From: mha23x@gmail.com   
      
   Host genetic variation impacts microbiome composition across human body sites   
      
   Ran BlekhmanEmail author, Julia K. Goodrich, Katherine Huang, Qi Sun, Robert   
   Bukowski, Jordana T. Bell, Timothy D. Spector, Alon Keinan, Ruth E. Ley, Dirk   
   Gevers and Andrew G. Clark   
   Genome Biology201516:191   
   DOI: 10.1186/s13059-015-0759-1©  Blekhman et al. 2015   
   Received: 16 June 2015Accepted: 24 August 2015Published: 15 September 2015   
   Abstract   
      
   Background   
   The 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.   
      
   Results   
   Here, 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.   
      
   Conclusions   
   Our 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.   
      
   Background   
      
   Recent advances in high-throughput sequencing technologies have unveiled wide   
   variability in the microbial communities that coat the human body [1, 2].   
   There are differences in the microbiota across body sites, which constitute   
   distinct ecological niches    
   [1, 3, 4]. Within each body site, the composition of the microbiome may change   
   rapidly, but community features can remain constant for years [5, 6]. There is   
   great variability in the microbiome across individuals, with some differences   
   associated with    
   chronic conditions, including obesity, diabetes, and inflammatory bowel   
   disease (IBD) [7, 8, 9, 10, 11, 12]. Recent studies in germ-free animals have   
   shown that these shifts in the microbiome can have an effect on host traits   
   and could be causal in    
   disease phenotypes [7, 12, 13, 14]. Therefore, understanding the factors that   
   impact the composition of the microbiome in healthy individuals is critical to   
   elucidate the role of the microbiome in disease and for development of   
   therapeutics targeting the    
   microbiome.   
      
   The composition of the human microbiome is influenced by multiple   
   environmental factors. For example, changes in host diet affect gut microbiome   
   communities at the taxonomic and functional level [5, 15]. In addition, intake   
   of drugs and antibiotics can    
   modulate the gut microbiome [16, 17]. Moreover, studies have shown variation   
   in the gut microbiome can be controlled by interactions with pathogens and   
   parasites [18, 19]. Lastly, social contact and interaction with the   
   environment have also been    
   implicated in shaping the microbial flora in the gut and skin [20, 21, 22].   
      
   Along with this clear evidence for the influence of environmental factors,   
   there is also support for a host genetic component in structuring of human   
   microbial communities [23]. For example, single nucleotide polymorphisms   
   (SNPs) in the MEFV gene are    
   associated with changes in human gut bacterial community structure [24], and   
   IBD-risk loci are associated with changes in gut microbiome composition [25].   
   Researchers have also shown that a loss-of-function polymorphism in the gene   
   FUT2, which is a known    
   risk factor for Crohn’s disease, may modulate energy metabolism of the gut   
   microbiome [26]. Investigating individuals with inflammatory bowel disease,   
   Knights et al. have shown that NOD2 risk allele count is correlated with an   
   increase in the relative    
   abundance of Enterobacteriaceae [27].   
      
   In addition to targeted and candidate gene approaches, researchers have also   
   used host genome-wide genetic variation to find interactions with the   
   microbiome. For example, in a recent study using 416 twin pairs to assess the   
   heritability of the    
   microbiome, Goodrich et al. identified microbial taxa for which relative   
   abundance is more similar in monozygotic compared to dizygotic twins [14]. In   
   the laboratory mouse, quantitative trait locus (QTL)-mapping approaches have   
   found multiple loci    
   associated with gut microbial community composition, some of which overlap   
   genes involved in immune response [28, 29]. Moreover, researchers have shown   
   that host mitochondrial DNA haplogroups are correlated with the structure of   
   microbiome communities [   
   30]. However, to date, there are no genome-wide studies that attempt to   
   characterize specific genes and pathways in the human genome that shape the   
   composition of the microbiome, although the value of such studies has often   
   been suggested [31, 32].   
      
   Here, we performed a genome-wide analysis to identify human genes and pathways   
   correlated with microbiome composition, using data generated by the Human   
   Microbiome Project (HMP). In the last few years, the HMP has sampled and   
   cataloged the microbial    
   diversity across multiple body sites in a few hundred individuals [33]. Since   
   genotype data are not yet available for the individuals included in the HMP   
   study, we extracted host genomic information from the ‘human c   
   ntamination’ reads in the HMP    
   shotgun metagenomic sequencing. This allowed us to generate genome-wide   
   genetic variation data from 93 individuals, which we then tested for   
   association with the microbiome profiles generated by the HMP.   
      
   Results and discussion   
      
   Mining the human microbiome project data for host reads   
      
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