Estevez M, Gardner KL
Update on the genetics of migraine.
Hum Genet. 2004 Feb;114(3):225-35.
The field of migraine genetics has seen an explosion of information over the last year. In a recent breakthrough, missense mutations in a chromosome 1q23 gene, ATP1A2, encoding a Na+, K+-ATPase, have been identified in four distinct pedigrees with a rare form of familial hemiplegic migraine (FHM). ATP1A2 is expressed in the brain, like the voltage gated calcium channel gene, CACNA1A, previously identified as the first hemiplegic migraine gene (FHM1). The shared hemiplegic migraine phenotype of mutations in ATP1A2 and CACNA1A raises the possibility that they coordinately regulate ion homeostasis that determines susceptibility to the initiation of both migraine aura and the pain phase of migraine. For the more common and genetically complex forms of migraine, genome-wide screens have identified several new loci on 4q24, 6p12.2-21.1, 11q24, and 14q21.2-q22.3, suggesting additional migraine genes in these regions. In addition, a recent large case-control association study has linked single nucleotide polymorphisms in the insulin receptor/INSR gene with migraine. However, these polymorphisms do not result in detectable changes in receptor function. The continuing genetic identification of key proteins involved in migraine will refine our understanding of this common and sometimes debilitating disorder, which can strike during the most productive years of a person's life. Given the co-morbidity of migraine with depression and bipolar disorder, our knowledge of the causes of migraine may also contribute to our understanding of these disorders. [Abstract]

Kors EE, Vanmolkot KR, Haan J, Frants RR, van den Maagdenberg AM, Ferrari MD
Recent findings in headache genetics.
Curr Opin Neurol. 2004 Jun;17(3):283-8.
PURPOSE OF REVIEW: The progress in headache genetics, especially migraine genetics, recently jumped ahead with some major discoveries. RECENT FINDINGS: Family and epidemiological studies further strengthen the genetic contribution to migraine and two recent observations gave new molecular insights in the disease. Studies on the genetics of familial hemiplegic migraine revealed, in addition to the previously identified familial hemiplegic migraine type 1 gene CACNA1A on chromosome 19, the familial hemiplegic migraine type 2 gene ATP1A2, encoding the alpha2-subunit of sodium/potassium pumps. Recent genome screens in families with migraine identified susceptibility loci on chromosomes 4, 6, 11 and 14. SUMMARY: The findings in familial hemiplegic migraine confirm that dysfunction in ion transport is a key factor in migraine pathophysiology and might help us in the elucidation of migraine molecular pathways. The identification of several migraine susceptibility loci underline its genetically complex nature. [Abstract]

Rainero I, Grimaldi LM, Salani G, Valfrè W, Rivoiro C, Savi L, Pinessi L
Association between the tumor necrosis factor-alpha -308 G/A gene polymorphism and migraine.
Neurology. 2004 Jan 13;62(1):141-3.
In a group of 299 migraine patients and 306 control subjects, the association of the -308 G/A polymorphism in the tumor necrosis factor-alpha gene (TNFalpha) with the occurrence and clinical characteristics of migraine was tested. Homozygosity for the G allele was associated with an increased risk of migraine (odds ratio [OR] = 2.85, p < 0.001). When the patients were divided into subgroups, the association was confirmed in patients affected by migraine without aura (OR = 3.30, p < 0.001) but not in migraine with aura. These data suggest that the TNFalpha gene or a linked locus significantly modulates the risk for migraine. [Abstract]

