The HUNT study identifies host genetic factors reproducibly associated with human gut microbiota composition.

The HUNT GWAS identified 12 reproducible SNP-species associations across six genomic loci influencing gut microbiota composition.

• The discovery cohort comprised 12,652 individuals from the Trøndelag Health Study (HUNT).
• Replication was performed in Nordic cohorts with n = 16,017–21,976 individuals.
• The six genomic loci identified were LCT, ABO, HLA-DQB1, MUC12, SLC37A2, and FUT2.
• LCT and ABO were known loci, while HLA-DQB1, MUC12, SLC37A2, and FUT2 were described as novel associations.
• All 12 SNP-species associations were described as reproducible across the replication cohorts.

Genetic signals at three loci were associated with gut microbiota functional modules.

• The three loci associated with gut microbiota functional modules were LCT, ABO, and FUT2.
• These associations extend beyond taxonomic composition to functional capacity of the gut microbiota.
• This suggests that host genetic variation influences not only which microbial species are present but also their functional activity.

Follow-up analyses linked host-microbiota associations to the pathogenesis of celiac disease and hemorrhoidal disease.

• The HLA-DQB1 locus, known for its role in celiac disease, was among the identified loci.
• The associations at these loci suggest mechanistic connections between host-microbiota interactions and specific disease pathogenesis.
• Both celiac disease and hemorrhoidal disease were implicated through follow-up analyses of the identified loci.

Mendelian randomization analyses provided evidence supporting a causal effect of body mass index on gut microbiota composition.

• The causal inference was made using Mendelian randomization, which uses genetic variants as instrumental variables to infer causality.
• BMI was found to causally influence gut microbiota composition, rather than only being observationally associated.
• This finding suggests that interventions targeting BMI may have downstream effects on gut microbiota.

The FUT2 locus was identified as a novel genomic region associated with gut microbiota composition.

• FUT2 (fucosyltransferase 2) encodes an enzyme involved in secretion of blood group antigens into bodily fluids and the gut.
• FUT2 was associated with both gut microbiota species composition and functional modules.
• This locus joins ABO and LCT as host genetic factors related to glycan and carbohydrate metabolism influencing microbiota.

The MUC12 and SLC37A2 loci were identified as novel genomic regions associated with gut microbiota species composition.

• MUC12 encodes a mucin protein involved in the intestinal mucosal barrier, a plausible biological pathway for microbiota influence.
• SLC37A2 encodes a sugar phosphate exchanger, suggesting a metabolic mechanism for host-microbiota interaction.
• Both loci had not been previously reported as associated with gut microbiota composition.