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Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota.

ABSTRACT: Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr-/- mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 × 10-8) associations at multiple additional loci identify other important points of host-microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.

SUBMITTER: Wang J

PROVIDER: S-EPMC5626933 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota.

Wang Jun J Thingholm Louise B LB Skiecevičienė Jurgita J Rausch Philipp P Kummen Martin M Hov Johannes R JR Degenhardt Frauke F Heinsen Femke-Anouska FA Rühlemann Malte C MC Szymczak Silke S Holm Kristian K Esko Tönu T Sun Jun J Pricop-Jeckstadt Mihaela M Al-Dury Samer S Bohov Pavol P Bethune Jörn J Sommer Felix F Ellinghaus David D Berge Rolf K RK Hübenthal Matthias M Koch Manja M Schwarz Karin K Rimbach Gerald G Hübbe Patricia P Pan Wei-Hung WH Sheibani-Tezerji Raheleh R Häsler Robert R Rosenstiel Philipp P D'Amato Mauro M Cloppenborg-Schmidt Katja K Künzel Sven S Laudes Matthias M Marschall Hanns-Ulrich HU Lieb Wolfgang W Nöthlings Ute U Karlsen Tom H TH Baines John F JF Franke Andre A

Nature genetics 20161010 11

Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the V ...[more]

PMID: 27723756

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Project description:BackgroundBipolar disorder is a highly heritable neuropsychiatric condition affecting more than 1% of the human population. Lithium salts are commonly prescribed as a mood stabilizer for individuals with bipolar disorder. Lithium is clinically effective in approximately half of treated individuals, and their genetic backgrounds are known to influence treatment outcomes. While the mechanism of lithium's therapeutic action is unclear, it stimulates adult neural progenitor cell proliferation, similar to some antidepressant drugs.MethodsTo identify common genetic variants that modulate lithium-induced proliferation, we conducted an EdU incorporation assay in a library of 80 genotyped human neural progenitor cells treated with lithium. These data were used to perform a genome-wide association study to identify common genetic variants that influence lithium-induced neural progenitor cell proliferation. We manipulated the expression of a putatively causal gene using CRISPRi/a (clustered regularly interspaced short palindromic repeats interference/activation) constructs to experimentally verify lithium-induced proliferation effects.ResultsWe identified a locus on chr3p21.1 associated with lithium-induced proliferation. This locus is also associated with bipolar disorder risk, schizophrenia risk, and interindividual differences in intelligence. We identified a single gene, GNL3, whose expression temporally increased in an allele-specific fashion following lithium treatment. Experimentally increasing the expression of GNL3 led to increased proliferation under baseline conditions, while experimentally decreasing GNL3 expression suppressed lithium-induced proliferation.ConclusionsOur experiments reveal that common genetic variation modulates lithium-induced neural progenitor proliferation and that GNL3 expression is necessary for the full proliferation-stimulating effects of lithium. These results suggest that performing genome-wide associations in genetically diverse human cell lines is a useful approach to discover context-specific pharmacogenomic effects.

Project description:Simple Summary This study examined the differences and similarities in gut microbial diversity and ecological assembly processes of Datong yaks, including domestic males and females and wild males, which were fed together on the Qinghai-Tibet Plateau in a mixed group. The results revealed that mixed grouping could influence the gut microbiota of these three groups of yaks and improve the gut microbial diversity of domestic females. The findings of this study can help to understand the effects of mixed grouping on the gut microbiota of livestock on the Qinghai-Tibet Plateau and improve the production of Datong yaks. Abstract The Datong yak (Bos grunniens) is the first artificial breed of yaks in the world and has played an important role in the improvement of domestic yak quality on the Qinghai-Tibet Plateau. The Datong yak breeding farm in the Qinghai province of China is the main place for the breeding and feeding of Datong yaks. It hosts domestic Datong yaks and wild male yaks, mainly in mixed groups. Different managements have different effects on livestock. The gut microbiota is closely related to the health and immunity of Datong yaks, and mixed grouping can affect the composition and diversity of the gut microbiota of Datong yaks. To reveal the effects of mixed grouping on the gut microbiota of Datong yaks and wild yaks and identify the main dominant factors, we compared the gut microbial diversities of domestic males and females and wild males based on 16S rRNA V3–V4 regions using fresh fecal samples. The data showed significant differences in the gut microbial diversity of these three groups, and the α-diversity was the highest in wild males. Different factors influence the gut microbiota, and the main influencing factors were different in different groups, including sex differences, host genetics, and physical interactions. We also compared ecological assembly processes in the three groups. The results showed that mixed grouping contributed to the improvement of gut microbial diversity in domestic females. Our study provides effective and feasible suggestions for the feeding and management of the Datong yaks.

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Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota.

Publications

Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota.

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