; CT Finnicum; XR Liu; DV Zhernakova; MJ Bonder; TH Hansen; F Frost; MC Ruhlemann; W Turpin; JY Moon; HN Kim; K Lull; E Barkan; SA Shah; M Fornage; J Szopinska-Tokov; ZD Wallen; D Borisevich; L Agreus; A Andreasson; C Bang; L Bedrani; JT Bell; H Bisgaard; M Boehnke; DI Boomsma; RD Burk; A Claringbould; K Croitoru; GE Davies; Cornelia Duijn; Liesbeth Duijts; G Falony; JY Fu; A Graaf; T Hansen; G Homuth; DA Hughes; RG Ijzerman; Matthew O. Jackson; Vincent Jaddoe; M Joossens; T Jorgensen; D Keszthelyi; R Knight; M Laakso; M Laudes; LJ Launer; W Lieb; AJ Lusis; AAM Masclee; Henriette Moll; Z Mujagic; Q Qibin; D Rothschild; H Shin; SJ Sorensen; CJ Steves; J Thorsen; NJ Timpson; RY Tito; S Vieira-Silva; U Volker; H Volzke; U Vosa; KH Wade; S Walter; K Watanabe; S Weiss; FU Weiss; O Weissbrod; HJ Westra; G Willemsen; H Payami; D Jonkers; AA Vasquez; EJCN de Geus; KA Meyer; J Stokholm; E Segal; E Org; C Wijmenga; HL Kim; RC Kaplan; TD Spector; André Uitterlinden; Fernando Rivadeneira; A Franke; MM Lerch; L Franke; S Sanna; M D'Amato; O Pedersen; AD Paterson; Robert Kraaij; J Raes; A Zhernakova

doi:10.1038/s41588-020-00763-1

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

A Kurilshikov, Maria Medina Gomez, R Bacigalupe, Djawad Radjabzadeh, J Wang, A Demirkan, CI Le Roy, JAR Garay, CT Finnicum, XR Liu, DV Zhernakova, MJ Bonder, TH Hansen, F Frost, MC Ruhlemann, W Turpin, JY Moon, HN Kim, K Lull, E BarkanSA Shah, M Fornage, J Szopinska-Tokov, ZD Wallen, D Borisevich, L Agreus, A Andreasson, C Bang, L Bedrani, JT Bell, H Bisgaard, M Boehnke, DI Boomsma, RD Burk, A Claringbould, K Croitoru, GE Davies, Cornelia Duijn, Liesbeth Duijts, G Falony, JY Fu, A Graaf, T Hansen, G Homuth, DA Hughes, RG Ijzerman, Matthew O. Jackson, Vincent Jaddoe, M Joossens, T Jorgensen, D Keszthelyi, R Knight, M Laakso, M Laudes, LJ Launer, W Lieb, AJ Lusis, AAM Masclee, Henriette Moll, Z Mujagic, Q Qibin, D Rothschild, H Shin, SJ Sorensen, CJ Steves, J Thorsen, NJ Timpson, RY Tito, S Vieira-Silva, U Volker, H Volzke, U Vosa, KH Wade, S Walter, K Watanabe, S Weiss, FU Weiss, O Weissbrod, HJ Westra, G Willemsen, H Payami, D Jonkers, AA Vasquez, EJCN de Geus, KA Meyer, J Stokholm, E Segal, E Org, C Wijmenga, HL Kim, RC Kaplan, TD Spector, André Uitterlinden, Fernando Rivadeneira, A Franke, MM Lerch, L Franke, S Sanna, M D'Amato, O Pedersen, AD Paterson, Robert Kraaij, J Raes, A Zhernakova

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

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

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EMC MM-04-54-08-A
EMC MM-03-54-04-A
EMC OR-01-54-02

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10.1038/s41588-020-00763-1

https://cris.maastrichtuniversity.nl/ws/files/89542830/Keszthelyi_2021_Large_scale_association_analyses_identify_host.pdfLicence: Article 25fa Dutch Copyright Act

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Kurilshikov, A., Medina Gomez, M., 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., ... Zhernakova, A. (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

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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 = "A Kurilshikov and {Medina Gomez}, Maria and R Bacigalupe and Djawad Radjabzadeh and J Wang and A Demirkan and {Le Roy}, CI and JAR Garay and CT Finnicum and XR Liu and DV Zhernakova and MJ Bonder and TH Hansen and F Frost and MC Ruhlemann and W Turpin and JY Moon and HN Kim and K Lull and E Barkan and SA Shah and M Fornage and J Szopinska-Tokov and ZD Wallen and D Borisevich and L Agreus and A Andreasson and C Bang and L Bedrani and JT Bell and H Bisgaard and M Boehnke and DI Boomsma and RD Burk and A Claringbould and K Croitoru and GE Davies and Cornelia Duijn and Liesbeth Duijts and G Falony and JY Fu and A Graaf and T Hansen and G Homuth and DA Hughes and RG Ijzerman and {O. Jackson}, Matthew and Vincent Jaddoe and M Joossens and T Jorgensen and D Keszthelyi and R Knight and M Laakso and M Laudes and LJ Launer and W Lieb and AJ Lusis and AAM Masclee and Henriette Moll and Z Mujagic and Q Qibin and D Rothschild and H Shin and SJ Sorensen and CJ Steves and J Thorsen and NJ Timpson and RY Tito and S Vieira-Silva and U Volker and H Volzke and U Vosa and KH Wade and S Walter and K Watanabe and S Weiss and FU Weiss and O Weissbrod and HJ Westra and G Willemsen and H Payami and D Jonkers and AA Vasquez and {de Geus}, EJCN and KA Meyer and J Stokholm and E Segal and E Org and C Wijmenga and HL Kim and RC Kaplan and TD Spector and Andr{\'e} Uitterlinden and Fernando Rivadeneira and A Franke and MM Lerch and L Franke and S Sanna and M D'Amato and O Pedersen and AD Paterson and Robert Kraaij and J Raes and A Zhernakova",

