The human gut microbiome is a complex ecosystem that is involved in its host’s metabolism, immunity and health. Although interindividual variations in gut microbial composition are mainly driven by environmental factors, some gut microorganisms are heritable and thus can be influenced by host genetics. In the past 5 years, 12 microbial genome-wide association studies (mbGWAS) with >1,000 participants have been published, yet only a few genetic loci have been consistently confirmed across multiple studies. Here we discuss the state of the art for mbGWAS, focusing on current challenges such as the heterogeneity of microbiome measurements and power issues, and we elaborate on potential future directions for genetic analysis of the microbiome.
This is a preview of subscription content, access via your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Falony, G. et al. Population-level analysis of gut microbiome variation. Science 352, 560–564 (2016).
Kurilshikov, A. et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat. Genet. 53, 156–165 (2021).
Lopera-Maya, E. A. et al. Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project. Nat. Genet. https://doi.org/10.1038/s41588-021-00992-y (2022).
Gacesa, R. et al. The Dutch Microbiome Project defines factors that shape the healthy gut microbiome. Preprint at bioRxiv https://doi.org/10.1101/2020.11.27.401125 (2020).
Qin, Y. et al. Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort. Nat. Genet. https://doi.org/10.1038/s41588-021-00991-z (2022).
Pasolli, E. et al. Extensive unexplored human microbiome diversity revealed by over 150,000 genomes from metagenomes spanning age, geography, and lifestyle. Cell 176, 649–662 (2019).
Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018).
Zhernakova, A. et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352, 565–569 (2016).
Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014).
Goodrich, J. K. et al. Genetic determinants of the gut microbiome in UK twins. Cell Host Microbe 19, 731–743 (2016).
Turpin, W. et al. Association of host genome with intestinal microbial composition in a large healthy cohort. Nat. Genet. 48, 1413–1417 (2016).
Hughes, D. A. et al. Genome-wide associations of human gut microbiome variation and implications for causal inference analyses. Nat. Microbiol. 5, 1079–1087 (2020).
Xu, F. et al. The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for complex human diseases. Microbiome 8, 145 (2020).
Liu, X. et al. A genome-wide association study for gut metagenome in Chinese adults illuminates complex diseases. Cell Discov. 7, 9 (2021).
Blekhman, R. et al. Host genetic variation impacts microbiome composition across human body sites. Genome Biol. 16, 191 (2015).
Davenport, E. R. et al. Genome-wide association studies of the human gut microbiota. PLoS ONE 10, e0140301 (2015).
Pilia, G. et al. Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet. 2, e132 (2006).
Rühlemann, M. C. et al. Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome. Nat. Genet. 53, 147–155 (2021).
Bonder, M. J. et al. The effect of host genetics on the gut microbiome. Nat. Genet. 48, 1407–1412 (2016).
Wang, J. et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat. Genet. 48, 1396–1406 (2016).
Pang, X. et al. Mosquito C-type lectins maintain gut microbiome homeostasis. Nat. Microbiol. 1, 16023 (2016).
Suzuki, T. A. & Ley, R. E. The role of the microbiota in human genetic adaptation. Science 370, eaaz6827 (2020).
Hove, H., Nørgaard, H. & Mortensen, P. B. Lactic acid bacteria and the human gastrointestinal tract. Eur. J. Clin. Nutr. 53, 339–350 (1999).
Yang, H. et al. An ancient deletion in the ABO gene affects the composition of the porcine microbiome by altering intestinal N-acetyl-galactosamine concentrations. Preprint at bioRxiv https://doi.org/10.1101/2020.07.16.206219 (2020).
Rausch, P. et al. Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (secretor) genotype. Proc. Natl Acad. Sci. USA 108, 19030–19035 (2011).
Folseraas, T. et al. Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. J. Hepatol. 57, 366–375 (2012).
Tong, M. et al. Reprograming of gut microbiome energy metabolism by the FUT2 Crohn’s disease risk polymorphism. ISME J. 8, 2193–2206 (2014).
Burgueño-Bucio, E., Mier-Aguilar, C. A. & Soldevila, G. The multiple faces of CD5. J. Leukoc. Biol. 105, 891–904 (2019).
Burton, P. R. et al. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
Scott, L. J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).
Saxena, R. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).
Timpson, N. J. et al. Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes 58, 505–510 (2009).
Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).
Menzel, S. et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat. Genet. 39, 1197–1199 (2007).
Uda, M. et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia. Proc. Natl Acad. Sci. USA 105, 1620–1625 (2008).
Sinnott-Armstrong, N. et al. Genetics of 35 blood and urine biomarkers in the UK Biobank. Nat. Genet. 53, 185–194 (2021).
Locke, A. E. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).
Yengo, L. et al. Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry. Hum. Mol. Genet. 27, 3641–3649 (2018).
Karlsson Linnér, R. et al. Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences. Nat. Genet. 51, 245–257 (2019).
