Migraine and GI Disorders: Shared Genetics, Distinct Patterns

A recent study reveals shared genetics between migraine and non-immune-related GI disorders, though differences emerged depending on the GI condition in question. The genetic correlations were most apparent in the central nervous system, pointing to the importance of neurobiological mechanisms.

It’s well known that migraine and gastrointestinal (GI) disorders, especially irritable bowel syndrome (IBS), often go together. But is this comorbidity reflected at a genetic level, too? That’s the question at the heart of a recent study from researchers at Brigham and Women’s Hospital and Harvard Medical School, Boston, US.

The group, led by Daniel Chasman, used a number of methods to discover shared genetics between migraine and GI disorders, particularly non-immune-related disorders like IBS, peptic ulcer disease, gastrointestinal reflux, and others.

The genetic correlations with migraine were strongest among genes active in the central nervous system, suggesting a key role for neurologic mechanisms in the co-occurrence of migraine and certain GI conditions. The team also found evidence for causal effects of certain GI conditions on migraine, though not the reverse.

From a therapeutic perspective, some of the shared genetics between migraine and GI disorders were at regions of the genome associated with established treatments, including the gene that encodes the CGRP receptor. Despite low overall genetic similarity between migraine and immune-related GI disorders collectively termed inflammatory bowel disease (IBD), the genetic findings suggest that current CGRP-targeted treatments for migraine may be effective at treating those conditions.

“The study’s finding that shared genetic factors between migraine and gastrointestinal disorders point toward underlying neurologic mechanisms is intriguing,” said Thomas Folkmann Hansen, University of Copenhagen, Denmark, in an email to Migraine Science Collaborative.

“The study provides strong genetic evidence supporting the epidemiological link between migraine and GI disorders, reinforcing that the relationship is not purely due to shared environmental factors such as diet, medication, or stress. This strengthens the case for a common neurobiological basis rather than an immunological or vascular explanation,” he added.

The research appeared in the December 2024 issue of Neurology Genetics.

Looking at the bigger picture
For more than a decade, Chasman and colleagues have been interested in using genome-wide approaches to understand what makes people genetically susceptible to migraine. Previous research had shown a strong genetic overlap between IBS and migraine in a family-based setting. But the researchers were keen to take a broader look at the shared genetic landscape of migraine and a host of GI conditions.

“To augment [the previous] findings, we examined the genetic overlap of migraine and IBS, as well as other GI conditions that share symptoms with IBS, in [a] population-based setting – an approach that highlights shared common genetic variation, in contrast to potentially rarer genetic effects or interactions between genetics and lifestyle that may be specific to families,” Chasman told MSC via email.

To do so, Chasman and colleagues relied on data from previous genome-wide association studies (GWAS) of migraine and a series of non-immune-related GI conditions including not only IBS but also diverticular disease, functional dyspepsia, gastrointestinal reflux, and peptic ulcer disease. Relationships between migraine and these GI conditions were contrasted with relationships with immune-mediated GI conditions like Crohn’s disease, ulcerative colitis, and IBD or its constituents.

The researchers used two main methodological approaches to analyze the GWAS data: Genetic correlation and Mendelian randomization.

Genetic correlation refers to the genetic relationship between two traits, on a scale from -1 to 1. In the current study, a genetic correlation of 1 signifies that all the genetic influences on migraine and each of the GI conditions are the same (a completely positive correlation), whereas a score of -1 indicates a completely negative genetic correlation between the traits. A score of 0 means that there is no genetic correlation between migraine and the GI conditions.

“Understanding the genetic correlation between two conditions provides insight into the extent to which they may be separate manifestations of shared genetic risk,” Chasman explained.

Further, he said, “a strong genetic correlation implies that therapeutics targeting the biology underlying shared genetic risk may reduce the susceptibility to both conditions.”

The second technique, Mendelian randomization, is an analytic approach that uses genetic variation to infer causality – here, whether or not there are causal effects of migraine on one of the GI conditions, or the reverse. Like genetic correlation, the results of Mendelian randomization have treatment implications.

“Although there are many caveats to interpreting a Mendelian randomization analysis, a positive result may imply that the therapeutic intervention targeting the causal condition may reduce susceptibility to the other condition,” said Chasman.

An important role for neurologic signaling
Pooling the data from the various GWAS revealed a strongly significant genetic correlation between migraine and many of the GI conditions, at the genome-wide level. IBS showed the strongest correlation (0.37), with robust associations for additional non-immune-related GI conditions including gastroesophageal reflux disease (0.34), functional dyspepsia (0.34), and peptic ulcer disease (0.29).

