Pearls and pitfalls in genetic studies of migraine

Abstract

Purpose of review: Migraine is a prevalent neurovascular brain disorder with a strong genetic component, and different methodological approaches have been implemented to identify the genes involved. This review focuses on pearls and pitfalls of these approaches and genetic findings in migraine. Summary: Common forms of migraine (i.e. migraine with and without aura) are thought to have a polygenic make-up, whereas rare familial hemiplegic migraine (FHM) presents with a monogenic pattern of inheritance. Until a few years ago only studies in FHM yielded causal genes, which were identified by a classical linkage analysis approach. Functional analyses of FHM gene mutations in cellular and transgenic animal models suggest abnormal glutamatergic neurotransmission as a possible key disease mechanism. Recently, a number of genes were discovered for the common forms of migraine using a genome-wide association (GWA) approach, which sheds first light on the pathophysiological mechanisms involved. Conclusions: Novel technological strategies such as next-generation sequencing, which can be implemented in future genetic migraine research, may aid the identification of novel FHM genes and promote the search for the missing heritability of common migraine.

Age-specific association of migraine with cryptogenic TIA and stroke

“…Therefore, the association of migraine and cryptogenic cases or ischemic stroke overall is unlikely to be directly causal. Rather, given that migraine has a strong genetic component, 39 the association of migraine and cryptogenic stroke is possibly explained at the genetic level or by shared RFs that are unknown.…”

Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

“…Multiple mutations of ion channels and transporters have been associated with familial hemiplegic migraine (de Vries et al 2009). Recent genetic studies have also implicated ion channel dysfunction in common forms of migraine (Eising et al 2013). These discoveries offer a gateway to understanding the mechanisms underlying migraine headache.…”

“…Our results support a potential causal relationship between the frameshift TRESK mutation and migraine susceptibility. migraine; TRESK K ϩ channel; background K ϩ current; trigeminal ganglion; neuronal excitability MIGRAINE IS ONE OF THE MOST common neurovascular disorders with a strong genetic component (Eising et al 2013;Victor et al 2010). One of the major symptoms of migraine, the recurring headache, is highly debilitating, poorly understood, and difficult to treat (Burstein and Jakubowski 2005;Goadsby et al 2009;Pietrobon and Moskowitz 2013).…”

“…However, the CR variant forms a nonfunctional channel per se in Xenopus oocytes and exhibits the same dominant-negative effect on WT TRESK currents as the frameshift mutation (Andres-Enguix et al 2012). This calls into question a direct causal relationship between TRESK dysfunction and migraine phenotype (Andres-Enguix et al 2012;Eising et al 2013;Lafreniere et al 2010). On the other hand, previous works have illustrated the importance of studying migraine-associated gene mutations in neurons involved in migraine pathophysiology (Fioretti et al 2011;Hullugundi et al 2014;Liu et al 2013;Tao et al 2012;Tottene et al 2009;van Den Maagdenberg et al 2004).…”

Familial hemiplegic migraine: A model for the genetic studies of migraine

“…Central nervous system (CNS) disorders are over-represented in the Online Mendelian Inheritance in Man (OMIM) database of monogenic conditions. This, together with other arguments, led some authors to suggest that an important proportion of hereditary CNS disorders might be due to rare variants with a strong effect (17), which cannot be identified by GWAS but by extensive sequencing in patients and small families, after careful phenotyping (6,16). For all these reasons, the experience gained in clinical and genetic studies of patients and families with FHM is important in the overall field of migraine genetics.…”