NEW YORK — Researchers have identified more than a dozen genetic loci associated with how often someone has a bowel movement, findings that could provide insight into gastrointestinal conditions like irritable bowel syndrome.
Irritable bowel syndrome affects about 10 percent of the worldwide population and can be marked by either constipation or diarrhea. But the mechanisms underlying gut dysmotility have been unclear.
By conducting a genome-wide association study of stool frequency, an international team of researchers sought to identify genes involved in gut motility. As they reported in the journal Cell Genomics on Wednesday, they traced the loci to genes involved in neurotransmitter or neuropeptide signaling and expressed in the enteric motor neurons that control peristalsis to frequency of bowel movements. One highlighted gene in particular — BDNF — has already been targeted by therapies to induce bowel movements.
"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 IBS," corresponding author Mauro D'Amato from CIC bioGUNE in Spain said in a statement.
As a direct assessment of GI motility requires clinical procedures, the researchers instead relied on study participants' self-reports of how many bowel movements they have per day as a proxy. Using that and genetic data from the UK Biobank and four other, smaller population-based cohorts, the researchers conducted a GWAS meta-analysis that encompassed 167,875 individuals of European descent.
This analysis uncovered 3,751 genome-wide significant associations at 14 independent loci. The strongest signal was on chromosome 11, near the brain-derived neurotrophic factor, or BDNF, gene. Overall, the genes implicated by these loci were involved in neurotransmitter or neuropeptide signaling, and single-cell transcriptomic data further noted that their expression was enriched within enteric neurons, especially motor neurons thought to be involved in the peristaltic contractions that move food along the digestive tract.
A phenome-wide association study additionally found that these 14 stool frequency loci were also linked to traits like fecal abundance of a particular gut microbe.
For five of these 14 signals, the researchers homed in on candidate causative SNPs, including ones associated with eQTLs for genes expressed in enteric and motor neurons.
They also identified one that is associated with an eQTL for a long noncoding antisense RNA that modulates the expression of BDNF, a neurotrophin that is expressed in both the central and peripheral nervous systems, has a key role in neuronal growth and survival, and affects a number of gut functions like sensation, motility, and neuroplasticity and neuroprotection. Further, individuals who have been given recombinant BDNF have increased GI and colonic transit, the researchers noted. The allele implicated by D'Amato and his colleagues is linked to more frequent stools, shorter colonic transit time, and reduced stool consistency.
The researchers further developed a polygenic score for stool frequency and found that the distribution of scores differed for individuals with IBS. Risk of IBS marked by diarrhea, for instance, increased at an upper range of scores. This finding suggested to the researchers that, following further development and validation, their score could help in the early identification and treatment of people with IBS.
"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," D'Amato said. "This would be a major step forward in IBS, a common condition for which there is currently no effective treatment that works for all."