Final Report:  From migraine aura loci to aura genes

Summary

In this study, we aimed to identify rare genetic alterations specific for migraine with aura (missense variants) that would change the function of the proteins the genes encode. We focused on two susceptibility regions (on chromosome 9q and 12p) that we identified earlier in 351 subjects from 36 Finnish migraine with aura families.  Our Finnish Migraine Genome project, with data on more than 8,300 individuals, was also available for this study.

We first narrowed the regions in the 351 subjects by using dense genotyping. Then we analyzed the narrowed regions using modern DNA sequencing methods to identify potential functionally interesting rare genetic variants for migraine with aura.

We identified one interesting missense variant in the HIATL1 gene in several individuals with migraine with aura. However, this variant was also identified in individuals with migraine without aura in this family. On chromosome 12p, we were able to confirm the already narrow linkage region of 2.6 Mb. Sequencing analyses on the 53 genes on the susceptibility region revealed one functionally interesting missense variant in the NUDAF9 gene. The variant was identified only in single individuals with migraine with aura in a few families.

Our findings did not confirm our hypothesis that migraine families with a high burden of migraine with aura patients are likely to have more penetrant rare variants segregating in the families. Our findings rather suggest that the identified variant(s), especially on chromosome 9, is not specific to migraine with aura, but rather to migraine in the studied families.

Hypothesis vs Findings

We hypothesized that migraine with aura is a complex and heterogeneous genetic disease where common variants, low frequency, and rare coding variants together account for the disease outcome and that there are specific rare or low frequency variants for migraine with aura. We further hypothesized that migraine families with a high burden of migraine with aura are likely to have more penetrant, low frequency, or rare variants that contribute to aura. Identifying genes for migraine with aura will provide important insights into the basic mechanisms of migraine pathophysiology, and even more broadly into how the brain functions.

Our findings did not confirm our hypothesis that migraine families with a high burden of migraine with aura patients are likely to have more penetrant rare variants that contribute to migraine with aura. Our findings rather suggest that the identified variants are not specific to migraine with aura, but rather to migraine.

Unanswered Questions

We were not able to find a high impact rare variant co-segregating solely with the migraine with aura phenotype in the studied families. Both variants were detected mostly in migraine with and without aura patients but also in patients with pure migraine without aura. The question to be answered is whether the variants are susceptibility variants for migraine headache in the studied families. Furthermore, the role of low frequency and common variants in the studied families is unknown.

What this Research Means to You

We are grateful to the Migraine Research Foundation for the grant that allowed us to further study the two migraine susceptibility loci.   We will continue our studies on the 9q and 12p migraine loci. Even though we did not find any causal exonic variant for migraine with aura, it is possible that the susceptibility variant is located outside exons or is a common variant involved in gene regulation.

Identifying causal variants for migraine with aura will improve our understanding of migraine aura pathophysiology and identify genes for future studies. Identifying genes for migraine with aura is of importance also because migraine with aura has been associated with several other serious diseases, including stroke. A better understanding of the mechanisms underlying migraine with aura may potentially lead to therapies that are more effective.