Novel Migraine Pathways Could Guide Drug Development

An analysis of genetic data from more than 1.3 million people has revealed new biological pathways associated with migraine that could potentially be targeted for drug development. Researchers published their findings in Nature Genetics.

“Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes,” wrote corresponding author Gyda Bjornsdottir, PhD, of deCODE Genetics, a subsidiary of Amgen Inc. based in Reykjavik, Iceland, and study coauthors.

The analysis combined large genome-wide association study (GWAS) datasets from 6 European populations in an attempt to detect sequence variants associated with the two main subtypes of migraine: migraine with aura and migraine without aura. Among participants sequenced, 17,000 had migraine with aura, 12,000 had migraine without aura, and 80,000 had any migraine.

>>NEWS: Peripheral Auditory Deficits More Likely in Patients With Migraine, Parkinson, Multiple Sclerosis

Migraine was associated with 44 variants, according to the study. Twelve of the associations were novel, while 4 new associations were identified for migraine with aura (in PRRT2, PALMD, ABO, and LRRK2), and 13 variants were classified for migraine without aura.

The research team reported rare variants with large effects highlighting 3 genes. First, a rare frameshift variant in the PRRT2 gene conferred a large risk of migraine with aura and epilepsy, but not migraine without aura. Second, a burden test of rare loss-of-function variants in the SCN11A gene, which plays a key role in pain sensation, showed strong protection against migraine. Meanwhile, a common missense variant in SCN11A was associated with modest migraine risk.

Third, a rare variant pointing to the KCNK5 gene conferred large protection against migraine and brain aneurysms. The finding either identifies a common pathway between the two diseases or suggests that some cases of undetected brain aneurysms may be misclassified as migraine, the team explained.

“In all, our findings are consistent with the results of previous GWAS analyses that have established migraine as a complex neurovascular brain disorder,” researchers wrote. “However, our results also highlight several distinct biological pathways involved in migraine with aura and migraine without aura that warrant further study.”

References

Bjornsdottir G, Chalmer MA, Stefansdottir L, et al. Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura. Nat Genet. 2023;55(11):1843-1853. doi:10.1038/s41588-023-01538-0

A large international study of migraine reveals new biological pathways for treatment. News release. deCODE Genetics; October 26, 2023. Accessed November 21, 2023.