A migraine is one of the most common health issues worldwide, affecting up to one in five people. But the mechanisms that drive migraines aren’t well understood. In fact, doctors and scientists are still trying to figure out if a migraine is primarily a vascular or a neurological disorder. A new genome-wide association study published in Nature Genetics suggests that a migraine may primarily stem from problems with the blood supply system.

The data in this paper comes from a meta-analysis of 22 genome-wide association studies, a combined dataset of more than 35,000 migraine cases and even more controls. The primary meta-analysis found associations between migraines and 38 independent genomic regions, 34 of which this study associated for the first time with migraines.

When the authors characterized the genes near these associated loci, they found that a number of them were previously associated with vascular disease. Others are involved in smooth muscle contraction (smooth muscle lines larger blood vessels) and regulation of vascular tone. Some of these genes were also associated with arterial functioning.

Since migraines are highly comorbid with stroke and cardiovascular disease, the association with these genes is not surprising. But the results clearly support the idea that vascular dysfunction and smooth muscle dysfunction play a role in migraines.

Gastrointestinal issues are also commonly associated with migraines, as they are often accompanied by vomiting, nausea, and diarrhea. However, this study did not find any link between migraines and genes expressed in the gut. The authors suggest that this is because the GI tract is made of smooth muscle tissues, and smooth muscle genes are strongly associated with migraines; therefore the search for associations between GI-specific genes and migraines may be a bit of a red herring.

What the authors didn’t find was any statistically significant associations between migraines and genes commonly expressed in brain tissue. Other studies, however, have found these types of associations. The authors suggest that the new work may not have had an appropriate number of tissue samples to uncover this type of linkage.

Another line of thinking has proposed that migraines are a disease linked to nervous system ion channels, pores on the surface of cells that help transmit the electrical pulses of neural signals. Two of the genes that this study found linked to migraines code for ion channels, and three of the genes are known to be important for regulating ion levels. Though this data can’t definitively point to ion channels as one of the causes of a migraine, it does suggest that more research is needed on this relationship.

Among migraine sufferers, there are two common types of migraines: with and without aura. Migraines with aura are characterized by dramatic changes in vision, which might include vision loss, seeing bright lights, or seeing wavy lines. The authors did a sub-analysis of these two types of migraines, finding that the more common type (without aura) was associated with the same genes as migraines in general.

The sub-analysis for migraines with aura did not find any loci associated with this condition, likely because it’s relatively rare, so the test didn’t have much statistical power.

Overall, among the 38 genes that this study found to be statistically associated with migraines, the vast majority were linked to vascular and smooth muscle tissues. These findings bolster the existing hypothesis that migraines are a disease with a considerable vascular component. The study provides some interesting guideposts about what directions future research might take, both in terms of the vascular and the ion channel connections to migraines.

Nature Genetics, 2016. DOI: 10.1038/ng.3598 (About DOIs).