Migraine sufferers know two things very well: the attacks are awful (sometimes disabling) and difficult to treat. Migraine is among the most common chronic pain disorders worldwide, with up to 20% of adults affected.

Although recent advances have been made in the underlying biology of migraine, research that uncovers novel therapeutic targets are necessary. Now, a large international study led by deCODE Genetics (a subsidiary of Amgen) provides novel insights into the biology of migraine enabling detection of rare variants protecting against migraine, opening an avenue for potential development of novel drug targets. The results highlight several genes that affect one of the migraine subtypes over the other and point to new biological pathways that could be targeted for therapeutic developments.

This work is published in Nature Genetics in the paper, “Rare variants with large effects provide functional insights into the pathology of migraine subtypes with and without aura.”

The group combined large GWAS datasets from six European populations and analyzed genetic data from over 1.3 million participants—of which 80,000 had migraines—focusing on detecting sequence variants associated with migraines. The research included two main subtypes of migraine: migraine with aura (often referred to as classical migraine) and migraine without aura.

“What makes our study unique is that it includes large datasets from sequenced individuals enabling detection of rare variants protecting against migraine, potentially opening an avenue for development of novel drug targets,“ said Kari Stefansson, MD, CEO of deCODE genetics.

The study revealed associations with 44 variants, 12 of which are novel. Four novel migraine with aura associations were revealed (in PRRT2, PALMD, ABO, and LRRK2) and 13 variants associated primarily with migraine without aura.

Of particular interest were three rare variants with large effects pointing to distinct pathologies underlying different types of migraine. A rare frameshift variant in the PRRT2 gene confers a large risk of migraine with aura and with another brain disease, epilepsy, but not of migraine without aura. In SCN11A, a gene known to play a key role in pain sensation, the scientists detected several rare loss-of-function variants associated with protection effects against migraine, while a common missense variant in the same gene is associated with modest risk of migraine. Finally, a rare variant pointing to the KCNK5 gene, confers large protection against severe migraine and brain aneurysms, either identifying a common pathway between the two diseases or suggesting that some cases of early brain aneurysms may be misclassified as migraine.

The joint effort of the international research team was led by scientists at deCODE genetics in Iceland and included collaborating scientists from the Copenhagen Hospital Biobank and Danish Blood Bank Study, the HUSK study in Norway, the Intermountain Health study in the United States, and data generated by the large population-based studies from the UK Biobank and FinnGen.

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