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 Le Roy; Juan Antonio Raygoza Garay; Casey T. Finnicum; Xingrong Liu; Daria Zhernakova; Marc Jan Bonder; Tue H. Hansen; Fabian Frost; Malte C. Ruhlemann; 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 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 Jorgensen; 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; Soren J. Sorensen; Claire J. Steves; Jonathan Thorsen; Nicholas J. Timpson; Raul Y. Tito; Sara Vieira-Silva; Uwe Volker; Henry Volzke; Urmo Vosa; 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

doi:10.1038/s41588-020-00763-1

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

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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 Le Roy, Juan Antonio Raygoza Garay, Casey T. Finnicum, Xingrong Liu, …

Nature genetics, Vol.53(2), pp.156-165

01/02/2021

DOI: https://doi.org/10.1038/s41588-020-00763-1

PMID: 33462485

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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.

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Title: Large-scale association analyses identify host factors influencing human gut microbiome composition
Creators: Alexander Kurilshikov - University of Groningen
Carolina Medina-Gomez - Erasmus MC Univ Med Ctr, Dept Internal Med, Rotterdam, Netherlands
Rodrigo Bacigalupe - KU Leuven
Djawad Radjabzadeh - Erasmus MC Univ Med Ctr, Dept Internal Med, Rotterdam, Netherlands
Jun Wang - KU Leuven
Ayse Demirkan - University of Groningen
Caroline Le Roy - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Juan Antonio Raygoza Garay - University of Toronto
Casey T. Finnicum - Avera McKennan Hosp, Avera Inst Human Genet, Sioux Falls, SD USA
Xingrong Liu - Karolinska Institutet
Daria Zhernakova - University of Groningen
Marc Jan Bonder - University of Groningen
Tue H. Hansen - University of Copenhagen
Fabian Frost - College Station Medical Center
Malte C. Ruhlemann - Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Williams Turpin - University of Toronto
Jee-Young Moon - Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA
Han-Na Kim - Sungkyunkwan University
Kreete Lull - University of Tartu
Elad Barkan - Weizmann Inst Sci, Dept Comp Sci & Cell Biol, Rehovot, Israel
Shiraz A. Shah - Copenhagen Univ Hosp, COPSAC, Copenhagen, Denmark
Myriam Fornage - Supreme Council Of Health
Joanna Szopinska-Tokov - Supreme Council Of Health
Zachary D. Wallen - University of Alabama
Dmitrii Borisevich - University of Copenhagen
Lars Agreus - Karolinska Institutet
Anna Andreasson - Stockholm University
Corinna Bang - Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Larbi Bedrani - University of Toronto
Jordana T. Bell - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Hans Bisgaard - Copenhagen Univ Hosp, COPSAC, Copenhagen, Denmark
Michael Boehnke - Biostat
Dorret Boomsma - Vrije Univ, Biol Psychol, Amsterdam, Netherlands
Robert D. Burk - Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA
Annique Claringbould - University of Groningen
Kenneth Croitoru - University of Toronto
Gareth E. Davies - Avera McKennan Hosp, Avera Inst Human Genet, Sioux Falls, SD USA
Cornelia M. van Duijn - Erasmus MC
Liesbeth Duijts - Erasmus MC Univ Med Ctr, Generat R Study, Rotterdam, Netherlands
Gwen Falony - KU Leuven
Jingyuan Fu - University of Groningen
Adriaan van der Graaf - University of Groningen
Torben Hansen - University of Copenhagen
Georg Homuth - College Station Medical Center
David A. Hughes - University of Bristol
Richard G. Ijzerman - College Station Medical Center
Matthew A. Jackson - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Vincent W. V. Jaddoe - Erasmus MC
Marie Joossens - KU Leuven
Torben Jorgensen - University of Copenhagen
Daniel Keszthelyi - Maastricht University
Rob Knight - Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
Markku Laakso - University of Eastern Finland
Matthias Laudes - College Station Medical Center
Lenore J. Launer - NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA
Wolfgang Lieb - Univ Kiel, Inst Epidemiol, Kiel, Germany
Aldons J. Lusis - Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90024 USA
Ad A. M. Masclee - Maastricht University
Henriette A. Moll - Erasmus MC Univ Med Ctr, Dept Pediat, Rotterdam, Netherlands
Zlatan Mujagic - Maastricht University
Qi Qibin - Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA
Daphna Rothschild - Weizmann Inst Sci, Dept Comp Sci & Cell Biol, Rehovot, Israel
Hocheol Shin - Sungkyunkwan University
Soren J. Sorensen - University of Copenhagen
Claire J. Steves - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Jonathan Thorsen - Copenhagen Univ Hosp, COPSAC, Copenhagen, Denmark
Nicholas J. Timpson - University of Bristol
Raul Y. Tito - KU Leuven
Sara Vieira-Silva - KU Leuven
Uwe Volker - College Station Medical Center
Henry Volzke - College Station Medical Center
Urmo Vosa - University of Groningen
