Candidate Gene Analysis of Migraine Susceptibility Regions on Chromosome 1q and 19p

Abstract

Migraine is a common, debilitating neurovascular disease charactensed by severe recurrent headache, nausea and vomiting, photophobia and phonophobia. It is clinically diagnosed based on criteria specified by the International Headache Society (IHS), defining two major classes of migraine: migraine with aura (MA) and migraine without aura (MO) MA sufferers experience neurovascular disturbances that precede the headache phase of an attack. Although migraine is partly influenced by environmental determinants, there is a significant genetic component, with disease heritability estimated to be up to 60% and mode of transmission multifactorial. The disorder is common with a large Dutch study reporting lifetime prevalence estimates of 33% in women and 13.3% in men, with an earlier study estimating 24% of women and 12% of men in the overall population. Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. Inherited ion channel mutations or 'channelopathies' are increasingly found to be the cause of various neurological disorders in humans. In familial hemiplegic migraine (FHM), a rare subtype of migraine with aura, mutations in the CACNA1A gene (localised at C19p13) have been fbund (FHM1). This gene codes for the alphalA subunit of the neuronal voltage-dependent P/Q-type calcium channel. Recently a second gene, ATP1A2 (FHM2) (localised at C1q23), was implicated in some EHM families. The ATP1A2 ion channel gene, codes for the alpha2 subunit of the Na+, K+ ion ATPase pump. These findings of mutations in these genes have focused attention on central nervous system ionic channels and helped to better understand EHM pathophysiology, where the best genetic evidence providing molecular insight into migraine still comes flom the mutations detected in the rare form of migraine with aura; FHM. Migraine family studies, at the Genomic Research Centre (GRC), have utilised linkage analysis methods in providing results that have indicated suggestive linkage to the FHM1-CACNA1A region on l9p13, in a large multigenerational family (Migraine Family 1; MEl) affected with typical migraine. Also linkage studies conducted within the GRC have implicated an additional susceptibility region on chromosome 1q31, but still not ruling out a second susceptibility region on C1q23, with the possibility of there being two distinct loci, on the chromosome lq region. The focus of research in this thesis is on two main chromosomal regions, which were tested for migraine susceptibility on chromosome 1 and chromosome 19. The research involved a cross-disciplinary approach utilising association, linkage and mutation screening approaches. This research implicated a specific variant on chromosome 1 and further supported the heterogeneic nature of migraine. Future directions into migraine research should involve further investigation of this specific variant and this genomic region. Such studies may aid in the development of more precise diagnosis and treatment methods for this complex disorder.