Trabace S, Brioli G, Lulli P, Morellini M, Giacovazzo M, Cicciarelli G, Martelletti P
Tumor necrosis factor gene polymorphism in migraine.
Headache. 2002 May;42(5):341-5.
OBJECTIVE: To better define the involvement of human leukocyte antigen region (HLA) genes in migraine via an association study of the tumor necrosis factor (TNF) genes, located in the HLA class III region, with migraine with and without aura. BACKGROUND: Migraine without aura and migraine with aura are disorders involving multiple factors-environmental and genetic. In a previous study, we hypothesized a protective role for the HLA-DR2 antigen, providing additional basis for the proposed genetic heterogeneity between migraine without aura and migraine with aura. The cytokines produced by TNF genes are polypeptide effectors of inflammatory reaction and endothelial function.METHODS: Tumor necrosis factor (TNF)-308 (TNF-308A and TNF-308G alleles) and lymphotoxin alpha (TNFB*1 and TNFB*2 alleles) polymorphisms were analyzed by the NcoI-cleaved polymerase chain reaction-amplified fragments in 47 patients with migraine without aura, 32 patients with migraine with aura, and 101 migraine-free controls.RESULTS: The frequency of TNFB*2 allele was significantly increased in our patients with migraine without aura as compared with the control group (78.72% versus 61.4%, Pc =.004), but no significant differences were found between patients with migraine with aura and controls. Additionally, there was a significant decrease of TNFB*1 homozygotes in patients with migraine without aura compared with the control group (2.13% versus 16.8%, Pc =.0201). Carriage of the TNFB*2 allele confers a high risk for the development of migraine without aura. No significant association was found at TNF-308 polymorphism. CONCLUSION: These data support the hypothesis that lymphotoxin alpha could be a susceptibility gene in migraine without aura and confirm previous data indicating that migraine with and without aura are distinct entities with different genetic backgrounds. [Abstract]

Lea RA, Ovcaric M, Sundholm J, MacMillan J, Griffiths LR
The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura.
BMC Med. 2004 Feb 12;2(1):3.
BACKGROUND: The C677T variant in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with increased levels of circulating homocysteine and is a mild risk factor for vascular disease. Migraine, with and without aura (MA and MO), is a prevalent and complex neurovascular disorder that may also be affected by genetically influenced hyperhomocysteinaemia. To determine whether the C677T variant in the MTHFR gene is associated with migraine susceptibility we utilised unrelated and family-based case-control study designs. METHODS: A total of 652 Caucasian migraine cases were investigated in this study. The MTHFR C677T variant was genotyped in 270 unrelated migraine cases and 270 controls as well as 382 affected subjects from 92 multiplex pedigrees. RESULTS: In the unrelated case-control sample we observed an over-representation of the 677T allele in migraine patients compared to controls, specifically for the MA subtype (40% vs. 33%) (chi2 = 5.70, P = 0.017). The Armitage test for trend indicated a significant dosage effect of the risk allele (T) for MA (chi2 = 5.72, P = 0.017). This linear trend was also present in the independent family-based sample (chi2 = 4.25, Padjusted = 0.039). Overall, our results indicate that the T/T genotype confers a modest, yet significant, increase in risk for the MA subtype (odds ratio: 2.0 - 2.5). No increased risk for the MO subtype was observed (P &gt; 0.05). CONCLUSIONS: In Caucasians, the C677T variant in the MTHFR gene influences susceptibility to MA, but not MO. Investigation into the enzyme activity of MTHFR and the role of homocysteine in the pathophysiology of migraine is warranted. [Abstract]

On Site Link: Migraine with Aura and Homocysteine Derivatives

Oterino A, Valle N, Bravo Y, Muñoz P, Sánchez-Velasco P, Ruiz-Alegría C, Castillo J, Leyva-Cobián F, Vadillo A, Pascual J
MTHFR T677 homozygosis influences the presence of aura in migraineurs.
Cephalalgia. 2004 Jun;24(6):491-4.
It has been suggested that folate metabolism could be involved in migraine pathogenesis. We analysed the 5',10'-methylenetetrahydrofolate reductase (MTHFR) genotypic distribution in a large migraine sample. We genotyped 230 migraine patients (152 migraine without aura (MO) and 78 migraine with aura (MA)) and 204 nonheadache controls. The incidence of TT homozygosis for migraine in general (12%), MO (9%) and MA (18%) did not significantly differ from that found in healthy controls (13%). Differences were significant when the frequency of TT homozygosis between MA and MO (P = 0.03, OR = 2.34, 95% CI = 1.04-5.26) was compared. There was a tendency for a higher frequency of the MTHFR T allele in the MA group (42%) as compared to MO (29%) and controls (36%). These differences were significant only in the case of MA vs. MO (P = 0.006, OR = 1.75, 95% CI = 1.15-2.65). These results could indicate that the MTHFR C677T polymorphism, causing mild hyperhomocystinaemia, might be a genetic risk factor for experiencing aura among migraineurs. Overall, however, there was no association between migraine and the C677T MTHFR polymorphism. [Abstract]