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

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month = feb,

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

language = "English",

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Kurilshikov, A, Medina Gomez, M, 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, Duijn, C, Duijts, L, Falony, G, Fu, JY, Graaf, A, Hansen, T, Homuth, G, Hughes, DA, Ijzerman, RG, O. Jackson, M, Jaddoe, V, Joossens, M, Jorgensen, T, Keszthelyi, D, Knight, R, Laakso, M, Laudes, M, Launer, LJ, Lieb, W, Lusis, AJ, Masclee, AAM, Moll, H, Mujagic, Z, Qibin, Q, Rothschild, D, Shin, H, Sorensen, SJ, Steves, CJ, Thorsen, J, Timpson, NJ, Tito, RY, Vieira-Silva, S, Volker, U, Volzke, H, Vosa, U, Wade, KH, Walter, S, Watanabe, K, Weiss, S, Weiss, FU, Weissbrod, O, Westra, HJ, Willemsen, G, Payami, H, Jonkers, D, Vasquez, AA, de Geus, EJCN, Meyer, KA, Stokholm, J, Segal, E, Org, E, Wijmenga, C, Kim, HL, Kaplan, RC, Spector, TD, Uitterlinden, A , Rivadeneira, F, Franke, A, Lerch, MM, Franke, L, Sanna, S, D'Amato, M, Pedersen, O, Paterson, AD, Kraaij, R, Raes, J & Zhernakova, A 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, Maria

AU - Bacigalupe, R

AU - Radjabzadeh, Djawad

AU - Wang, J

AU - Demirkan, A

AU - Le Roy, CI

AU - Garay, JAR

AU - Finnicum, CT

AU - Liu, XR

AU - Zhernakova, DV

AU - Bonder, MJ

AU - Hansen, TH

AU - Frost, F

AU - Ruhlemann, MC

AU - Turpin, W

AU - Moon, JY

AU - Kim, HN

AU - Lull, K

AU - Barkan, E

AU - Shah, SA

AU - Fornage, M

AU - Szopinska-Tokov, J

AU - Wallen, ZD

AU - Borisevich, D

AU - Agreus, L

AU - Andreasson, A

AU - Bang, C

AU - Bedrani, L

AU - Bell, JT

AU - Bisgaard, H

AU - Boehnke, M

AU - Boomsma, DI

AU - Burk, RD

AU - Claringbould, A

AU - Croitoru, K

AU - Davies, GE

AU - Duijn, Cornelia

AU - Duijts, Liesbeth

AU - Falony, G

AU - Fu, JY

AU - Graaf, A

AU - Hansen, T

AU - Homuth, G

AU - Hughes, DA

AU - Ijzerman, RG

AU - O. Jackson, Matthew

AU - Jaddoe, Vincent

AU - Joossens, M

AU - Jorgensen, T

AU - Keszthelyi, D

AU - Knight, R

AU - Laakso, M

AU - Laudes, M

AU - Launer, LJ

AU - Lieb, W

AU - Lusis, AJ

AU - Masclee, AAM

AU - Moll, Henriette

AU - Mujagic, Z

AU - Qibin, Q

AU - Rothschild, D

AU - Shin, H

AU - Sorensen, SJ

AU - Steves, CJ

AU - Thorsen, J

AU - Timpson, NJ

AU - Tito, RY

AU - Vieira-Silva, S

AU - Volker, U

AU - Volzke, H

AU - Vosa, U

AU - Wade, KH

AU - Walter, S

AU - Watanabe, K

AU - Weiss, S

AU - Weiss, FU

AU - Weissbrod, O

AU - Westra, HJ

AU - Willemsen, G

AU - Payami, H

AU - Jonkers, D

AU - Vasquez, AA

AU - de Geus, EJCN

AU - Meyer, KA

AU - Stokholm, J

AU - Segal, E

AU - Org, E

AU - Wijmenga, C

AU - Kim, HL

AU - Kaplan, RC

AU - Spector, TD

AU - Uitterlinden, André

AU - Rivadeneira, Fernando

AU - Franke, A

AU - Lerch, MM

AU - Franke, L

AU - Sanna, S

AU - D'Amato, M

AU - Pedersen, O

AU - Paterson, AD

AU - Kraaij, Robert

AU - Raes, J

AU - Zhernakova, A

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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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

Abstract

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