Mendelian and complex causes of migraine: Bridging the gap

Abstract

Migraine, and particularly migraine with aura (MA), has a strong genetic component. The best evidence for this are the significantly increased familial risk of migraine, the significantly higher concordance rate of migraine in monozygotic than in dizygotic twin pairs (1,2) and the three identified genes, CACNA1A, ATP1A2 and SCNA1, that can cause familial hemiplegic migraine (FHM), a rare monogenic subtype of migraine associated with hemiparesis during aura (3). Migraine is also a prominent part of the phenotype of several mendelian diseases, including Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and other genetic vasculopathies (4). CADASIL is a monogenic form of small-vessel disease of the brain, characterized by recurrent ischemic stroke in 60–85% of patients and cognitive decline in nearly all patients after the age of 50 years. MA is the third cardinal manifestation of the disease, present in up to 40% of patients and often the first clinical manifestation, presenting some 10 years ahead of the other symptoms (5). CADASIL is caused by dominant mutations in the NOTCH3 gene, which encodes a transmembrane receptor primarily expressed in the vasculature and important for the structural and functional integrity of small arteries (6). NOTCH3 has 33 exons but all CADASIL mutations occur in the exons 2–24 encoding the 34 epidermal growth factor–like repeats, with strong clustering in exons 3 and 4, and, lead to an odd number of cysteine residues causing the NOTCH3 protein to abnormally accumulate in the vessel. The dominant view is that the primary determinant of the CADASIL disease involves novel pathogenic roles for mutant Notch3 receptor rather than compromised NOTCH3 function (5). Genetically modified mice that recapitulate the pre-symptomatic stage of the CADASIL disease have been recently obtained. Of interest, recent work showed that transgenic mice expressing a Notch3 protein with an archetypal CADASIL mutation (Arg90Cys) in smooth muscle cells have a lower threshold for evoking cortical spreading depression (CSD) than wild-type mice, consistent with a MA phenotype (7). Menon et al. (8) analyzed the NOTCH3 gene for its involvement with common migraine. They conducted an association study, which tests for significant differences in allele frequencies between case and controls, with two common polymorphisms located in exons 3 and 4 of NOTCH3, in a community-based setting. They elegantly demonstrate that rs1043994 (684A>G), located in exon 4 of the gene, is associated with an increased risk of developing MA. As is now a requirement for publication of genetic association studies, in order to distinguish true findings from spurious associations, Menon et al. have used a pre-planned replication sample to confirm or refute findings in the discovery cohort. While the association with rs1043994 was replicated, the second polymorphism (rs3815188, [381C>T], in exon 3) that was associated with migraine in the discovery cohort could not be confirmed in the second sample. Interestingly, rs1043994 increased the risk of MA but not of migraine without aura (MO), similarly to the CADASIL mutation in NOTCH3 (5). This is in line with heritability studies suggesting that MA and MO may have at least partly distinct genetic backgrounds (3). Of note, however, both the discovery and the replication cohort had a limited sample size, with 260 cases or less, and the power to detect an association with both polymorphisms, which have a minor allele frequency between 8% and 12%, was relatively low. Indeed, as for other complex genetic diseases, the odds ratio (OR) of developing migraine associated with