The genetics of migraine

Clinical, pathophysiological and genetic studies indicate that migraine without aura (MO) and migraine with aura (MA) are distinct entities. Compared with the general population, first degree relatives of probands with MO have a two-fold increased risk of MO. The mode of inheritance is most likely multifactorial inheritance without generational difference, but genetic heterogeneity can not be excluded. Compared with the general population, first degree relatives of probands with MA have a four-fold increased risk of MA. The mode of inheritance is most likely multifactorial inheritance without generational differences. Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of MA. A gene for FHM maps to chromosome 19. Some families with FHM do not link to this locus, indicating genetic heterogeneity of FHM. The gene for FHM is soon to be cloned. Loci for the more common types of migraine MO; and MA will problably be identified in the near future.     

Headache,migraine and cardiovascular risk factors: The HUNT study

Background: Migraine with aura (MA) has been found to be a risk factor for cardiovascular disease including ischaemic stroke and myocardial infarction. Studies have also reported a higher prevalence of unfavourable cardiovascular risk factors amongst migraineurs, but results have been conflicting as to whether this is restricted to MA or also holds true for migraine without aura (MO). This study aims to examine the relation between headache and cardiovascular risk factors in a large cross‐sectional population‐based study. Methods: A total of 48 713 subjects (age ≥20 years) completed a headache questionnaire and were classified according to the headache status in the Nord‐Trøndelag Health Study in Norway 1995–1997 (HUNT 2). Framingham 10‐year risk for myocardial infarction and coronary death could be calculated for 44 098 (90.5%) of these. Parameters measured were blood pressure, body mass index, serum total and high‐density lipoprotein cholesterol. Results: Compared to controls, Framingham risk score was elevated in non‐migraine headache sufferers (OR 1.17, 95% CI 1.10–1.26), migraineurs without aura (OR 1.17, 95% CI 1.04–1.32) and most pronounced amongst migraineurs with aura (OR 1.54, 95% CI 1.21–1.95). Framingham risk score consistently increased with headache frequency. For non‐migrainous headache and MO, the increased risk was accounted for by the lifestyle factors smoking, high BMI and low physical activity, whilst such factors did not explain the elevated risk associated with MA. Conclusions: Both MA, MO and non‐migrainous headache are associated with an unfavourable cardiovascular risk profile, but different mechanisms seem to underlie the elevated risk in MA than in the other headache types.     

Migraine genetics

Migraine with aura (MA) and migraine without aura (MO) are primary headaches prevalent in the general population that carry a substantial familial liability. Based on the model of migraine as a complex disease, a multifactorial type of inheritance has been suggested, but familial hemiplegic migraine (FHM), classified as a subtype of MA, shows an autosomal dominant transmission pattern and is due to mutations in three genes encoding for neural channel subunits. These FHM mutations, however, account for a minority of the FHM families and are not usually found in sporadic HM or in the typical migraines MA/MO. This implies that the genetic predisposition to the typical migraines may be different and that FHM could be better classified as a type of syndromic migraine rather than a MA subtype. Linkage and genome-wide scans have disclosed several chromosomal liability loci in selected families with MA/MO. It is likely that typical migraine genes will be discovered in the future. Epigenetic mechanisms, especially those acting in the early stages of neural development, are here proposed to be involved in the genetics of the typical migraines, especially if the typical migraines are modeled as evolutionarily conserved behaviors (sickness behavior) enacted out of a genetic repertoire.     

Is the CACNA1A gene involved in familial migraine with aura?

The discovery of mutations in the neural calcium channel (CACNA1A) gene in familial hemiplegic migraine (FHM), variant of migraine with aura, led to the suggestion that this gene might be involved in familial migraine with aura (FMA). We investigated whether the mutations in FHM are present in FMA patients, analyzing genomic DNA by PCR, single stranded conformation polymorphism, sequencing and restriction enzyme. No mutations were found. A known polymorphism (5682–14C>T) was found in exon 36. These findings suggest that the mutations found in FHM and the other known mutations of the CACNA1A gene are not the genetic basis of FMA. Genetic alterations in FMA patients may be localized on chromosome 19 but not in the CACNA1A exons we investigated. Received: 25 January 2002 / Accepted in revised form: 25 February 2002     

Familial risk of migraine: A population-based study

Estimates of familial aggregation of migraine have varied considerably due, in part, to methodological differences among studies. We concluded a population-based study of 73 clinically confirmed probands with migraine, 72 matched control probands, and 511 of their first-degree relatives, all of whom were directly interviewed. The risk of migraine was 50% more likely in relatives of migraine probands than in relatives of controls. Migraine risk was considerably higher among relatives of probands with disabling migraine compared with relatives of probands with minimal disability. Moreover, for probands with minimal disability, no excess risk of migraine in female relatives was observed. Finally, in relatives risk of 4.04 was observed. No excess risk was observed among relatives of male probands who had migraine without aura. This study suggests that familial factors (environment related to the family or genetic factors) account for less than one-half of all migaine cases in the population. Degree of disability in the proband appears to influence familial risk. These results suggest that the development of migraine is determined by complex gentic as well as environmental factors.     

