Large-scale association analyses identify host factors influencing human gut microbiome composition
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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. Analysis of human genotypes and 16S microbiome data of 18,473 individuals from 25 cohorts through a genome-wide association study, a phenome-wide association study and Mendelian randomization identifies host genetic and microbial trait associations.
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The lack of significant genetic correlations after Bonferroni correction is likely due to the relatively low heritability of microbiota traits.
“Although LDSC analysis suggested potential genetic associations between gut-brain disorders and microbial features, none remained statistically significant after Bonferroni correction—likely due to the low heritability of microbiota traits [24].”
From The hidden genetic and microbial networks connecting neuropsychiatric and digestive disorders (2025) · cites this paper as [24]
The Results section, “Heritability of microbial taxa and alpha diversity” (page unavailable), finds evidence of heritability for only a subset of bacterial taxa, supporting the low-heritability premise. The cited paper does not attribute a lack of Bonferroni-significant genetic correlations between gut-brain disorders and microbial features to low heritability; its LDSC results concern heritability of microbial taxa, not those correlations. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPolymorphisms in the FUT2/FUT1 secretor locus and variants near the ABO gene modulate fucosylated mucin production and favor mucin specialists like Ruminococcus torques.
“whereas polymorphisms in the FUT2/FUT1 secretor locus and variants near the ABO gene modulate fucosylated mucin production and favor mucin specialists like Ruminococcus torques.63,64”
From Gut dysbiosis in oncology: a risk factor for immunoresistance (2026) · cites this paper as [63]
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Role of the Microbiome in Regulating Bone Metabolism and Susceptibility to Osteoporosis
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The Role of Faecalibacterium, Roseburia, and Butyrate in Inflammatory Bowel Disease
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Host genetic determinants drive compartment‐specific assembly of tea plant microbiomes
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The Gut-Prostate Axis: A New Perspective of Prostate Cancer Biology through the Gut Microbiome
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A phenome-wide comparative analysis of genetic discordance between obesity and type 2 diabetes
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- Authors
- 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., Barkan, E., Shah, S. A., Fornage, M., Szopinska-Tokov, J., Wallen, Z. D., Borisevich, D., Agreus, L., Andreasson, A., Bang, C., Bedrani, L., Bell, J. T., Bisgaard, H., Boehnke, M., Boomsma, D. I., Burk, R. D., Claringbould, A., Croitoru, K., Davies, G. E., van Duijn, C. M., Duijts, L., Falony, G., Fu, J., van der Graaf, A., Hansen, T., Homuth, G., Hughes, D. A., Ijzerman, R. G., Jackson, M. A., Jaddoe, V. W. V., Joossens, M., Jørgensen, T., Keszthelyi, D., Knight, R., Laakso, M., Laudes, M., Launer, L. J., Lieb, W., Lusis, A. J., Masclee, A. A. M., Moll, H. A., Mujagic, Z., Qibin, Q., Rothschild, D., Shin, H., Sørensen, S. J., Steves, C. J., Thorsen, J., Timpson, N. J., Tito, R. Y., Vieira-Silva, S., Völker, U., Völzke, H., Võsa, U., Wade, K. H., Walter, S., Watanabe, K., Weiss, S., Weiss, F. U., Weissbrod, O., Westra, H.-J., Willemsen, G., Payami, H., Jonkers, D. M. A. E., Arias Vasquez, A., de Geus, E. J. C., Meyer, K. A., Stokholm, J., Segal, E., Org, E., Wijmenga, C., Kim, H.-L., Kaplan, R. C., Spector, T. D., Uitterlinden, A. G., Rivadeneira, F., Franke, A., Lerch, M. M., Franke, L., Sanna, S., D’Amato, M., Pedersen, O., Paterson, A. D., Kraaij, R., Raes, J., & Zhernakova, A.