Kara I, Sazci A, Ergul E, Kaya G, Kilic G
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 Mar 17;111(1-2):84-90.
Although controversial, diminished activity of 5,10 methylenetetrahydrofolate reductase (MTHFR), a regulatory enzyme of homocysteine metabolism, may predispose to migraine in Turkish people. In a case-control study, we determined the prevalence of two common MTHFR polymorphisms,C677T and A1298C, in 102 migraine patients (23 migraine with aura, 70 migraine without aura and nine with tension-type headache) and compared it to that of 136 healthy controls. The frequencies of the T allele of MTHFR677 and the C allele of MTHFR1298 were significantly higher in the total migraine population (33.82%, 33.82%) than in controls (25.38% and 24.26%), respectively.The genotypes T677T and C1298C were the only genotypes significantly associated with migraine (OR=5.702; 95% CI=1.184-27.457; P=0.015) and (OR=8.933; 95% CI=1.953-40.869; P=0.001), respectively). Individuals with migraine with aura with C1298C and C677C/C1298C genotypes were even more profoundly associated with migraine risk than others (OR=14.105; 95% CI=2.417-82.320; P=0.0001) and (OR=10.050; 95% CI=1.580-63.907; P=0.003), respectively. However individuals with migraine without aura with T677T and C1298C genotypes showed the same susceptibility (OR=7.444; 95% CI=1.503-36.863); P=0.005). Patients with C1298C and C677C/C1298C genotypes may also predispose to tension-type headache (OR=8.375; 95% CI=0.685-102.458); P=0.049). [Abstract]

Kowa H, Yasui K, Takeshima T, Urakami K, Sakai F, Nakashima K
The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine.
Am J Med Genet. 2000 Dec 4;96(6):762-4.
Increased homocysteine levels are associated with various pathological conditions in humans, including stroke and cardiovascular disorders. Homocysteine acts as an excitatory amino acid in vivo and may influence the threshold of migraine headache. Frosst et al. [1995] reported an association between the homozygous C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and serum homocysteine levels. This study was designed to determine the prevalence of the MTHFR mutation in Japanese patients with migraine and tension-type headache (TH). Seventy-four patients with migraine headaches (22 with aura and 52 without aura), 47 with THs, and 261 normal controls were recruited. Genotyping of MTHFR C677T polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. We detected that the incidence of the homozygous transition (T/T) in migraine sufferers (20.3%) was significantly higher than that in controls (9.6%). Moreover, the frequency of the T/T genotype in individuals with migraine headaches with aura was remarkably high (40.9%). The MTHFR T allele was more frequent in the migraine group than in the control group. Our results support the conclusion that the MTHFR gene, causing mild hyperhomocysteinemia may be a genetic risk factor for migraine. [Abstract]

Colson NJ, Lea RA, Quinlan S, MacMillan J, Griffiths LR
The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups.
Neurogenetics. 2004 Jun;5(2):129-33.
Migraine is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a role in migraine, as variations in hormone levels are associated with migraine onset in many sufferers of the disorder. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. Estrogen receptors have been localized to the brain in regions considered to be involved in migraine pathogenesis. Hence it is possible that genetic variation in the estrogen receptor gene may play a role in migraine susceptibility. This study thus examined the estrogen receptor 1 (ESRalpha) gene for a potential role in migraine pathogenesis and susceptibility. A population-based cohort of 224 migraine sufferers and 224 matched controls were genotyped for the G594A polymorphism located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant difference between migraineurs and non-migraineurs in both the allele frequencies (P=0.003) and genotype distributions (P=0.008) in this sample. An independent follow-up study was then undertaken using this marker in an additional population-based cohort of 260 migraine sufferers and 260 matched controls. This resulted in a significant association between the two groups with regard to allele frequencies (P=8 x 10(-6)) and genotype distributions (P=4 x 10(-5)). Our findings support the hypothesis that genetic variation in hormone receptors, in particular the ESR1 gene, may play a role in migraine. [Abstract]

