Genetic Determinants of the Gut Microbiome in UK Twins

Abstract

Summary Studies in mice and humans have revealed intriguing associations between host genetics and the microbiome. Here we report a 16S rRNA-based analysis of the gut microbiome in 1,126 twin pairs, a subset of which was previously reported. Tripling the sample narrowed the confidence intervals around heritability estimates and uncovered additional heritable taxa, some of which are validated in other studies. Repeat sampling of subjects showed heritable taxa to be temporally stable. A candidate gene approach uncovered associations between heritable taxa and genes related to diet, metabolism and olfaction. We replicate an association between Bifidobacterium and the lactase (LCT) gene locus and identify an association between the host gene ALDH1L1 and SHA-98 bacteria, suggesting a link between formate production and blood pressure. Additional genes detected are involved in barrier defense and self/non-self recognition. Our results indicate that diet-sensing, metabolism, and immune defense are important drivers of human-microbiome co-evolution.

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

“…An analysis of 127 Hutterites reported several heritable taxa [39], but the statistical significance of these results after multiple testing correction has not been reported. Additionally, several recent studies have identified a significant heritability of bacterial α-diversity [28,30,39]. In contrast, a recent analysis of 1,046 Israeli individuals from different ancestral origins but a relatively shared environment did not replicate any of the above results, and did not identify statistically significant host-genomics associations with either the overall microbiome composition or individual taxa [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].…”

“…This lack of consistency could originate either from differences in the underlying analysis methods or from lack of reproducibility, necessitating further investigation of the reported associations. The only genetic variants consistently shown to be microbiome-associated in multiple mGWAS are located in close proximity to the LCT gene, which is associated with lactase persistence [8,27,30,31,46]. However, while important, this association may be confounded by lactose consumption [46].…”

“…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].…”

“…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.…”