The largest genome-wide association study (GWAS) to date looking at links between human genetics and microbial species found in the gut has identified and replicated 11 genetic variants shaping the composition of the gut microbiome, nine of which have been reported for the first time. Two back-to-back studies, published today in Nature Genetics, highlight the role genes involved in gut physiology can play in shaping the gut microbiome, which in turn plays an essential role in human health.
“We have learnt a lot about the role played by genetics in the gut microbiome,” says Tove Fall, PhD, professor of molecular epidemiology at Uppsala University. “Several of the genetic connections that we found have to do with very specific biological mechanisms. These concern, for instance, which molecules are present on the surface of gut cells and are thereby available as food for bacteria. They also relate to the way in which the gut reacts to molecules produced by bacteria.”
Fall and colleagues analyzed genetic data and gut bacteria from over 16,000 adults across four Swedish population-based studies. This led them to identify a total of 15 genetic variants across eight genes that were significantly associated with 14 common bacterial species. A replication study conducted in a Norwegian cohort of more than 12,000 people confirmed the initial findings for 11 genetic variants across six genes.
Two of the genes identified had already been reported and replicated in previous GWAS studies. These were the LCT gene encoding for the lactase enzyme, which breaks down lactose during digestion, and the ABO gene, which encodes for a glycosyltransferase enzyme that determines the oligosaccharides present on the cell surface.
Among the nine newly found genetic variants were genes encoding sensors for fatty acids produced by the microbiota, genes involved in bile acid metabolism and variants that determine the composition of the mucosal layer that lines the gut.
“We saw that some of these genetic variants were linked to the risk of gluten intolerance, hemorrhoids and cardiovascular diseases,” says Claes Ohlsson, MD, PhD, professor at the University of Gothenburg. “This suggests that changes in the composition of intestinal bacteria could provide a way to better understand how genetic risks affect health.”
The authors caution that their findings may not be generalizable to the global population, due to the fact that both study cohorts focused on individuals of European ancestry from the Nordics. More work will be needed to confirm these findings in diverse populations and identify links where rare variants or less prevalent microbial species are involved.
Going forward, the researchers expect to see a growing number of associations between the microbiome and gene variants, particularly among genes related to gut physiology. They stressed that this study paves the way for future research to establish causal links between these associations and eventually for the development of therapeutic interventions that take into account both human genetics and microbiome profiles.