Zheng, T. et al. Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease. Gut 70, 1538–1549 (2021).
Perola, M. et al. Combined genome scans for body stature in 6,602 European twins: evidence for common Caucasian loci. PLoS Genet. 3, e97 (2007).
Weedon, M. N. et al. A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat. Genet. 39, 1245–1250 (2007).
Sanna, S. et al. Common variants in the GDF5–UQCC region are associated with variation in human height. Nat. Genet. 40, 198–203 (2008).
Galarneau, G. et al. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat. Genet. 42, 1049–1051 (2010).
Danjou, F. et al. Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels. Nat. Genet. 47, 1264–1271 (2015).
Palmer, C. & Pe’er, I. Statistical correction of the winner’s curse explains replication variability in quantitative trait genome-wide association studies. PLoS Genet. 13, e1006916 (2017).
Lloréns-Rico, V., Vieira-Silva, S., Gonçalves, P. J., Falony, G. & Raes, J. Benchmarking microbiome transformations favors experimental quantitative approaches to address compositionality and sampling depth biases. Nat. Commun. 12, 3562 (2021).
Vandeputte, D. et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature 551, 507–511 (2017).
Turley, P. et al. Multi-trait analysis of genome-wide association summary statistics using MTAG. Nat. Genet. 50, 229–237 (2018).
Schloissnig, S. et al. Genomic variation landscape of the human gut microbiome. Nature 493, 45–50 (2013).
Xie, H. et al. Shotgun metagenomics of 250 adult twins reveals genetic and environmental impacts on the gut microbiome. Cell Syst. 3, 572–584 (2016).
Zeevi, D. et al. Structural variation in the gut microbiome associates with host health. Nature 568, 43–48 (2019).
Costea, P. I. et al. metaSNV: a tool for metagenomic strain level analysis. PLoS ONE 12, e0182392 (2017).
Olm, M. R. et al. inStrain profiles population microdiversity from metagenomic data and sensitively detects shared microbial strains. Nat. Biotechnol. 39, 727–736 (2021).
DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).
Andreu-Sánchez, S. et al. A benchmark of genetic variant calling pipelines using metagenomic short-read sequencing. Front. Genet. 12, 537 (2021).
Ramiro, R. S., Durão, P., Bank, C. & Gordo, I. Low mutational load and high mutation rate variation in gut commensal bacteria. PLoS Biol. 18, e3000617 (2020).
Chen, L. et al. The long-term genetic stability and individual specificity of the human gut microbiome. Cell 184, 2302–2315 (2021).
Steri, M. et al. Overexpression of the cytokine BAFF and autoimmunity risk. N. Engl. J. Med. 376, 1615–1626 (2017).
Plomin, R., Haworth, C. M. A. & Davis, O. S. P. Common disorders are quantitative traits. Nat. Rev. Genet. 10, 872–878 (2009).
Franzosa, E. A. et al. Species-level functional profiling of metagenomes and metatranscriptomes. Nat. Methods 15, 962–968 (2018).
Schirmer, M. et al. Dynamics of metatranscription in the inflammatory bowel disease gut microbiome. Nat. Microbiol. 3, 337–346 (2018).
Long, S. et al. Metaproteomics characterizes human gut microbiome function in colorectal cancer. npj Biofilms Microbiomes 6, 14 (2020).
Zierer, J. et al. The fecal metabolome as a functional readout of the gut microbiome. Nat. Genet. 50, 790–795 (2018).
Bar, N. et al. A reference map of potential determinants for the human serum metabolome. Nature 588, 135–140 (2020).
Chen, S. et al. Runx2+ niche cells maintain incisor mesenchymal tissue homeostasis through IGF signaling. Cell Rep. 32, 108007 (2020).
Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science 350, 1084–1089 (2015).
Matson, V. et al. The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).
We thank K. McIntyre for help developing the manuscript. A.Z. is supported by European Research Council Starting grant 715772, Netherlands Organization for Scientific Research (NWO) VIDI grant 016.178.056, CVON grant 806 2018-27 and NWO Gravitation grant ExposomeNL 024.004.017. J.F. is supported by CVON grant 2018-27, European Research Council Consolidator grant 101001678 and NWO VICI grant VI.C.202.022.
The authors declare no competing interests.
Peer review information Nature Genetics thanks Andre Franke and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Sanna, S., Kurilshikov, A., van der Graaf, A. et al. Challenges and future directions for studying effects of host genetics on the gut microbiome. Nat Genet 54, 100–106 (2022). https://doi.org/10.1038/s41588-021-00983-z
This article is cited by
Heritability and recursive influence of host genetics on the rumen microbiota drive body weight variance in male Hu sheep lambs
Nature Reviews Nephrology (2023)
Nature Reviews Gastroenterology & Hepatology (2022)
Nature Genetics (2022)