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Genetic Associations Studies Elucidate Genetic Basis of Migraine

Results from Genetic Associations Studies Elucidate Genetic Basis of Migraine

A growing body of evidence has confirmed the important role of inheritance in migraine and has implicated specific genes in the pathogenesis of specific migraine subtypes. Defects in CACNA1A and ATP1A2 have been linked to familial hemiplegic migraine,[1, 2] and polymorphisms in genes encoding several proteins (eg, MTHF-R, HLA-DRB1, ESR1, DRD4, PGR) have been associated with more common forms of migraine, including migraine with and without aura.[3-7] The picture emerging from this research suggests that common forms of migraine are characterized by genetic heterogeneity and complexity.

Results from two recent genetic association studies have contributed importantly to this emerging picture. Freillinger and colleagues for the International Headache Genetic Consortium have reported results from the first genetic association study of migraine without aura.[8] The study was based on data from 2,236 patients with migraine without aura and 4,580 population-based controls. Out of 12 single-nucleotide polymorphisms (SNPs) selected for replication testing, two showed significant convincing replication, one at chomosome 1q22, in MEF2D, and another at chromosome 3p24, near TGFBR2. There was weaker evidence of replication for two other SNPs at the PHACTR1 and ASTN2 loci. Additionally, associations were replicated for two previously reported migraine loci, in or near TRPM8 and LRP1.

Genetic analyses investigating genetic susceptibility for migraine have been conducted using DNA samples from the population of Norfolk Island, a small remote South Pacific island populated by descendants of 11 British sailors who participated in the mutiny of the HMS Bounty and 9 Tahitian women.[9, 10] The Norfolk Island population was chosen for study because of its high prevalence of migraine (25.5%), approximately two-fold higher than in other Caucasian populations, and because the relative homogeneity of the population due to its geographic isolation and strict immigration regulations provided advantages in genetic analysis. In the Norfolk Island population, as in other study populations, migraine appears to affect women disproportionately. Therefore, the Norfolk Island population was used to examine the entire X chromosome for migraine susceptibility loci.[10] The genetic association study implicated two primary clusters of SNPs in migraine susceptibility, a novel locus made up of a cluster of 10 SNPs at Xq12 and a previously identified cluster of 11 SNPs at Xq27. A further analysis of these loci conducted among 5,122 women with migraine from the Women’s Genome Health Study supported the association at the novel Xq12 locus. The SNP within the cluster in the Xq12 locus with the strongest effect was within the HEPH gene, which is involved in iron regulation within the brain. The SNP with HEPH suggests a novel pathway in migraine pathogenesis, one which may be useful in developing targeted migraine therapies in the future.

1. Dichgans, M., et al., Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet, 2005. 366(9483): p. 371-7. 2. Ophoff, R.A., et al., Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell, 1996. 87(3): p. 543-52. 3. Colson, N.J., et al., The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups. Neurogenetics, 2004. 5(2): p. 129-33. 4. Colson, N.J., et al., Investigation of hormone receptor genes in migraine. Neurogenetics, 2005. 6(1): p. 17-23. 5. Kara, I., et al., Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk. Brain Res Mol Brain Res, 2003. 111(1-2): p. 84-90. 6. Mochi, M., et al., A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes. Neurol Sci, 2003. 23(6): p. 301-5. 7. Rainero, I., et al., Association between migraine and HLA-DRB1 gene polymorphisms. J Headache Pain, 2005. 6(4): p. 185-7. 8. Freilinger, T., et al., Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet, 2012. 44(7): p. 777-782. 9. Cox, H., et al., A genome-wide analysis of ‘Bounty’ descendants implicates several novel variants in migraine susceptibility. Neurogenetics, 2012. 13(3): p. 261-266. 10. Maher, B.H., et al., An X Chromosome Association Scan of the Norfolk Island Genetic Isolate Provides Evidence for a Novel Migraine Susceptibility Locus at Xq12. PLoS ONE, 2012. 7(5): p. e37903.