Genetics of migraine in the age of genome-wide association studies

Abstract

Genetic factors importantly contribute to migraine. However, unlike for rare monogenic forms of migraine, approaches to identify genes for common forms of migraine have been of limited success. Candidate gene association studies were often negative and positive results were often not replicated or replication failed. Further, the significance of positive results from linkage studies remains unclear owing to the inability to pinpoint the genes under the peaks that may be involved in migraine. Problems hampering these studies include limited sample sizes, methods of migraine ascertainment, and the heterogeneous clinical phenotype. Three genome-wide association studies are available now and have successfully identified four new genetic variants associated with migraine. One new variant (rs1835740) modulates glutamate homeostasis, thus integrates well with current concepts of neurotransmitter disturbances. This variant may be more specific for severe forms of migraine such as migraine with aura than migraine without aura. Another variant (rs11172113) implicates the lipoprotein receptor LRP1, which may interact with neuronal glutamate receptors, thus also providing a link to the glutamate pathway. In contrast, rs10166942 is in close proximity to TRPM8, which codes for a cold and pain sensor. For the first time this links a gene explicitly implicated in pain related pathways to migraine. The potential function of the fourth variant rs2651899 (PRDM16) in migraine is unclear. All these variants only confer a small to moderate change in risk for migraine, which concurs with migraine being a heterogeneous disorder. Ongoing large international collaborations will likely identify additional gene variants for migraine.

Irritable Bowel Syndrome and Migraine: Bystanders or Partners?

“…On the other hand, several genetic polymorphisms probably increase thrombotic disorders among the migraineurs; however, these putative genes are extremely different from those linked to IBS. For examples, migraine related candidate genes include factor V Leiden , factor V ( H1299R ), prothrombin ( G20210A ), factor XIII ( V34L ), β-fibrinoge n and lipoprotein receptor ( LRP1 ) etc, whereas IBS related candidate genes consist of serotonin transporter ( SLC6A4 ), norepinephrine transporter ( NET ), alpha-2A-adrenergic receptors ( ADRA2A ), interleukin-10 ( IL-10 ), G protein β3 subunit ( GNβ3 ) and sodium channel ( SCN5A ) etc 73,75,76. In fact, the potential functions of these genetic variants are controversial because they result in a small to moderate risk of developing migraine which means that migraine is a heterogeneous disorder.…”

Genetic Variation in Cytokine-Related Genes and Migraine Susceptibility

“…A number of large GWAS aiming to identify associations between genetic variants and migraine have been conducted, with the first being published by the International Headache Genetics Consortium (IHGC) in 2010 (Anttila et al, 2010;Schurks, 2012). Two subsequent GWAS conducted by the Dutch-Icelandic migraine genetics consortium (DICE) and the Women's Genome Health Study (WGHS) failed to replicate the results from the first GWAS and only identified modest associations (Ligthart et al, 2011).…”

Overview of Migraine

“…If one parent has migraine, there is a 50% chance of the offspring developing migraine. 51 Should both parents have migraine, the risk of migraine is 80%. The suspicion of a migraine diagnosis should be high when multiple family members have disabling episodic headaches.…”