Genetic architecture and mechanisms of host-microbiome interactions from a multi-cohort analysis of outbred laboratory rats
The intestinal microbiome influences health and disease. Its composition is affected by host genetics and environmental exposures. Understanding host genetic effects is critical but challenging in humans, due to the difficulty of detecting, mapping and interpreting them. To address this, we analyse host genetic effects in four cohorts of outbred laboratory rats exposed to distinct but controlled environments. We show that polygenic host genetic effects are consistent across cohort environments. We identify three replicated microbiome-associated loci, one of which involves the sialyltransferase gene St6galnac1 and Paraprevotella. We find a similar association in a human cohort, between ST6GAL1 and Paraprevotella, both of which have been linked with immune and infectious diseases. Moreover, we find indirect (i.e. social) genetic effects on microbiome phenotypes, which substantially increase the total genetic variance. Finally, we identify a novel mechanism whereby indirect genetic effects can contribute to "missing heritability".
Authors
- Leah C. Solberg Woods (ORCID: https://orcid.org/0000-0002-7943-798X)
- Felipe M. S. Dias (ORCID: https://orcid.org/0000-0001-5232-4312)
- Hélène Tonnelé (ORCID: https://orcid.org/0000-0001-6015-0471)
- Marc Jan Bonder (ORCID: https://orcid.org/0000-0002-8431-3180)
- Thiago Missfeldt Sanches (ORCID: https://orcid.org/0000-0001-6962-9569)
- Oksana Polesskaya (ORCID: https://orcid.org/0000-0003-3024-114X)
- Riyan Cheng (ORCID: https://orcid.org/0000-0002-8670-795X)
- Christopher P. King (ORCID: https://orcid.org/0000-0002-6641-237X)
- Amelie Baud (ORCID: https://orcid.org/0000-0003-2448-0283)
- Peter A. Doris (ORCID: https://orcid.org/0000-0002-0565-7939)
- Keita Ishiwari (ORCID: https://orcid.org/0000-0002-6190-2249)
- Jerry B. Richards
- Terry E. Robinson (ORCID: https://orcid.org/0000-0001-7861-3737)
- Abraham A. Palmer (ORCID: https://orcid.org/0000-0003-3634-0747)
- Jordan A. Tripi
- Rob Knight (ORCID: https://orcid.org/0000-0002-0975-9019)
- Wenyan Han (ORCID: https://orcid.org/0000-0003-0886-1430)
- Alexander Lamparelli (ORCID: https://orcid.org/0000-0003-1908-9562)
- Anthony M. George (ORCID: https://orcid.org/0000-0003-4691-8960)
- Paul Meyer (ORCID: https://orcid.org/0000-0001-5665-2292)
- Elena Bosch (ORCID: https://orcid.org/0000-0003-2848-103X)
- Apurva S. Chitre (ORCID: https://orcid.org/0000-0003-1709-9214)
- Alesa H. Netzley (ORCID: https://orcid.org/0000-0003-0171-3363)
- Denghui Chen (ORCID: https://orcid.org/0000-0002-6541-3418)
- Jorge Garcia-Calleja (ORCID: https://orcid.org/0000-0002-4614-4574)
- Aidan P. Horvath
- Shelly B. Flagel (ORCID: https://orcid.org/0000-0002-7309-9908)
- Hao Chen (ORCID: https://orcid.org/0000-0002-2680-6921)
- Connor D. Martin (ORCID: https://orcid.org/0000-0002-6989-5653)
- Tomasz Kościółek (ORCID: https://orcid.org/0000-0002-9915-7387)
- Benjamin B. Johnson (ORCID: https://orcid.org/0000-0001-7269-5145)
- Oliver Stegle (ORCID: https://orcid.org/0000-0002-8818-7193)
- Antonio González (ORCID: https://orcid.org/0000-0003-0658-6607)
- Ángel García-Martínez (ORCID: https://orcid.org/0000-0002-0149-3770)
- Katie Holl (ORCID: https://orcid.org/0009-0007-9166-7423)
- Tengfei Wang
Institutions
- University Medical Center Groningen (NL)
- Texas Medical Center (US)
- University of Tennessee Health Science Center (US)
- University of Groningen (NL)
- Universitat Pompeu Fabra (ES)
- German Cancer Research Center (DE)
- Medical College of Wisconsin (US)
- Heidelberg University (DE)
- University of Michigan (US)
- University of California San Diego (US)
- La Jolla Bioengineering Institute (US)
- Institut de Biologia Evolutiva (ES)
- Centre for Genomic Regulation (ES)
- European Molecular Biology Laboratory (DE)
- La Jolla Institute For Molecular Medicine (US)
- The University of Texas Health Science Center (US)
- Wake Forest University (US)
- University at Buffalo, State University of New York (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-18
- DOI
- https://doi.org/10.1038/s41467-025-66105-z
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00