- Affiliations
- University Medical Center Groningen (NL)
- Rega Institute for Medical Research (BE)
- Erasmus MC (NL)
- Chinese Academy of Sciences (CN)
- Avera McKennan Hospital & University Health Center (US)
- Karolinska Institutet (SE)
- University of Copenhagen (DK)
- Universitätsmedizin Greifswald (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Mount Sinai Hospital (CA)
- Albert Einstein College of Medicine (US)
- Ewha Womans University (KR)
- University of Tartu (EE)
- Weizmann Institute of Science (IL)
- Copenhagen University Hospital (DK)
- The University of Texas Health Science Center at Houston (US)
- Radboud University Medical Center (NL)
- University of Alabama at Birmingham (US)
- University of Toronto (CA)
- King's College London (GB)
- University of Michigan (US)
- Vrije Universiteit Amsterdam (NL)
- University of Bristol (GB)
- Amsterdam University Medical Centers (NL)
- University of California San Diego (US)
- University of Eastern Finland (FI)
- University Hospital Schleswig-Holstein (DE)
- National Institutes of Health (US)
- University of California, Los Angeles (US)
- Maastricht University Medical Centre (NL)
- Kangbuk Samsung Hospital (KR)
- Linköping University (SE)
- Amsterdam Neuroscience (NL)
- Harvard University (US)
- University of North Carolina at Chapel Hill (US)
- Fred Hutch Cancer Center (US)
- Ikerbasque (ES)
- Hospital for Sick Children (CA)
- Corresponding author
- Kurilshikov, Alexander
- Zhernakova, Alexandra
- ORCID
- Kurilshikov, Alexander
- Medina-Gomez, Carolina
- Bacigalupe, Rodrigo
- Radjabzadeh, Djawad
- Le Roy, Caroline I.
- Raygoza Garay, Juan Antonio
- Finnicum, Casey T.
- Liu, Xingrong
- Zhernakova, Daria V.
- Bonder, Marc Jan
- Hansen, Tue H.
- Frost, Fabian
- Rühlemann, Malte C.
- Turpin, Williams
- Moon, Jee-Young
- Kim, Han-Na
- Lüll, Kreete
- Barkan, Elad
- Shah, Shiraz A.
- Fornage, Myriam
- Szopinska-Tokov, Joanna
- Wallen, Zachary D.
- Borisevich, Dmitrii
- Andreasson, Anna
- Bang, Corinna
- Bell, Jordana T.
- Bisgaard, Hans
- Boehnke, Michael
- Boomsma, Dorret I.
- Burk, Robert D.
- Claringbould, Annique
- Croitoru, Kenneth
- van Duijn, Cornelia M.
- Duijts, Liesbeth
- Falony, Gwen
- Fu, Jingyuan
- van der Graaf, Adriaan
- Hansen, Torben
- Homuth, Georg
- Hughes, David A.
- Ijzerman, Richard G.
- Jackson, Matthew A.
- Jaddoe, Vincent W. V.
- Joossens, Marie
- Jørgensen, Torben
- Knight, Rob
- Laakso, Markku
- Laudes, Matthias
- Launer, Lenore J.
- Lieb, Wolfgang
- Lusis, Aldons J.
- Masclee, Ad A. M.
- Mujagic, Zlatan
- Rothschild, Daphna
- Sørensen, Søren J.
- Steves, Claire J.
- Thorsen, Jonathan
- Timpson, Nicholas J.
- Tito, Raul Y.
- Vieira-Silva, Sara
- Völker, Uwe
- Völzke, Henry
- Võsa, Urmo
- Wade, Kaitlin H.
- Walter, Susanna
- Watanabe, Kyoko
- Weiss, Stefan
- Weiss, Frank U.
- Weissbrod, Omer
- Westra, Harm-Jan
- Willemsen, Gonneke
- Payami, Haydeh
- Jonkers, Daisy M. A. E.
- Meyer, Katie A.
- Stokholm, Jakob
- Segal, Eran
- Org, Elin
- Wijmenga, Cisca
- Kim, Hyung-Lae
- Kaplan, Robert C.
- Spector, Tim D.
- Uitterlinden, Andre G.
- Rivadeneira, Fernando
- Lerch, Markus M.
- Franke, Lude
- Sanna, Serena
- D’Amato, Mauro
- Pedersen, Oluf
- Paterson, Andrew D.
- Kraaij, Robert
- Raes, Jeroen
- Zhernakova, Alexandra
- Venue
- Nature Genetics
- Published
- 2021-01-18
- Volume
- 53
- Issue
- 2
- Pages
- 156-165
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC8515199
- OpenAlex
- W3121407008
- Cited by
- 1,786
- References
- 81
- Citations by year
- 2026: 221 · 2025: 394 · 2024: 616 · 2023: 383 · 2022: 122 · 2021: 50
- FWCI
- 99.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- VU Research Portal (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (024.004.017)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Keywords
- gut microbiota composition, host genetics, host-microbe interactions, genome-wide association study, phenome-wide association study, Mendelian randomization, Bifidobacterium, ulcerative colitis, rheumatoid arthritis, 16S rRNA gene sequencing
- MeSH terms
- Gastrointestinal Microbiome, Adolescent, Adult, Bifidobacterium, Child, Child, Preschool, Female, Humans, Male, Metabolism, RNA, Ribosomal, 16S, Genetic Variation, Cohort Studies, Linkage Disequilibrium, Quantitative Trait Loci, Lactase, Genome-Wide Association Study, Mendelian Randomization Analysis
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