Investigation of an LDLR gene polymorphism (19p13.2) in susceptibility to migraine without aura

We performed a genetic association study with the LDL receptor gene (LDLR) on chromosome 19p13.2 in 360 migraine patients, 220 with migraine without aura (MO) and 140 with migraine with aura (MA), and 200 controls, by analysing two polymorphic markers, a G142A transition in exon 10 and a triallelic (TA)n repeat in exon 18. The allelic distribution of the (TA)n polymorphism was significantly different between migraine without aura (MO) and both controls and migraine with aura (MA). We suggest a possible predisposition to MO in the studied population through this polymorphism or another polymorphism in linkage disequilibrium with (TA)n.     

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.     

Investigation of the low-density lipoprotein receptor gene and cholesterol as a risk factor for migraine

The Low-Density Lipoprotein Receptor (LDLR) gene is a cell surface receptor that plays an important role in cholesterol homeostasis. We investigated the (TA)n polymorphism in exon 18 of the LDLR gene on chromosome 19p13.2 performing an association analysis in 244 typical migraine-affected patients, 151 suffering from migraine with aura (MA), 96 with migraine without aura (MO) and 244 unaffected controls. The populations consisted of Caucasians only, and controls were age- and sex-matched. The results showed no significant difference between groups for allele frequency distributions of the (TA)n polymorphism even after separation of the migraine-affected individuals into subgroups of MA and MO affected patients. This is in contradiction to Mochi et al. who found a positive association of this variant with MO. Our study discusses possible differences between the two studies and extends this research by investigating circulating cholesterol levels in a migraine-affected population.     

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.     

Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura

OBJECTIVE: To assess the involvement of the 19p13 familial hemiplegic migraine (FHM) locus in migraine with and without aura. BACKGROUND: Migraine with and without aura are likely to be polygenetic multifactorial disorders. FHM is a rare dominantly inherited type of migraine with aura. In about 50% of families, FHM is caused by mutations in the P/Q-type calcium channel alpha(1A)-subunit (CACNA1A) gene on chromosome 19p13. The CACNA1A gene is thus a good candidate gene for "nonhemiplegic" migraine with or without aura. METHODS: The authors performed an affected sibpair analysis using flanking and CACNA1A intragenic markers. The authors assessed the occurrence of shared parental marker alleles among 189 affected siblings from 36 extended families with typical migraine with or without aura. RESULTS: Sibling pairs with any form of migraine had inherited the same 19p13 CACNA1A-containing region significantly more frequently than expected by chance (maximum multipoint lod score = 1.22). This result was almost exclusively dependent on the increased sharing found in sibling pairs with migraine with aura (maximum multipoint lod score = 1.41). The locus-specific relative risk for a sibling (lambda(s)) to suffer from migraine with aura, defined as the increase in risk of the trait attributable to the 19p13 locus, was lambda(s) = 1.56. When combining migraine with and without aura, lambda(s) was 1.22. CONCLUSIONS: The increased allele sharing in the CACNA1A gene region on 19p13 is consistent with an important involvement of this region in migraine, especially migraine with aura.     

Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13

Two microsatellite markers, tightly linked to CACNA1A, were genotyped in migraine with aura (MA) families to determine if this gene, which underlies the 19p13 linked forms of familial hemiplegic migraine, is also linked to MA. Two-point parametric lod and nonparametric linkage scores did not support linkage. Transmission disequilibrium testing provided no evidence for linkage of MA to CACNA1A. In a large dataset of 64 Canadian MA families, the authors did not find evidence to support an MA susceptibility gene in the region of 19p13.     

Mapping of a second locus for familial hemiplegic migraine to 1q21–q23 and evidence of further heterogeneity

Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine with aura. We previously mapped an FHM gene on the short arm of chromosome 19. Mutations in this gene, recently shown to be the α1 subunit of a P/Q-type voltage-dependent calcium channel, CACNL1A4, are involved in approximately 50% of unselected FHM families and in all families where migraine attacks are associated with permanent cerebellar ataxia. As a first step toward the identification of other FHM genes, we conducted a genetic linkage analysis in one large French pedigree and showed significant linkage to two microsatellite markers D1S2635 (Z_max: 3.33 at = 0.05) and D1S2705 (Z_max: 3.64 at = 0.05), establishing the existence of a second locus for FHM (FHM2) on chromosome 1q21–q23. Analysis of six additional FHM families favored linkage to this locus in two of them; linkage was excluded in the last four families, indicating further heterogeneity. Chromosome 1–linked families differ from the ones linked to chromosome 19, because penetrance in those families is much lower, and in some of their members, epileptic seizures occur during severe migraine attacks.     