Kaitlin H. Wade - University of Bristol
Susanna Walter - Univ Linkoping, Dept Biomed & Clin Sci, Linkoping, Sweden
Kyoko Watanabe - University of Amsterdam
Stefan Weiss - College Station Medical Center
Frank U. Weiss - College Station Medical Center
Omer Weissbrod - Harvard University
Harm-Jan Westra - University of Groningen
Gonneke Willemsen - Vrije Univ, Biol Psychol, Amsterdam, Netherlands
Haydeh Payami - University of Alabama
Daisy M. A. E. Jonkers - Maastricht University
Alejandro Arias Vasquez - Supreme Council Of Health
Eco J. C. de Geus - Vrije Univ, Biol Psychol, Amsterdam, Netherlands
Katie A. Meyer - Univ N Carolina, Dept Nutr, Chapel Hill, NC USA
Jakob Stokholm - Copenhagen Univ Hosp, COPSAC, Copenhagen, Denmark
Eran Segal - Weizmann Inst Sci, Dept Comp Sci & Cell Biol, Rehovot, Israel
Elin Org - University of Tartu
Cisca Wijmenga - University of Groningen
Hyung-Lae Kim - Ewha Womans University
Robert C. Kaplan - Hutchinson
Tim D. Spector - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Andre G. Uitterlinden - Erasmus MC Univ Med Ctr, Dept Internal Med, Rotterdam, Netherlands
Fernando Rivadeneira - Erasmus MC
Andre Franke - Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Markus M. Lerch - College Station Medical Center
Lude Franke - University of Groningen
Serena Sanna - University of Groningen
Mauro D'Amato - Karolinska Institutet
Oluf Pedersen - University of Copenhagen
Andrew D. Paterson - Sick
Robert Kraaij - Erasmus MC Univ Med Ctr, Dept Internal Med, Rotterdam, Netherlands
Jeroen Raes - KU Leuven
Alexandra Zhernakova - University of Groningen
Publication Details: Nature genetics, Vol.53(2), pp.156-165
Publisher: NATURE PORTFOLIO
Number of pages: 19
First online publication date: 18/01/2021
Publication Date: 01/02/2021
Date accepted for publication: 14/12/2020
Grant note: MR/N01183X/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC)
Identifiers: 99828362302346; WOS:000608658900003
Academic Unit: School of Biosciences; Surrey Institute for People-Centred AI
Language: English
Resource Type: Journal article
Data Access Statement: Full GWAS summary statistics for mbQTLs are available at www.mibiogen.org, built using the MOLGENIS framework80. 16S data availability: BSPSPC and FOCUS data is available from the Sequence Read Archive (SRA) under accession PRJNA673102. All CARDIA data, including 16S rRNA sequencing, cannot be made publicly available due to the confidentiality restrictions. The data can be requested from CARDIA Study Data Coordinating Center at the University of Alabama at Birmingham, following CARDIA Confidentiality Certification rules. The process for obtaining data through CARDIA is outlined at https://www.cardia.dopm.uab.edu/publications-2/publications-documents. COPSAC data are available on SRA (PRJNA683912). DanFunD data are not deposited on the public databases due to legal and ethical restrictions. Access to the data and biological material can be granted by the DanFunD steering committee (https://www.frederiksberghospital.dk/ckff/sektioner/SBE/danfund/Sider/How-to-collaborate.aspx). FGFP data are available on the European Genome-Phenome Archive (EGA) under accession EGAS00001004420. GEM data are available on the SRA (PRJEB14839). Generation R and Rotterdam Study data cannot be made publicly available due to ethical and legal restrictions; these data are available upon request to the data manager of the Rotterdam Study (f.vanrooij@erasmusmc.nl) or of the Generation R Study (c.kruithof@erasmusmc.nl), subject to local rules and regulations. HCHS/SOL data are available from the European Nucleotide Archive (ENA) under accession ERP117287. KSCS data are available at the public repository, Clinical and Omics data archives in the Korea National Institute of Health under accession R000635. LLD and MIBS data are available from EGA (EGAS00001001704 and EGAS0000100924). METSIM data are available on the SRA (SRP097785). NGRC data are available on the ENA (ERP016332). The NTR has a data access committee that reviews data requests and will make data available to interested researchers. The data come from extended twin families and pedigree structures with twins, which create privacy concerns and thus cannot be shared on publicly available databases. Researchers may contact eco.de.geus@vu.nl for data requests. PNP is available on the ENA (PRJEB11532). POPCOL is available on the EGA (EGAS00001004869). SHIP and SHIP-TREND data can be obtained from the SHIP data management unit via an online data access application form (https://www.fvcm.med.uni-greifswald.de/dd_service/data_use_intro.php). TwinsUK data are available on the ENA under accession ERP015317. Code availability All code used in the study is available on the Consortium GitHub (https://github.com/alexa-kur/miQTL_cookbook) or on the websites of corresponding software packages.

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

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