Molecular Genetics of Migraine

Abstract

Migraine is a common neurological disorder with a significantly heritable component. It is a complex disease and despite numerous molecular genetic studies, the exact pathogenesis causing the neurological disturbance remains poorly understood. Although several known molecular mechanisms have been associated with an increased risk for developing migraine, there remains significant scope for future studies. The majority of studies have investigated the most plausible candidate genes involved in common migraine pathogenesis utilising criteria that takes into account a combination of physiological functionality in conjunction with regions of genomic association. Thus, far genes involved in neurological, vascular or hormonal pathways have been identified and investigated on this basis. Genome‐wide association studies (GWAS) studies have helped to identify novel regions that may be associated with migraine and have aided in providing the basis for further molecular investigations. However, further studies utilising sequencing technologies are required to characterise the genetic basis for migraine.

Key Concepts:

  • Migraine can present with variable phenotypes, which may confound results from gene association studies where some traits are more prevalent than others contributing to variability between populations.

  • Migraine is a genetically heterogeneous disorder and this may contribute to the difficulty in replicating gene associations in different populations.

  • Pedigree‐based studies may assist to reduce genetic and phenotypic heterogeneity to identify molecular mechanisms or pathways involved in pathogenesis that may then be investigated at a population level.

  • Current migraine genetic studies focus on genes involved in hormonal, vascular or neurological pathways.

  • GWAS have provided some success in identifying novel genomic regions for investigation.

  • Investigation of the mitochondrial genome is an emerging area of investigation in migraine research.

  • Sequencing will assist to identify novel rare or family‐specific variants that may implicate genes for further research.

Keywords: migraine; migraine with aura; migraine without aura; GWAS; association; linkage

Figure 1.

A schematic representation illustrating the pathogenic pathways of migraine. Central to the migraine pathways is the trigeminal nervous system, which is indicated as a blue arrow. Activated trigeminal nerves carry pain signals from the meninges and from meningeal blood vessels to the trigeminal nucleus in the brainstem from which the pain signals are further carried to the sensory cortex via the thalamus. According to the neural hypothesis, activation of the trigeminal nerves is caused by CSD, which is indicated as a dotted arrow in the figure. According to the neurovascular hypothesis, neuroinflammation as a consequence of CSD may further sustain the sensation of pain.

Figure 2.

Flow diagram illustrating the production of homocysteine as part of the amino acid and purine biosynthesis pathway. Included in the illustration is the role of a key enzyme in this process, MTHFR. Dysfunction of MTHFR results in increased levels of homocysteine in the blood and an increased risk of developing MA.

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Further Reading

Charbit AR, Akerman S and Goadsby PJ (2010) Dopamine: what's new in migraine? Current Opinion in Neurology 23(3): 275–281.

Colson NJ, Lea RA, Quinlan S and Griffiths LR (2006) The role of vascular and hormonal genes in migraine susceptibility. Molecular Genetics and Metabolism 88(2): 107–113.

Goadsby PJ and Akerman S (2012) The trigeminovascular system does not require a peripheral sensory input to be activated – migraine is a central disorder. Focus on ‘Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system’. Cephalalgia 32(1): 3–5.

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Panconesi A (2008) Serotonin and migraine: a reconsideration of the central theory. Journal of Headache and Pain 9(5): 267–276.

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Stuart, Shani, Maher, Bridget H, Oikari, Lotta, and Griffiths, Lyn R(Jan 2013) Molecular Genetics of Migraine. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022493]