The genetics of migraine

The search for genes involved in the pathophysiology of migraine poses major difficulties. First, there is no objective diagnostic method to assess the status of the individuals studied. Second, migraine is a polygenic multifactorial disorder. Familial hemiplegic migraine (FHM) is the only known autosomal dominant subtype of migraine. In half the families with FHM who have been studied, there are mutations in the calcium-channel gene CACNA1A, located on chromosome 19. In other families, a locus has been mapped on chromosome 1. The role of these loci in typical migraine is still unknown. A susceptibility locus for migraine with aura has been located on chromosome 19 (but is distinct from CACNA1A) and a genome-wide linkage analysis has mapped a susceptibility locus on chromosome 4. Another locus for migraine may be on the X chromosome. Finally, many positive association studies have been published, but few have been replicated.     

Auditory cognitive event-related potentials in migraine with and without aura in children and adolescents

BACKGROUND AND PURPOSE: Cognitive Event-Related Potentials (CERP) reflect sensory information processing: cognitive function and early memory. Studies of CERP in adult migraneurs yielded contradictory results. The aim of our study was to evaluate CERP in children and adolescents with migraine with and without aura during the interictal period. MATERIAL AND METHODS: The study was carried out on 111 children aged 7-18 years (mean 12.92 (2.78) with idiopathic attack headaches. In this group migraine with aura (MA) was diagnosed in 27 patients, migraine without aura (MO) in 36 children and episodic tension-type (TH) headaches in 48 patients. RESULTS: The latencies N2 and P3 were significantly longer (p < 0.05 and p < 0.01, respectively) in the group of all migraneurs (MA + MO, n = 63) as compared with the TH group. In the MO group not only N2 and P3 latency, but also P2 latency (p < 0.05) were longer, if particular types of migraine were compared with tension-type headaches. There were no statistically significant differences between mean latencies in MA and TH groups. Analyzing CERP amplitudes, the N1/P2 amplitude was significantly higher in MO patients than in the TH group only. We found longer P2, N2 and P3 latencies and higher N1/P2 amplitude in MO patients in comparison with MA patients. We found correlation between P3 latency and the age of patients with migraine. There were no statistically significant correlations for either headache type between CERP parameters and illness duration, sex of patients and unilateral localisation of headache. CONCLUSIONS: The CERP parameter changes in children with migraine point out the disturbances of cognitive functions also for auditory modalities. It suggests generalized dysfunction of cortical information processing in the interictal period of migraine.     

The genetic basis of migraine: how much do we know?

Migraine with and without aura is thought to be genetically complex with aggregation in families due to a combination of environmental and genetic tendencies. Twin studies are most important in establishing the multifactorial nature of migraine with heritability approaching 50%. Familial hemiplegic migraine (FHM) on the other hand is an autosomal dominant, highly penetrant, though rare form of migraine with strong genetic tendency. Fifty percent of families with FHM are linked to chromosome 19p13 and mutations demonstrated for some in a brain expressed calcium channel alpha 1A subunit, CACNL1A4. Other FHM loci have been identified on chromosome 1q and further genetic heterogeneity is likely. The exact role of the mutated calcium channel in the pathway leading to hemiplegic migraine is yet to be established. Changes in the electrophysiologic properties of the mutated forms of the CACNL1A4 calcium channel expressed in heterologous systems help establish the functional significance of the mutations and suggest that chromosome 19p-linked FHM, an episodic disorder, represents a CNS channelopathy. Additional candidate genes causative for migraine might include other calcium channel subunits and related proteins important for neuronal membrane stability. Delineating the cascade of biochemical events leading to hemiplegic migraine will serve as a model for understanding the pathophysiology of more common forms of migraine. The evidence suggesting that some families of migraine with and without aura might also be related to the chromosome 19p locus, chromosome Xq28 locus, or DRD2 receptor polymorphisms is reviewed.     

Monoamine oxidases A and B gene polymorphisms in migraine patients

Abnormal cortical activity and brainstem functioning are considered the possible etiopathogenetic factors of migraine. Monoamine oxidase A and B (MAO-A and -B) regulate the levels of monoamine neurotransmitters, so changes in their activity could participate in migraine pathogenesis. We have investigated the possible association of MAO-A and -B alleles and haplotypes with two common types of migraine, i.e. migraine without aura (MO) and migraine with aura (MA), on the sample of 110 migraineours (80 MO and 30 MA) and 150 controls. MAO-A promoter and MAO-B intron 13 polymorphisms were genotyped by the PCR-based methods. In addition, we have reevaluated the reported association between MAO-B intron 13 polymorphism and platelet MAO-B activity. The platelet MAO-B activity was determined fluorimetrically using kynuramine as a substrate. We have found a tendency toward association of the shorter variant of MAO-A gene promoter with migraine without aura in male subjects. Regarding investigated MAO-B polymorphism, no association with migraine or with platelet MAO-B activity was found. The suggestive association of the variant in MAO-A gene with migraine is considered worthy of independent replication. On the other hand, further studies on MAO-B polymorphism in migraine do not seem promising.     

