Novel insights into the genetic architecture and mechanisms of host/microbiome interactions from a multi-cohort analysis of outbred laboratory rats

The intestinal microbiome influences health and disease. Its composition is affected by host genetics and environmental exposures. Understanding host genetic effects is critical but challenging in humans, due to the difficulty of detecting, mapping and interpreting them. To address this, we analysed host genetic effects in four cohorts of outbred laboratory rats exposed to distinct but controlled environments. We found that polygenic host genetic effects were consistent across environments. We identified three replicated microbiome-associated loci. One involved a sialyltransferase gene and Paraprevotella and we found a similar association, between ST6GAL1 and Paraprevotella , in a human cohort. Given Paraprevotella ‘s known immunity-potentiating functions, this suggests ST6GAL1 ‘s effects on IgA nephropathy and COVID-19 breakthrough infections may be mediated by Paraprevotella . Moreover, we found evidence of indirect genetic effects on microbiome phenotypes, which substantially increased their total genetic variance. Finally, we identified a novel mechanism whereby indirect genetic effects can contribute to “missing heritability”.