Tzourio C, El Amrani M, Poirier O, Nicaud V, Bousser MG, Alpérovitch A
Association between migraine and endothelin type A receptor (ETA -231 A/G) gene polymorphism.
Neurology. 2001 May 22;56(10):1273-7.
BACKGROUND: Previous studies have described an association between migraine and endothelin, a potent vasoconstrictor. OBJECTIVE: To test the association between migraine and gene polymorphisms of the endothelin system. METHODS: A population-based study of elderly individuals (n = 1,188) in Nantes (western France) was conducted. Lifetime migraine was defined according to the International Headache Society criteria, after an interview with a headache specialist. Five polymorphisms in genes encoding endothelin 1, endothelin type A (ET(A)), and type B receptors were determined in more than 90% of the sample. RESULTS Migraine was diagnosed in 140 participants (11.9%). The ETA (-231 A/G) polymorphism was the only polymorphism significantly associated with migraine. There was a trend of decreasing prevalence of migraine with number of copies of the G allele (AA genotype: 15.7% of participants with migraine, AG: 9.7%, GG: 2.9%; p < 0.001). Carrying the G allele was associated with a sex- and age-adjusted odds ratio of 0.50 (95% CI, 0.34 to 0.74). The association was observed in both sexes and was stronger in participants with a family history of severe headaches than in those without. CONCLUSIONS: A variant of the ET(A) receptor gene modulates the risk for migraine. These results offer new insights into the pathophysiology of the vascular component of migraine. [Abstract]

Paterna S, Di Pasquale P, D'Angelo A, Seidita G, Tuttolomondo A, Cardinale A, Maniscalchi T, Follone G, Giubilato A, Tarantello M, Licata G
Angiotensin-converting enzyme gene deletion polymorphism determines an increase in frequency of migraine attacks in patients suffering from migraine without aura.
Eur Neurol. 2000;43(3):133-6.
Many authors have reported an association between the angiotensin-converting enzyme (ACE)-D allele and coronary heart disease and other cardiovascular diseases. The mechanism underlying the positive associations between the ACE-D alleles and diseases are not yet clear. Previous reports showed an association between migraine without aura and ACE-D allele polymorphism. The study is aimed to evaluate if the DD genotype could also be associated with the frequency and duration of migraine without aura. In 302 patients suffering from migraine without aura (at least for 1 year), with no history of cardiovascular diseases and major risk factors for ischemic events, the genotypes of the ACE gene, plasma ACE activity, and the frequency (weekly) and duration of migraine attacks were evaluated. No drugs were given before (4 weeks) and during the study. The same evaluations were performed in 201 subjects without migraine. The molecular biologist and the physician evaluating the patient data were blinded to the clinical history and ACE-DD gene determination. Genotypes were determined by polymerase chain reaction amplification. Plasma ACE activity was performed by the HPLC method. The groups were similar for sex, age and smoking habit (migraines: 302 patients (200 F/102 M), mean age 37.8 +/- 8.2 years; control: 201 subjects (127 F/74 M), mean age 37.5 +/- 9.3 years). Patients with migraine without aura showed higher incidence of the ACE-DD gene (48.34%) than control subjects (37.32%), p < 0.05. The frequency of migraine (average attacks per week) was higher in patients with DD (2.11 +/- 1.9) than in patients with ID (1.54 +/- 1. 44), p < 0.05. No difference in duration of migraine attacks (hours per week) was observed. Plasma ACE activity was increased in patients with the ACE-DD gene. Our data suggest that ACE-DD gene polymorphism could have an important role in determining migraine attacks and the frequency of these attacks. Further data are needed through further studies, especially on the biomolecular level. [Abstract]

Rainero I, Pinessi L, Salani G, Valfrè W, Rivoiro C, Savi L, Gentile S, Giudice RL, Grimaldi LM
A polymorphism in the interleukin-1alpha gene influences the clinical features of migraine.
Headache. 2002 May;42(5):337-40.
OBJECTIVE: To evaluate whether a particular genotype of the interleukin-1alpha (IL1A) gene affects the clinical features of migraine.BACKGROUND: Proinflammatory mediators have been reported to play a role in the pathophysiology of migraine. Recent studies suggest that polymorphisms in the interleukin-1 genes influence the age at onset and subsequent course of several chronic inflammatory diseases.METHODS: In a group of 269 patients with migraine, we tested the association of the -889 C/T biallelic polymorphism of the IL1A gene with several clinical features of the disease. RESULTS:Patients with migraine carrying the T/T genotype show an age at onset of the disease that is significantly (P <.01) lower than IL1A C/C or C/T carriers. In addition, the same genotype was significantly (P <.05) more frequent in patients with migraine with aura than in patients with migraine without aura.CONCLUSIONS: The results of our study suggest a role for the IL1A gene in modifying the clinical features of migraine. [Abstract]