Analysis of chromosome 1 microsatellite markers and the FHM2-ATP1A2 gene mutations in migraine pedigrees

OBJECTIVES: The aims of the study were: (i) to extend our linkage analysis of chromosome 1q microsatellite markers in predominantly migraine with aura pedigrees and (ii) to test the novel FHM-2 ATP1A2 gene for involvement in these migraine affected pedigrees and a previous pedigree (MF14) showing evidence of linkage of markers to C1q31.METHODS: A chromosome 1 scan (31 markers) was performed in 21 multiplex pedigrees affected predominantly with migraine with aura (MA). The known FHM-2 ATP1A2 gene mutations were tested, by sequencing, for the involvement in MA and migraine without aura (MO) in these pedigrees. Sequencing was performed in the coding areas of the ATP1A2 gene through three MA individuals from MF14.RESULTS: Evidence for linkage was obtained at C1q23 to markers spanning the ATP1A2 gene. However, testing of the known ATP1A2 gene mutations (for FHM) in common migraine probands of pedigrees showing excess allele sharing was negative. Sequencing of the entire coding areas of the gene through all the three MA affected from MF14 was also negative for mutations.DISCUSSION: Microsatellite markers on chromosome 1q23 show evidence of excess allele sharing in MA and some MO pedigrees, suggesting linkage to the common forms of migraine and the presence of a susceptibility gene in this region. The FHM-2 (ATP1A2 gene) does not seem to be involved in the common types of migraine. Despite certain clinical characteristics, the genetic correlation between FHM and familial typical migraine remains unclear. Several candidate genes lie within the C1q23 and C1q31 cytogenetic regions; therefore, further studies are needed.     

Association between angiotensin-converting enzyme insertion/deletion polymorphism and migraine: a meta-analysis

Background: Many studies investigated the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and migraine, with controversial results. Thus, we performed a meta-analysis to better evaluate the correlation of this polymorphism and migraine. Methods: We retrieved studies published up to September 2014 about the ACE gene polymorphism and migraine from electronic database. Pooled odds ratios (ORs) with 95% confidence interval (CI) were calculated to examine the strength of association between the ACE I/D polymorphism and migraine, using random-effects models. Results: We identified 14 separate studies, in which 7334 migraineurs and 22 990 healthy controls were eligible for the meta-analysis. The results showed no relationship between the ACE I/D polymorphism and any migraine. Stratification revealed a protective effect in the Turkish population against migraine with aura for the II genotype model (II vs. DD: pooled OR = 0.366, 95% CI = 0.137–0.980; II vs. DI + DD: pooled OR = 0.370, 95% CI = 0.145–0.945). Similar results were obtained for Turkish people with migraine without aura (II vs. DD: pooled OR = 0.386; 95% CI = 0.166–0.900; II vs. DI + DD: pooled OR = 0.347; 95% CI = 0.156–0.773). Conclusions: The data suggest that the ACE II genotype could exert a protective effect against migraine with aura and without aura at least in the Turkish population.     

Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine

Background: Familial hemiplegic migraine (FHM) is a rare, dominantly inherited subtype of migraine with transient hemiplegia during the aura phase. Mutations in at least three different genes can produce the FHM phenotype. The mutated FHM genes code for ion transport proteins that animal and cellular studies have associated with disturbed ion homeostasis, altered cellular excitability, neurotransmitter release, and decreased threshold for cortical spreading depression. The common forms of migraine are characterized interictally by a habituation deficit of cortical and subcortical evoked responses that has been attributed to neuronal dysexcitability. FHM and the common forms of migraine are thought to belong to a spectrum of migraine phenotypes with similar pathophysiology, and we therefore examined whether an abnormal habituation pattern would also be found in FHM patients. Methods: In a group of genotyped FHM patients (five FHM‐1, four FHM‐2), we measured habituation of visual evoked potentials (VEP), auditory evoked potentials including intensity dependence (IDAP), the nociception‐specific blink reflex (nsBR) and compared the results to a group of healthy volunteers (HV). Results: FHM patients had a more pronounced habituation during VEP (P = 0.025) and nsBR recordings (P = 0.023) than HV. There was no difference for IDAP, but the slope tended to be steeper in FHM. Conclusion: Contrary to the common forms of migraine, FHM patients are not characterized by a deficient, but rather by an increased habituation in cortical/brain stem evoked activities. These results suggest differences between FHM and the common forms of migraine, as far as central neuronal processing is concerned.     

Circannual periodicity of migraine?

Seasonal rhythm of migraine attacks may support a role of the suprachiasmatic nucleus of the hypothalamus in the pathophysiology of migraine. The objective of this study was to provide evidence for seasonal variation in migraine. Eighty-nine female migraineurs volunteered to record every migraine attack in detail for 12 consecutive months. Attacks associated with sleep complaints were defined as insomnia-related. By using Edwards' model for recognition and estimation of cyclic trends, time-series analysis was made. Fifty-eight patients, of which 26 had migraine without aura (MO) and 32 had migraine with aura (MA), completed the study. A total of 1840 attacks were recorded. The mean age ± SD was 36.9 ± 6.0. Patients with a lifetime history of MA showed marked seasonal fluctuation with more attacks in the light season compared to the dark. Time of peak was May 21. Peak/low ratio was 1.30 (95% CI: 1.08–1.55). When insomnia-related attacks ( n  = 312) were removed the seasonal variation became insignificant. There is a seasonal trend with more migraine attacks in the light season compared to the dark season in females with MA, but not MO, living in an arctic area. This is caused by the seasonal variation of insomnia-related attacks in patients with MA.     

Genetics of migraine

Twin and family studies provide evidence of a genetic component in migraine, in particular migraine with aura (MA). Familial hemiplegic migraine (FHM) is a rare monogenic subtype of MA for which three causative genes have been identified: CACNA1A (FHM1), ATP1A2 (FHM2), and SCN1A (FHM3). Mutations in these genes are also found in some patients with sporadic hemiplegic migraine. Linkage studies have identified several gene loci for the more common forms of migraine; however, identification of the respective causative genes is still pending. This review summarizes recent developments in the genetics of migraine and their implications for molecular genetic testing. We further discuss the roles of CACNA1A, ATP1A2, and SCN1A in the pathophysiology of cortical spreading depression, which is the likely correlate of migraine aura.