25 Gut Microbiome Information Enables Additional Discovery in Genome-wide Association Studies in Swine

Abstract

Abstract Several studies have highlighted the relevance of gut microbiome composition in shaping fat deposition in mammals. In contrast, other studies have highlighted how the host genome can control the abundance of individual species in the gut microbiota’s make-up. There is the need to incorporate the different ‘-omics’ data (host genome, gut microbiome, high-throughput phenotyping) in a model that allows to extract information beyond the simple sum of each component’s contribution. We propose a systematic approach to detect host genomic variants that control the gut microbiome, which in turn contributes to the host fat deposition, when this latter is based on multiple phenotypic measures. Using a dataset that included longitudinal records of fat deposition on 1,180 pigs, we implemented a mediation test to describe how fat deposition in swine (Sus scrofa) is affected by the host genotype and the gut microbiome. The phenotypic outcome was described both by measured and latent variables, taking advantage of structural equation modeling. We also implemented a ‘traditional’ genome-wide association analysis, testing the (total) effect of host genomic variants on the phenotype. Results for all models were validated using both bootstrapping and permutation tests. The models identified several host genomic features having microbiome-mediated effects on fat deposition. Our work demonstrates how the host genome can affect the phenotypic trait by inducing a change in gut microbiome composition that leads to a change in the phenotype. The host genomic features identified through the mediation analysis do not entirely overlap the group of features identified by traditional GWAS. Microbiome-mediated analyses can help understand the genetic determination of complex phenotypes. The host genomic features that exert a mediated effect could not be identified by traditional genome-wide association analysis. These can contribute to filling the missing heritability gap and provide further insights into the host genome – gut microbiome interplay.