# Genome-wide association analyses highlight the role of the intestinal molecular environment in human gut microbiota variation

## TL;DR

This study finds that human genetic variants influence gut microbiota composition, particularly through fatty acid sensing and mucosal functions.

## Contribution

The study identifies new genetic loci linked to gut microbial variation and confirms prior associations using large population-based data.

## Key findings

- Variants in OR51E1–OR51E2 are associated with microbial richness.
- 15 significant genetic associations were identified, with 11 replicated across studies.
- New loci like MUC12 and SLC5A11 are linked to gut microbial composition.

## Abstract

Despite the importance of the gut microbiome to health, the role of human genetic variation in shaping its composition remains poorly understood. Here we report genome-wide association analyses of harmonized metagenomic data from 16,017 adults in four Swedish population-based studies, with replication in 12,652 people from the Norwegian HUNT study. We identified variants in the OR51E1–OR51E2 locus, encoding sensors for microbiome-derived fatty acids, associated with microbial richness. We further identified 15 study-wide significant genetic associations (P < 5.4 × 10−11) involving eight loci and 14 common bacterial species, of which 11 associations at six loci were replicated. The results confirm previously reported associations at LCT, ABO and FUT2, and provide evidence for new loci MUC12, CORO7–HMOX2, SLC5A11, FOXP1 and FUT3–FUT6, with supporting data from metabolomics and gene expression analyses. Our findings link gut microbial variation genetically to gastrointestinal functions, including enteroendocrine fatty acid sensing, bile composition and mucosal layer composition.

Population-based studies from Sweden with replication in Norway identify associations between host genetic variants and gut microbial composition and implicate short-chain fatty acid chemosensors as modulators of gut microbial richness.