Genome-wide association analyses of harmonized metagenomic data from 16,017 adults identified 15 study-wide significant genetic associations involving eight loci and 14 common bacterial species, linking gut microbial variation genetically to gastrointestinal functions including enteroendocrine fatty acid sensing, bile composition, and mucosal layer composition.
Key Findings
Results
Variants in the OR51E1-OR51E2 locus, encoding sensors for microbiome-derived fatty acids, were associated with microbial richness.
OR51E1 and OR51E2 encode olfactory receptors that function as sensors for microbiome-derived fatty acids.
This association was identified in the discovery cohort of 16,017 adults from four Swedish population-based studies.
The association links gut microbial diversity to enteroendocrine fatty acid sensing mechanisms.
Results
Fifteen study-wide significant genetic associations were identified involving eight loci and 14 common bacterial species.
Study-wide significance threshold was P < 5.4 × 10-11.
The 15 associations spanned eight distinct genomic loci.
14 common bacterial species were implicated across these associations.
Discovery was conducted in 16,017 adults from four Swedish population-based studies using harmonized metagenomic data.
Results
Eleven of the 15 study-wide significant associations at six loci were replicated in an independent Norwegian cohort.
Replication was performed in 12,652 people from the Norwegian HUNT study.
11 associations at six loci achieved replication out of 15 study-wide significant discovery associations.
Replicated loci included both previously reported and newly identified associations.
Results
Previously reported associations at LCT, ABO, and FUT2 loci with gut microbiota composition were confirmed.
LCT, ABO, and FUT2 are known loci previously associated with gut microbiota variation.
These associations were confirmed at study-wide significance (P < 5.4 × 10-11) in the Swedish discovery cohort.
Replication was achieved in the HUNT study for associations at these loci.
Results
New genetic loci associated with gut microbiota composition were identified, including MUC12, CORO7-HMOX2, SLC5A11, FOXP1, and FUT3-FUT6.
Five novel loci were identified: MUC12, CORO7-HMOX2, SLC5A11, FOXP1, and FUT3-FUT6.
Evidence for these new loci was supported by metabolomics and gene expression analyses.
MUC12 is related to mucosal layer composition, FUT3-FUT6 to fucosyltransferase activity, and CORO7-HMOX2 to bile composition.
These findings link gut microbial variation to gastrointestinal functions including bile composition and mucosal layer composition.
Methods
The study used harmonized metagenomic data from four Swedish population-based studies as the primary discovery cohort.
Total discovery sample size was 16,017 adults.
Data were drawn from four Swedish population-based studies.
Metagenomic data were harmonized across studies to enable pooled genome-wide association analyses.
Replication cohort comprised 12,652 individuals from the Norwegian HUNT study.
Results
The genetic associations identified link gut microbial variation to multiple gastrointestinal functions including enteroendocrine fatty acid sensing, bile composition, and mucosal layer composition.
Enteroendocrine fatty acid sensing was implicated through the OR51E1-OR51E2 locus.
Bile composition was implicated through the CORO7-HMOX2 locus.
Mucosal layer composition was implicated through MUC12.
Fucosyltransferase-related loci FUT2 and FUT3-FUT6 were associated with specific bacterial species.
Supporting evidence came from metabolomics and gene expression analyses.
Dekkers K, Pertiwi K, Baldanzi G, Lundmark P, Hammar U, Moksnes M, et al.. (2026). Genome-wide association analyses highlight the role of the intestinal molecular environment in human gut microbiota variation.. Nature genetics. https://doi.org/10.1038/s41588-026-02512-2