Future possibilities in migraine genetics

Abstract

Migraine with and without aura (MA and MO, respectively) have a strong genetic basis. Different approaches using linkage-, candidate gene- and genome-wide association studies have been explored, yielding limited results. This may indicate that the genetic component in migraine is due to rare variants; capturing these will require more detailed sequencing in order to be discovered. Next-generation sequencing (NGS) techniques such as whole exome and whole genome sequencing have been successful in finding genes in especially monogenic disorders. As the molecular genetics research progresses, the technology will follow, rendering these approaches more applicable in the search for causative migraine genes in MO and MA. To date, no studies using NGS in migraine genetics have been published. In order to gain insight into the future possibilities of migraine genetics, we have looked at NGS studies in other diseases and have interviewed three experts in the field of genetics and complex traits. The experts' ideas suggest that the preferred NGS approach depends on the expected effect size and the frequency of the variants of interest. Family-specific variants can be found by sequencing a small number of individuals, while a large number of unrelated cases are needed to find common and rare variants. NGS is currently hampered by high cost and technical problems concurrent with analyzing large amounts of data generated, especially by whole genome sequencing. As genome-wide association chips, exome sequencing and whole genome sequencing gradually become more affordable, these approaches will be used on a larger scale. This may reveal new risk variants in migraine which may offer previously unsuspected biological insights.

Fig. 1

The sequencing technique of choice in relation to the effect size and the population frequency of the variants. To find common (with a population frequency down to 5 %) and rare variants (population frequency of 1–2 %) with small effect size, many individuals are required while family-specific variants can be found by sequencing few individuals. Adapted from McCarthy et al. [44]

Fig. 2

Strategy for finding variants in cases with family segregation