Kusumi M, Ishizaki K, Kowa H, Adachi Y, Takeshima T, Sakai F, Nakashima K
Glutathione S-transferase polymorphisms: susceptibility to migraine without aura.
Eur Neurol. 2003;49(4):218-22.
Migraine is considered to be a polygenic multifactorial disease with various environmental and genetic etiologies. We investigated glutathione S-transferase (GST) P1 Ile(105)Val, T1 and M1 polymorphisms in 174 Japanese headache sufferers and 372 Japanese controls. The headache group consisted of 38 cases of migraine with aura, 95 migraine without aura (MWOA) and 41 tension-type headache sufferers. The M1 homozygous deletion genotype was significantly higher in MWOA (64%) compared with controls (46%; p < 0.01; odds ratio = 2.18, 95% confidence interval: 1.32-3.61, adjusted for age and gender). In a comparison of the current smokers, the M1 null frequencies in MWOA were further increased. GSTM1 may be one of the genetic risk factors for MWOA in the Japanese population. [Abstract]

Erdal ME, Herken H, Yilmaz M, Bayazit YA
Association of the T102C polymorphism of 5-HT2A receptor gene with aura in migraine.
J Neurol Sci. 2001 Jul 15;188(1-2):99-101.
OBJECTIVE: To find out the significance of the 5-HT2A receptor gene polymorphism in migraine. Study design: A PCR study in which 61 migraineurs and 44 healthy controls were included. METHODS: The T102C polymorphism of the 5-HT2A receptor gene was studied. The results of the migraineurs and controls were compared. The relationship between the gene polymorphism and aura was also assessed. RESULTS: The representations of the 5-HT2A genotypes were similar in migraineurs and controls (p>0.05) as well as in the male and female migraineurs (p>0.05). The family history of migraine did not associate with 5-HT2A receptor gene polymorphism (p>0.05). There was a significant relationship between the presence of C/C genotype and migraine with aura (p=0.02) while C/T and T/T genotypes were over represented in the patients with migraine without aura (p<0.01). CONCLUSION: The T102C polymorphism of the 5-HT2A receptor gene is not directly related to the increased risk of migraine. The associations between the genotypes of this gene and aura may suggest that 5-HT2A receptor gene polymorphism may be involved in determining the subtypes of or accompanying symptoms in the migraine disease. [Abstract]

On Site Link: Migraine with Aura and 5-HT2A Receptors

Nyholt DR, Curtain RP, Gaffney PT, Brimage P, Goadsby PJ, Griffiths LR
Migraine association and linkage analyses of the human 5-hydroxytryptamine (5HT2A) receptor gene.
Cephalalgia. 1996 Nov;16(7):463-7.
5-Hydroxytryptamine (5HT), commonly known as serotonin, which predominantly serves as an inhibitory neurotransmitter in the brain, has long been implicated in migraine pathophysiology. This study tested an MspI polymorphism in the human 5HT2A receptor gene (HTR2A) and a closely linked microsatellite marker (D13S126), for linkage and association with common migraine. In the association analyses, no significant differences were found between the migraine and control populations for both the MspI polymorphism and the D13S126 microsatellite marker. The linkage studies involving three families comprising 36 affected members were analysed using both parametric (FASTLINK) and non-parametric (MFLINK and APM) techniques. Significant close linkage was indicated between the MspI polymorphism and the D13S126 microsatellite marker at a recombination fraction (theta) of zero (lod score = 7.15). Linkage results for the MspI polymorphism were not very informative in the three families, producing maximum and minimum lod scores of only 0.35 and -0.39 at recombination fractions (theta) of 0.2 and 0.00, respectively. However, linkage analysis between the D13S126 marker and migraine indicated significant non-linkage (lod < -2) up to a recombination fraction (theta) of 0.028. Results from this study exclude the HTR2A gene, which has been localized to chromosome 13q14-q21, for involvement with common migraine. [Abstract]

