Genetic Analysis of Stool Frequency Reveals Involvement of Vitamin B1 Metabolism and Other Targetable Pathways in Gut Motility Regulation

To investigate the genetic determinants of stool frequency as a proxy for gut motility and identify associated pathways.

Study Design: A multiancestry genome-wide association study (GWAS) meta-analysis was conducted, combining data from European and East Asian cohorts.
Data Collection: Stool frequency data was collected from 268,606 individuals across five European and one East Asian cohort.
Genetic Analysis: Genome-wide significant loci were identified, and causal inference analyses were performed to explore associations with IBS and other traits.

Stool frequency is partially heritable and shares genetic architecture with gastrointestinal, psychiatric, and cardiovascular traits.
Causal inference analyses implicated pathways related to bile acid and cholinergic signaling.
Fine-mapping identified SLC35F3 and XPR1 as key loci, revealing a role for vitamin B1 metabolism in gut motility.
There is a strong association between dietary vitamin B1 intake and stool frequency in the general population.

The study highlights molecular mechanisms controlling gut motility.

The study relies on questionnaire data for stool frequency, which may not perfectly reflect gut motility.
The findings may not be generalizable beyond the studied populations.

The findings support the use of stool frequency as an endophenotype for genetic discovery related to IBS mechanisms.