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Genome-wide associations of human gut microbiome variation and implications for causal inference analyses

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Abstract
Recent population-based(1-4)and clinical studies(5)have identified a range of factors associated with human gut microbiome variation. Murine quantitative trait loci(6), human twin studies(7)and microbiome genome-wide association studies(1,3,8-12)have provided evidence for genetic contributions to microbiome composition. Despite this, there is still poor overlap in genetic association across human studies. Using appropriate taxon-specific models, along with support from independent cohorts, we show an association between human host genotype and gut microbiome variation. We also suggest that interpretation of applied analyses using genetic associations is complicated by the probable overlap between genetic contributions and heritable components of host environment. Using faecal 16S ribosomal RNA gene sequences and host genotype data from the Flemish Gut Flora Project (n = 2,223) and two German cohorts (FoCus,n = 950; PopGen,n = 717), we identify genetic associations involving multiple microbial traits. Two of these associations achieved a study-level threshold ofP = 1.57 x 10(-10); an association betweenRuminococcusandnearRAPGEF1on chromosome 9, and betweenCoprococcusandwithinLINC01787on chromosome 1. Exploratory analyses were undertaken using 11 other genome-wide associations with strong evidence for association (P < 2.5 x 10(-8)) and a previously reported signal of association between(MCM6/LCT) andBifidobacterium. Across these 14 single-nucleotide polymorphisms there was evidence of signal overlap with other genome-wide association studies, including those for age at menarche and cardiometabolic traits. Mendelian randomization analysis was able to estimate associations between microbial traits and disease (includingBifidobacteriumand body composition); however, in the absence of clear microbiome-driven effects, caution is needed in interpretation. Overall, this work marks a growing catalogue of genetic associations that will provide insight into the contribution of host genotype to gut microbiome. Despite this, the uncertain origin of association signals will likely complicate future work looking to dissect function or use associations for causal inference analysis.
Keywords
Immunology, Microbiology (medical), Applied Microbiology and Biotechnology, Genetics, Cell Biology, Microbiology, MENDELIAN RANDOMIZATION, SUSCEPTIBILITY LOCI, HOST GENETICS, IMPUTATION, METAANALYSIS, BUTYRATE, INSIGHTS, TOOL

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MLA
Hughes, David A., et al. “Genome-Wide Associations of Human Gut Microbiome Variation and Implications for Causal Inference Analyses.” NATURE MICROBIOLOGY, 2020, doi:10.1038/s41564-020-0743-8.
APA
Hughes, D. A., Bacigalupe, R., Wang, J., Ruehlemann, M. C., Tito, R. Y., Falony, G., … Raes, J. (2020). Genome-wide associations of human gut microbiome variation and implications for causal inference analyses. NATURE MICROBIOLOGY. https://doi.org/10.1038/s41564-020-0743-8
Chicago author-date
Hughes, David A., Rodrigo Bacigalupe, Jun Wang, Malte C. Ruehlemann, Raul Y. Tito, Gwen Falony, Marie Joossens, et al. 2020. “Genome-Wide Associations of Human Gut Microbiome Variation and Implications for Causal Inference Analyses.” NATURE MICROBIOLOGY. https://doi.org/10.1038/s41564-020-0743-8.
Chicago author-date (all authors)
Hughes, David A., Rodrigo Bacigalupe, Jun Wang, Malte C. Ruehlemann, Raul Y. Tito, Gwen Falony, Marie Joossens, Sara Vieira-Silva, Liesbet Henckaerts, Leen Rymenans, Chloe Verspecht, Susan Ring, Andre Franke, Kaitlin H. Wade, Nicholas J. Timpson, and Jeroen Raes. 2020. “Genome-Wide Associations of Human Gut Microbiome Variation and Implications for Causal Inference Analyses.” NATURE MICROBIOLOGY. doi:10.1038/s41564-020-0743-8.
Vancouver
1.
Hughes DA, Bacigalupe R, Wang J, Ruehlemann MC, Tito RY, Falony G, et al. Genome-wide associations of human gut microbiome variation and implications for causal inference analyses. NATURE MICROBIOLOGY. 2020;
IEEE
[1]
D. A. Hughes et al., “Genome-wide associations of human gut microbiome variation and implications for causal inference analyses,” NATURE MICROBIOLOGY, 2020.
@article{8669425,
  abstract     = {Recent population-based(1-4)and clinical studies(5)have identified a range of factors associated with human gut microbiome variation. Murine quantitative trait loci(6), human twin studies(7)and microbiome genome-wide association studies(1,3,8-12)have provided evidence for genetic contributions to microbiome composition. Despite this, there is still poor overlap in genetic association across human studies. Using appropriate taxon-specific models, along with support from independent cohorts, we show an association between human host genotype and gut microbiome variation. We also suggest that interpretation of applied analyses using genetic associations is complicated by the probable overlap between genetic contributions and heritable components of host environment. Using faecal 16S ribosomal RNA gene sequences and host genotype data from the Flemish Gut Flora Project (n = 2,223) and two German cohorts (FoCus,n = 950; PopGen,n = 717), we identify genetic associations involving multiple microbial traits. Two of these associations achieved a study-level threshold ofP = 1.57 x 10(-10); an association betweenRuminococcusandnearRAPGEF1on chromosome 9, and betweenCoprococcusandwithinLINC01787on chromosome 1. Exploratory analyses were undertaken using 11 other genome-wide associations with strong evidence for association (P < 2.5 x 10(-8)) and a previously reported signal of association between(MCM6/LCT) andBifidobacterium. Across these 14 single-nucleotide polymorphisms there was evidence of signal overlap with other genome-wide association studies, including those for age at menarche and cardiometabolic traits. Mendelian randomization analysis was able to estimate associations between microbial traits and disease (includingBifidobacteriumand body composition); however, in the absence of clear microbiome-driven effects, caution is needed in interpretation. Overall, this work marks a growing catalogue of genetic associations that will provide insight into the contribution of host genotype to gut microbiome. Despite this, the uncertain origin of association signals will likely complicate future work looking to dissect function or use associations for causal inference analysis.},
  author       = {Hughes, David A. and Bacigalupe, Rodrigo and Wang, Jun and Ruehlemann, Malte C. and Tito, Raul Y. and Falony, Gwen and Joossens, Marie and Vieira-Silva, Sara and Henckaerts, Liesbet and Rymenans, Leen and Verspecht, Chloe and Ring, Susan and Franke, Andre and Wade, Kaitlin H. and Timpson, Nicholas J. and Raes, Jeroen},
  issn         = {2058-5276},
  journal      = {NATURE MICROBIOLOGY},
  keywords     = {Immunology,Microbiology (medical),Applied Microbiology and Biotechnology,Genetics,Cell Biology,Microbiology,MENDELIAN RANDOMIZATION,SUSCEPTIBILITY LOCI,HOST GENETICS,IMPUTATION,METAANALYSIS,BUTYRATE,INSIGHTS,TOOL},
  language     = {eng},
  pages        = {20},
  title        = {Genome-wide associations of human gut microbiome variation and implications for causal inference analyses},
  url          = {http://dx.doi.org/10.1038/s41564-020-0743-8},
  year         = {2020},
}

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