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.

Host genetics and microbiome associations from the lens of genome wide association studies

“…Recent studies employing these technologies have uncovered evidence for both environmental and host genetic association with the microbiome composition [8,11,20,[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. However, to date there is no consensus regarding how and to what extent does host genetics shapes the gut microbiome, as compared to environmental factors.…”

“…However, while important, this association may be confounded by lactose consumption [46]. Several recent studies alleviated the multiple testing burden by testing for association with the entire microbiome composition rather than individual taxa, and identified genetic variants located in the vitamin D receptor gene and in several genes associated with health disorders [8,29,30]. A recent study further argued that a small number of genetic variants can infer over 10% of the microbiome β-diversity composition [29].…”

“…Several recent studies alleviated the multiple testing burden by testing for association with the entire microbiome composition rather than individual taxa, and identified genetic variants located in the vitamin D receptor gene and in several genes associated with health disorders [8,29,30]. A recent study further argued that a small number of genetic variants can infer over 10% of the microbiome β-diversity composition [29]. However, the results found in one study could not be replicated in others, with the exception of LCT related variants [8].…”

“…However, a potential shortcoming of the above studies is that they require previous knowledge of associated genes, and thus cannot discover new associations. Thus, recent studies have performed unbiased microbiome-genome wide association studies (mGWAS) spanning 93-1,812 individuals [8,[27][28][29][30][31].…”

The human gut microbiome as source of innovation for health: Which physiological and therapeutic outcomes could we expect?

“…Obviously, the host genetic is also playing a role in the selection of the composition and diversity of the commensal microorganisms that will be part of this personal ecosystem [4]. A recent study highlighted genome-wide significant associations for overall microbial variation at multiple genetic loci, stressing the VDR gene (encoding vitamin D receptor) as a key player [5]. Moreover, each location in or on the body has its own microbial diversity depending on local microenvironment (oxygen, pH.…”