Validation of the deCODE Migraine Questionnaire (DMQ3) for use in genetic studies

We assessed the reliability of the diagnosis of migraine with aura (MA) and migraine without aura (MO) based on the third edition of the deCODE Migraine Questionnaire (DMQ3) using a physician-conducted interview as an empirical index of validity. Amongst Danish migraine families recruited from specialist practice we selected 200 cases diagnosed according to the International Classification of Headache Disorders 2nd Edition in a validated physician-conducted telephone interview: 50 patients with exclusively MA, 50 with both MA and MO, 50 with exclusively MO and 50 controls. A written copy of the DMQ3 was mailed to the participant. The DMQ3-based diagnosis was compared with the interview-based diagnosis. Overall, the DMQ3 diagnosed migraine (MA, MO or both) with a sensitivity of 99% (109/110), a specificity of 86% (32/37) and a kappa statistic of 0.89. The most reliable subtype of migraine was MA (with or without co-occurring attacks of MO) which was diagnosed with a sensitivity of 92% (71/77), a specificity of 93% (65/70) and a kappa statistic of 0.85. Exclusively MO was diagnosed with a sensitivity of 91% (30/33), a specificity of 93% (106/114) and a kappa statistic of 0.80. Weakest was the diagnosis of both MO and MA which was diagnosed with a sensitivity of 63% (24/38), a specificity of 92% (100/109) and a kappa statistic of 0.57. In conclusion, the DMQ3 is a valid tool for diagnosing patients with migraine for genetic studies.     

A typical migraine susceptibility region localizes to chromosome 1q31

Migraine (with and without aura) is a prevalent neurovascular disease that shows strong familial aggregation, although the number of genes involved and the mode of inheritance is not clear. Some insight into the disease has been gained from genetic studies into a rare and very severe migraine subtype known as familial hemiplegic migraine (FHM). In this study, we took a family-based linkage and association approach to investigate the FHM susceptibility region on chromosome 1q31 for involvement in typical migraine susceptibility in affected Australian pedigrees. Initial multipoint ALLEGRO analysis provided strong evidence for linkage of Chr1q31 markers to typical migraine in a large multigenerational pedigree. The 1-LOD* unit support interval for suggestive linkage spanned approximately 18 cM with a maximum allele sharing LOD* score of 3.36 obtained for marker D1S2782 (P=0.00004). Subsequent analysis of an independent sample of 82 affected pedigrees added support to the initial findings with a maximum LOD* of 1.24 (P=0.008). Utilising the independent sample of 82 pedigrees, we also performed a family-based association test. Results of this analysis indicated distortion of allele transmission at marker D1S249 [global χ² ₍₅₎ of 15.00, P=0.010] in these pedigrees. These positive linkage and association results will need further confirmation by independent researchers. However, overall they provide good evidence for the existence of a typical migraine locus near these markers on Chr1q31, and reinforce the idea that an FHM gene in this genomic region may also contribute to susceptibility to the more common forms of migraine. Electronic Publication     

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.     

Migraine and MTHFR C677T genotype in a population-based sample

OBJECTIVE: Migraine with aura is associated with increased risk of stroke. The MTHFR C677T genotype has been associated with increased risk of migraine in selected clinical samples and with elevated homocysteine, a risk factor for stroke. We assessed the association of the MTHFR C677T variant with migraine and the mediating effect of cardiovascular risk factors and metabolic markers of genotype status. METHODS: We compared adult migraineurs with aura (MA; n = 187), without aura (MO; n = 226), and nonmigraineurs (n = 1,212) from the population-based Genetic Epidemiology of Migraine study. RESULTS: Compared with the wild-type genotype, the T/T genotype was associated with increased odds of MA (odds ratio [OR], 2.05; 95% confidence interval, 1.2-3.4; p < 0.006), with a trend of increasing numbers of T alleles (OR, 1.40; 95% confidence interval, 1.1-1.8; p < 0.007). ORs were slightly attenuated after adjusting for homocysteine. INTERPRETATION: Risk of MA is associated with MTHFR C674T homozygosity, independent of other cardiovascular risk factors.     

