Gut microbial diversity moderates polygenic risk of schizophrenia

Background: Schizophrenia (SCZ) is a heritable disorder with a polygenic architecture, and the gut microbiota seems to be involved in its development and outcome. In this study, we investigate the interplay between genetic risk and gut microbial markers. Methods: We included 159 first-episode, drug-naive SCZ patients and 86 healthy controls. The microbial composition of feces was characterized using the 16S rRNA sequencing platform, and five microbial alpha-diversity indices were estimated [Shannon, Simpson, Chao1, the Abundance-based Eoverage Estimator (ACE), and a phylogenetic diversity-based estimate (PD)]. Polygenic risk scores (PRS) for SCZ were constructed using data from large-scale genome-wide association studies. Effects of microbial alpha-diversity, microbial abundance, and PRS on SCZ were evaluated via generalized linear models. Results: We confirmed that PRS was associated with SCZ (OR = 2.08, p = 1.22x10(-5)) and that scores on the Shannon (OR = 0.29, p = 1.15x10(-8)) and Simpson (OR = 0.29, p = 1.25x10(-8)) indices were inversely associated with SCZ risk. We found significant interactions (p < 0.05) between PRS and alpha-diversity indices (Shannon, Simpson, and PD), with the effects of PRS being larger in those exhibiting higher diversity compared to those with lower diversity. Moreover, the PRS effects were larger in individuals with a high abundance of the genera Romboutsia, Streptococcus, and Anaerostipes than in those with low abundance (p < 0.05). All three of these genera showed protective effects against SCZ. Conclusion: The current findings suggest an interplay between the gut microbiota and polygenic risk of SCZ that warrants replication in independent samples. Experimental studies are needed to determine the underpinning mechanisms.