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Variants Linked to Microbiome Traits Implicated in Range of Traits, Conditions

NEW YORK – Host genetic variants associated with an individual's gut microbial community components may also influence traits ranging from metabolic or digestive traits to neurological or circulatory conditions, new research suggests.

"Understanding the precise relationships between the human genome, microbiome, and clinical traits remains limited yet central for research and efforts aimed at developing new therapies and personalized diagnostics of diseases with unclear etiologies," co-senior and corresponding author Seth Bordenstein, a biological sciences and pathology researcher affiliated with Vanderbilt, the Vanderbilt Microbiome Innovation Center, and the Vanderbilt Institute for Infection, Immunology, and Inflammation, and his colleagues wrote.

For a paper published in the Proceedings of the National Academy of Sciences on Monday, researchers at Vanderbilt University and the University of California at San Francisco brought together data from almost a dozen international microbiome-related genome-wide association studies, together with data from additional case-control studies to pin down more than 900 distinct variants associated with microbiome features found through 16S ribosomal RNA gene sequence- or metagenomics-based testing on fecal samples.

When the team took those microbiome-related variants forward in a phenome-wide association study that included some 90,000 participants in the Vanderbilt BioVU project, it searched for ties to more than 1,800 codes linked to phenotypes, conditions, or traits documented in individuals' electronic health records.

"Combined," the study's authors suggested, their results "establish triad relationships among the human genome, microbiome, and disease," the authors wrote, noting that "human genetic influences may offer opportunities for precision diagnostics of microbiome-associated diseases but also highlight the relevance of genetic background for microbiome modulation and therapeutics."

In particular, the investigators uncovered associations between microbiome-associated host genetic variants and conditions such as heart disease, type 1 diabetes, gout, psoriasis, celiac disease, and multiple sclerosis — results that were further validated through analyses on 1,419 phenotypes from more than 400,000 participants in the UK Biobank project.

"These results reveal the origins and diversity of [microbiome-associated variants] and their linkages with disease risk," the authors explained.

In some cases, a microbiome-associated variant linked to enhanced microbial levels coincided with increased disease risk, though the researchers saw the opposite relationship as well, suggesting some variants that boost microbial representation also correspond to lower-than-usual disease risk.

When they searched for microbiome-associated variants falling at expression quantitative trait loci — using expression clues spanning 48 tissue types from GTEx — the researchers highlighted nearly 400 such variants with ties to the expression of 688 genes in more than two dozen tissue types. Their analyses suggested that at least 15 of those tissues were enriched for variants from the microbiome-associated set.

The authors noted that "human genetic influences may offer opportunities for precision diagnostics, especially as the relationship between the relative abundance of specific microbes and disease risk is further elucidated."

"[O]ur results establish a set of relationships between the genome, microbiome, and human diseases," the authors wrote, noting that "genetic influences on microbiome variation associated with clinical traits could also pose operational hurdles for therapies that target microbial compositions, which are presumed to be malleable but may be less so due to underlying host factors."