An update on the familial headache syndromes]

Migraine is a common form of the chronic headache syndromes. Although the pathogenesis of migraine still remains enigmatic, there have been remarkable progress in headache research. Point mutations of P/Q-type Ca2+ channel alpha 1 subunit (CACNA1A) gene have been identified in familial hemiplegic migraine (FHM), which linked to chromosome 19 (FHM-1, OMIM 141500). Na-K ATPase alpha2 gene has been identified as the causative gene for FHM linked to 1q21-23 (FHM-2, OMIM 602481). Common forms of migraine (i.e. migraine with and without aura) seems to be caused from multifactorial genetic factors and environmental factors. An association study of allelic variation at Codon 23 (Cys or Ser) of 5HT2C-R gene in Japanese samples revealed that the Ser allele frequency in migraine with aura was significantly higher than that in the non-headache controls. However, negative association of this polymorphism have been reported in Caucasian migrainures. The C677T allelic variation of 5,10-methylenetetrahydrofolate reductase (MTHFR) are focused on in association with the coronary heart diseases and the cerebrovascular diseases. The T allelic frequency in migraine sufferers was significantly higher than that in controls. The C677T mutation of MTHFR is one of the genetic risk factors for migraine. These observations are confirmed in Turkish, Australian and Spanish samples. Positive associations of angiotensin converting enzyme (ACE) gene, endotheline receptor-A (ET-A) gene, and insulin receptor gene have been reported. Using the genomewide screen technology, significant linkage between the migraine with aura and a marker on 4q24 has been reported in Finnish families. The genome wide screen analysis will be one of the powerful strategies on exploring migraine gene. Genetic study of migraine headache is a promised and fruitful field and will provide deep understanding to migraine headache. Discovery of new responsible or susceptible genes to migraine will also open an avenue to develop new therapeutic strategy of migraine.     

A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes

We assessed the role of some dopamine metabolism genes in the genetic susceptibility to migraine. We performed an association study using three functional polymorphisms: a 48-base-pair (bp) tandem repeat in the D4 dopamine receptor gene (DRD4), a 40-bp tandem repeat in the dopamine transporter gene (DAT) and a dinucleotide repeat in the dopamine beta-hydroxylase (DBH) gene. Allelic and genotypic frequencies for each polymorphism were assayed in two migraine populations (93 individuals with migraine with aura (MA) and 101 with migraine without aura (MO)) and were compared with those in a control group (117 individuals). No significant differences were found between control and migraine groups for DAT and DBH polymorphisms. Instead, the distribution of alleles for the DRD4 gene in the MO group was significantly different from those in both MA and control groups, with the shortest and longest alleles being less frequent in MO. Our data indicate that MO, but not MA, shows significant genetic association with DRD4. Received: 11 July 2002 / Accepted in revised form: 2 December 2002 Correspondence to M. Mochi     

Genetic heterogeneity in Italian families with familial hemiplegic migraine.

OBJECTIVE: To verify linkage to chromosome 19p13, to detect mutations in the CACNA1A gene, and to correlate genetic results to their clinical phenotypes in Italian families with familial hemiplegic migraine (FHM). BACKGROUND: FHM is an autosomal dominant disease, classified as a subtype of migraine with aura. Only a proportion of FHM patients have been associated with chromosome 19p13. Among these, four missense mutations within the CACNA1A gene in five unrelated families have been described. METHODS: A linkage study was performed in 19 patients affected by FHM from five families by studying microsatellite markers associated with the 19p13 region. All familial and seven additional sporadic patients with FHM were analyzed to search for mutations within the CACNA1A gene by applying the double gradient-denaturant gradient electrophoresis technique. RESULTS: Lod score values did not establish significantly linkage to chromosome 19. However, seven new genetic variants were detected: six were new polymorphisms. The seventh was a missense mutation present in family 1, and it was associated with a hemiplegic migraine phenotype without unconsciousness and cerebellar ataxia. Because this missense mutation is absent in the general population and cosegregates with the disease, it may be a pathologic mutation. CONCLUSIONS: Genetic heterogeneity of FHM has been shown in familial and sporadic FHM patients of Italian origin. The new missense mutation-G4644T-is associated with milder clinical features compared with typical FHM.     

Clinical review of headache in pregnancy

Headache is a common disorder in the general population. Among women, the primary headache form that is more heavily affected by the physiologic hormonal variations occurring through a woman’s lifetime is migraine. Migraine without aura (MO) and migraine with aura (MA) show a different clinical pattern during pregnancy. MO improves or disappears while it is not infrequent for women to have their first attack of MA during this period; usually, during pregnancy MA do not improve. In MO women who continue to suffer from migraine during pregnancy, clinical observation and the few data currently available from the literature suggest that in the gestational period their attacks are nonetheless less disabling than those occurring outside this period. Even though the duration of the attacks is unchanged, their severity tends to be mild or moderate. Treatment of migraine during pregnancy is discussed.     

Association and linkage of allelic variants of the dopamine transporter gene in ADHD

Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5' region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P=0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n=3) tested blocks (P=0.0048); (3) within block two we detected a nominal P=0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P<0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.