Host genetic variation impacts microbiome composition across human body sites

Abstract

BackgroundThe composition of bacteria in and on the human body varies widely across human individuals, and has been associated with multiple health conditions. While microbial communities are influenced by environmental factors, some degree of genetic influence of the host on the microbiome is also expected. This study is part of an expanding effort to comprehensively profile the interactions between human genetic variation and the composition of this microbial ecosystem on a genome- and microbiome-wide scale.ResultsHere, we jointly analyze the composition of the human microbiome and host genetic variation. By mining the shotgun metagenomic data from the Human Microbiome Project for host DNA reads, we gathered information on host genetic variation for 93 individuals for whom bacterial abundance data are also available. Using this dataset, we identify significant associations between host genetic variation and microbiome composition in 10 of the 15 body sites tested. These associations are driven by host genetic variation in immunity-related pathways, and are especially enriched in host genes that have been previously associated with microbiome-related complex diseases, such as inflammatory bowel disease and obesity-related disorders. Lastly, we show that host genomic regions associated with the microbiome have high levels of genetic differentiation among human populations, possibly indicating host genomic adaptation to environment-specific microbiomes.ConclusionsOur results highlight the role of host genetic variation in shaping the composition of the human microbiome, and provide a starting point toward understanding the complex interaction between human genetics and the microbiome in the context of human evolution and disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0759-1) contains supplementary material, which is available to authorized users.

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.…”

“…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].…”

“…[37] and references therein for a comprehensive review). It has also been observed that many mGWAS hits are found near genes associated with complex diseases [24,[27][28][29]31,39,41,[47][48][49][50], and that multiple studies have implicated variants residing in the same genes, though the exact loci differed between studies [11,36,41].…”

“…One of the first studies to employ the above approach identified a significant correlation between the top microbiome principal coordinate (PCo) and top host-genome principal component (PC), based on human DNA residues extracted from stool samples [27]. 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.…”

“…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].…”