Results from an international genome wide association study reveal that frequency of defecation is heritable and is also linked to irritable bowel syndrome susceptibility.
“These results are very exciting and warrant follow-up studies: once more stool frequency genes are unequivocally identified, we may have a battery of new drug targets to be exploited for the treatment of constipation, diarrhea and common dysmotility syndromes like irritable bowel syndrome,” commented Mauro D’Amato, a professor at CIC bioGUNE in Spain who led the research, in a press statement.
Gastrointestinal motility impacts digestion, nutrient absorption and other aspects of human health such as the microbiome and how it interacts with the human body. Dysfunctional gut motility is seen in individuals with irritable bowel syndrome (IBS), a common gut disorder, but not much is known about the genetics of gut motility and how this might impact disease susceptibility.
The research team, led by Mauro D’Amato, a professor at CIC bioGUNE in Spain, carried out a large genome wide association study (GWAS) analysis including 167,875 individuals from five different countries. The participants mostly came from the UK Biobank, but also smaller population-based cohorts from the Netherlands (LifeLines-Deep), Belgium (Flemish Gut Flora Project), Sweden (PopCol) and the U.S. (Genes for Good). Stool frequency was used as a proxy for gut motility and the information was collected by questionnaire.
The analysis identified 14 points, or loci, on the genome containing variants that influenced stool frequency. Further study suggested the genes in these areas are associated with neurologic signaling and mostly expressed in enteric motor neurons. For example, the strongest GWAS association was linked with the BDNF gene. People with high or low stool frequency were more likely to carry genetic variants in the 14 genomic loci.
“We were surprised how much sense these new findings make, highlighting multiple molecules whose role in gut motility was already known from clinical studies, including the communication between the brain and the gut,” says Ferdinando Bonfiglio, a research associate at Monash University in Australia, who is first author of the study describing the research published in Cell Genomics.
The researchers also found a link between the genetics of stool frequency and IBS. They developed a polygenic risk score based on their GWAS data and were able to predict the likelihood of someone having IBS, although the score was more accurate for the IBS-diarrhea (D) subtype of the condition.
Using a group of independent UK Biobank participants to test the score, the investigators found that people in the highest 5% of the stool frequency polygenic score had over 4 times higher risk of having IBS-D compared with asymptomatic controls.
“The genetic information and the polygenic scores obtained in this study can be refined and eventually contribute to the classification of patients into different treatment groups, hopefully leading to improved therapeutic precision when aiming to bring gut dysmotility and altered bowel habits back to normal. This would be a major step forward in IBS, a common condition for which there is currently no effective treatment that works for all,” concludes D’Amato.