A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency

A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency Stool consistency and frequency patterns are complex traits that are often altered in GI disease, and recent studies published in Gut highlight the importance of stool frequency in relation to gut microbiota composition and the efficacy of pharmacological and dietary treatments in IBS. [1]][3] Despite reported heritability in invertebrates 4 and similar evidence from open-field defaecation models in rats, 5 the genetics of stool frequency has not been explored in humans.We undertook a genome-wide association study (GWAS) in two well-characterised population-based cohorts with genotype and defaecation data available: LifeLines-Deep (LLD) from the Netherlands (N=1546; 58% females; mean age 44 years (range 18-86)) and PopCol (PC) from Sweden (N=284; 60% females; mean age 54 years (range 22-71)). 6 7The average number of bowel movements per day (BM/d) was extracted from daily records kept by both populations and did not differ between cohorts (LLD=1.39±0.64SD; PC=1.42±0.74SD).Available CytoChip+Immunochip (LLD) and HumanOmniExpressExome (PC) Illumina single-nucleotide polymorphism (SNP) genotype data were imputed using IMPUTE2 (https://mathgen.stats.ox.ac.uk/ impute/impute_v2.html)with the Genome of the Netherlands (http://www.nlgenome.nl/) as reference.SNPs were filtered on minor allele frequency >0.05 and Hardy-Weinberg equilibrium p>1E-04, samples were filtered on infoscore ≥0.8 and population outliers were excluded using principal component analysis.In total, high-quality genotype data for 5 390 800 common SNPs and BM/d information were obtained for 1022 LLD and 259 PC individuals.Genotype-BM/d association tests were performed in SNPTEST (https://mathgen.stats.ox.ac.uk/genetics_software/snptest/ snptest.html)using logistic regression under an additive model correcting for age and sex, followed by a fixed-effect model meta-analysis with META (https:// mathgen.stats.ox.ac.uk/genetics_software/ meta/meta.html).Summary statistics for the top-10 loci from the meta-analysis and the corresponding effect of associated alleles on the frequency (increased/decreased) of defaecation are given in figure 1.