However, there was no genetic correlation between migraine and the three immune-mediated GI conditions considered in the study, including Crohn’s disease, ulcerative colitis, and IBD.

“The absence of genetic correlation between migraine and immune-related gastrointestinal disorders, such as Crohn’s disease and ulcerative colitis, is noteworthy, as it suggests a limited immunological component in the shared pathophysiology,” Hansen said.

Subgroup analyses revealed similar correlations in migraine patients with or without aura, although there was a stronger correlation between IBS and migraine without aura. Conversely, there was a significant correlation between peptic ulcer disease and migraine with aura, but not with migraine without aura.

The investigators also looked at the genetic correlations between migraine and the GI disorders in specific tissues, based on transcription of genes in those tissues, at a genome-wide level. Correlations were strongest for genes expressed in central nervous system tissue, with a weaker correlation in cardiovascular tissue. There was no significant correlation between migraine and GI disorders in GI-derived tissues.

“The findings in this paper support the hypothesis that neurologic signaling contributes to the comorbidity of migraine and some of the GI conditions. It further suggests additional contributions to shared susceptibility from the vascular system, although the signal is less strong,” Chasman said.

“The findings also support the idea that cell types and tissues that are directly in the GI system, the structural aspects of the GI system, are less likely to be relevant to the shared susceptibility mechanisms of migraine and the GI conditions,” he added.

A familiar gene
The researchers also found distinct patterns of local genetic sharing between migraine and the range of GI conditions. Local genetic sharing refers to genetic similarity between traits at specific regions of the genome.

In particular, local genetic sharing occurred at 22 genetic segments of DNA, seven of which had not been previously reported. These could be categorized into mostly distinct sets of regions shared between migraine and each of the GI conditions. That is, for instance, three regions shared between migraine and IBS were distinct from four shared with peptic ulcer disease, which were distinct from eight shared with diverticular disease.

When exploring candidate genes (genes identified in GWAS as related to a particular trait), the researchers found no genetic sharing with migraine at a few genes involved with serotonin activity; the serotonin system is thought to play a role in both conditions.

However, correlations emerged between migraine and several of the GI conditions at the CALCA/CALCB genes, which encode CGRP, perhaps the most familiar molecular player in migraine neurobiology. There was an inverse correlation between migraine and gastroesophageal reflux disease, and between migraine and peptic ulcer disease, where CALCA/CALCB increased the risk of migraine but decreased the risk of the GI disorder.

But there were stronger associations at CALCA/CALCB, and in the same direction (higher risk), between migraine and IBD, diverticular disease, and ulcerative colitis.

The findings with regard to IBD were unexpected, according to Chasman.

“The underlying biology of inflammatory bowel disease is thought to involve immune processes and structural features of the GI system, and not so much neurological and/or vascular processes that are prominent in migraine,” he said.

In addition, “It was surprising not only that the CALCA/B locus was involved in both migraine and inflammatory bowel disease, but also that the genetic effects were concordant. That is, the same genetic variants at this locus were associated with a higher risk of both migraine and inflammatory bowel disease,” said Chasman.

Finally, there was no evidence from the Mendelian randomization analyses that migraine could cause the GI disorders, but there was evidence to suggest that susceptibility to GI disorders – particularly peptic ulcer disease, gastrointestinal reflux disease, and diverticular disease – had causal effects on migraine.

Moving forward
Chasman and colleagues are already thinking about the next steps in exploring the genetic links between migraine and GI disorders.

“One of the most urgent issues is trying to identify exactly what aspect of the central nervous system may be relevant to the shared susceptibility to migraine and IBS, as well as some of the other GI disorders,” Chasman told MSC.

He also said future work should explore the therapeutic potential of targeting CGRP in diverticular disease and IBD, given what the genetic analyses in the current study showed.

“While CALCA and CALCB encode very similar subtypes of CGRP, the CALCA-related subtype is targeted for migraine, while the CALCB-related subtype may have roles that are more specific to the GI system. More research is needed.”

Hansen echoed those sentiments.

“Given the shared genetic overlap at the CALCA/B locus, an important next step is evaluating whether CGRP-targeted migraine therapies influence GI symptoms, either positively or negatively,” he said.

“Additionally, further investigation into metabolic and microbiome-related factors as potential mediators of this relationship could provide novel therapeutic directions.”

Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia.

Image credit: rost9/123RF Stock Photo.

Reference
Shared genetics of migraine and gastrointestinal disorders implicates underlying neurologic mechanisms yet heterogeneous etiologies.
Chasman et al.
Neurol Genet. 2024 Dec 10;10(6):e200201.