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

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.

SUBMITTER: Kurilshikov A

PROVIDER: S-EPMC8515199 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Kurilshikov Alexander A Medina-Gomez Carolina C Bacigalupe Rodrigo R Radjabzadeh Djawad D Wang Jun J Demirkan Ayse A Le Roy Caroline I CI Raygoza Garay Juan Antonio JA Finnicum Casey T CT Liu Xingrong X Zhernakova Daria V DV Bonder Marc Jan MJ Hansen Tue H TH Frost Fabian F Rühlemann Malte C MC Turpin Williams W Moon Jee-Young JY Kim Han-Na HN Lüll Kreete K Barkan Elad E Shah Shiraz A SA Fornage Myriam M Szopinska-Tokov Joanna J Wallen Zachary D ZD Borisevich Dmitrii D Agreus Lars L Andreasson Anna A Bang Corinna C Bedrani Larbi L Bell Jordana T JT Bisgaard Hans H Boehnke Michael M Boomsma Dorret I DI Burk Robert D RD Claringbould Annique A Croitoru Kenneth K Davies Gareth E GE van Duijn Cornelia M CM Duijts Liesbeth L Falony Gwen G Fu Jingyuan J van der Graaf Adriaan A Hansen Torben T Homuth Georg G Hughes David A DA Ijzerman Richard G RG Jackson Matthew A MA Jaddoe Vincent W V VWV Joossens Marie M Jørgensen Torben T Keszthelyi Daniel D Knight Rob R Laakso Markku M Laudes Matthias M Launer Lenore J LJ Lieb Wolfgang W Lusis Aldons J AJ Masclee Ad A M AAM Moll Henriette A HA Mujagic Zlatan Z Qibin Qi Q Rothschild Daphna D Shin Hocheol H Sørensen Søren J SJ Steves Claire J CJ Thorsen Jonathan J Timpson Nicholas J NJ Tito Raul Y RY Vieira-Silva Sara S Völker Uwe U Völzke Henry H Võsa Urmo U Wade Kaitlin H KH Walter Susanna S Watanabe Kyoko K Weiss Stefan S Weiss Frank U FU Weissbrod Omer O Westra Harm-Jan HJ Willemsen Gonneke G Payami Haydeh H Jonkers Daisy M A E DMAE Arias Vasquez Alejandro A de Geus Eco J C EJC Meyer Katie A KA Stokholm Jakob J Segal Eran E Org Elin E Wijmenga Cisca C Kim Hyung-Lae HL Kaplan Robert C RC Spector Tim D TD Uitterlinden Andre G AG Rivadeneira Fernando F Franke Andre A Lerch Markus M MM Franke Lude L Sanna Serena S D'Amato Mauro M Pedersen Oluf O Paterson Andrew D AD Kraaij Robert R Raes Jeroen J Zhernakova Alexandra A

Nature genetics 20210118 2

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<sup ...[more]

PMID: 33462485

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Project description:Bacterial vaginosis (BV) affects 20% of women worldwide and is associated with adverse reproductive health outcomes and increased risk for HIV. Typically, BV represents a shift in the vaginal microbiome from one that is dominated by Lactobacillus to one that is diverse. Persistent racial differences in BV and diverse vaginal microbiome composition overlap with racial disparities in risks for HIV and sexually transmitted infection, especially among women of African descent. Risk factors for BV and nonoptimal vaginal microbiome include sexual practices, yet racial differences persist when adjusted for behavioral factors, suggesting a host genetic component. Here, we perform a genome-wide association study on vaginal microbiome traits in Kenyan women. Linear regression and logistic regression were performed, adjusting for age and principal components of genetic ancestry, to evaluate the association between Lactobacillus crispatus, Lactobacillus iners, Gardnerella vaginalis, Shannon diversity index, and community state type (CST) with host genetic single nucleotide polymorphisms (SNPs). We identified novel genomic loci associated with the vaginal microbiome traits, though no SNP reached genome-wide significance. During pathway enrichment analysis, Toll-like receptors (TLRs), cytokine production, and other components of innate immune response were associated with L. crispatus, L. iners, and CST. Multiple previously reported genomic loci were replicated, including IL-8 (Shannon, CST), TIRAP (L. iners, Shannon), TLR2 (Shannon, CST), MBL2 (L. iners, G. vaginalis, CST), and MYD88 (L. iners, Shannon). These genetic associations suggest a role for the innate immune system and cell signaling in vaginal microbiome composition and susceptibility to nonoptimal vaginal microbiome.IMPORTANCE Globally, bacterial vaginosis (BV) is a common condition in women. BV is associated with poorer reproductive health outcomes and HIV risk. Typically, BV represents a shift in the vaginal microbiome from one that is dominated by Lactobacillus to one that is diverse. Despite many women having similar exposures, the prevalence of BV and nonoptimal vaginal microbiome is increased for women of African descent, suggesting a possible role for host genetics. We conducted a genome-wide association study of important vaginal microbiome traits in Kenyan women. We identified novel genetic loci and biological pathways related to mucosal immunity, cell signaling, and infection that were associated with vaginal microbiome traits; we replicated previously reported loci associated with mucosal immune response. These results provide insight into potential host genetic influences on vaginal microbiome composition and can guide larger longitudinal studies, with genetic and functional comparison across microbiome sites within individuals and across populations.

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

Publications

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

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