Kusumi M, Araki H, Ijiri T, Kowa H, Adachi Y, Takeshima T, Sakai F, Nakashima K
Serotonin 2C receptor gene Cys23Ser polymorphism: a candidate genetic risk factor of migraine with aura in Japanese population.
Acta Neurol Scand. 2004 Jun;109(6):407-9.
OBJECTIVES: The goal of this study is to clarify the association between migraine and Serotonin 2C receptor Cys23Ser polymorphism in Japanese population. MATERIALS AND METHOD: This study included 37 individuals with migraine with aura (MWA), 80 with migraine without aura, 43 with tension type headache (TH) and 360 with controls. The genotypes of Cys23Ser polymorphism were confirmed by polymerase chain reaction-restriction fragment length polymorphism techniques. RESULTS: The Ser allele frequency in control subjects is much less than that in Caucasian population. The Ser allele frequency in patients with MWA was higher than that in control subjects. CONCLUSION: The present study provides that 5HTR2c Cys23Ser polymorphism may be associated with MWA in Japanese population. [Abstract]

Johnson MP, Lea RA, Curtain RP, MacMillan JC, Griffiths LR
An investigation of the 5-HT2C receptor gene as a migraine candidate gene.
Am J Med Genet. 2003 Feb15;117B(1):86-9.
Migraine is a common complex disorder, currently classified into two main subtypes, migraine with aura (MA) and migraine without aura (MO). The strong preponderance of females to males suggests an X-linked genetic component. Recent studies have identified an X chromosomal susceptibility region (Xq24-q28) in two typical migraine pedigrees. This region harbours a potential candidate gene for the disorder, the serotonin receptor 2C (5-HT(2C)) gene. This study involved a linkage and association approach to investigate two single nucleotide variants in the 5-HT(2C) gene. In addition, exonic coding regions of the 5-HT(2C) gene were also sequenced for mutations in X-linked migraine pedigrees. Results of this study did not detect any linkage or association, and no disease causing mutations were identified. Hence, results for this study do not support a significant role of the 5-HT(2C) gene in migraine predisposition. [Abstract]

Burnet PW, Harrison PJ, Goodwin GM, Battersby S, Ogilvie AD, Olesen J, Russell MB
Allelic variation in the serotonin 5-HT2C receptor gene and migraine.
Neuroreport. 1997 Aug 18;8(12):2651-3.
The 5-HT2C (serotonin-2C) receptor has been implicated along with other components of the 5-HT system in the pathophysiology and pharmacotherapy of migraine. To investigate whether the 5-HT2C receptor gene contributes to the risk of migraine we performed an association study of allelic variation at codon 23 (Cys or Ser) of the gene in 242 migraineurs, including 73 with aura, and 129 controls. No differences nor trends in allele or genotype frequencies were seen in the migraineurs compared to the controls. Neither did the frequencies vary significantly in migraineurs with and without aura, or if men and women were analysed separately. In conjunction with an earlier negative linkage study, these data indicate that the 5-HT2C receptor gene does not contribute to the genetic predisposition to migraine. [Abstract]

Buchwalder A, Welch SK, Peroutka SJ
Exclusion of 5-HT2A and 5-HT2C receptor genes as candidate genes for migraine.
Headache. 1996 Apr;36(4):254-8.
Several lines of investigation suggest that the serotonergic system may be involved in the pathogenesis of migraine. In particular, drugs which block 5-HT2 receptor subtypes appear to be effective migraine prophylactic agents. Therefore, chromosomal DNA regions overlapping the 5-HT2A (13q14-q22) and 5-HT2C(Xq22-25) receptor loci were analyzed for possible linkage to the clinical diagnosis of migraine. No evidence for linkage to either chromosomal region was found, although a small subset of migrainous families showed positive likelihood of odds (LOD) scores. However, a homogeneity (HOMOG) analysis provided no statistical evidence for locus heterogeneity. The coding region of the 5-HT2A and 5-HT2C receptor genes was also analyzed in migraine patients and unaffected controls using polmerase chain reaction and direct sequencing. No mutations were found in the deduced amino acid sequence of either receptor in the sample of migraineurs tested. These results indicate that DNA-based mutations in the 5-HT2A and 5-HT2C receptors are not generally involved in the pathogenesis of migraine. [Abstract]

Racchi M, Leone M, Porrello E, Rigamonti A, Govoni S, Sironi M, Montomoli C, Bussone G
Familial migraine with aura: association study with 5-HT1B/1D, 5-HT2C, and hSERT polymorphisms.
Headache. 2004 Apr;44(4):311-7.
BACKGROUND: The serotonergic system has a significant role in the pathophysiology and pharmacology of migraine. OBJECTIVE: To study the association between the occurrence of migraine with aura and 5-HT(1B/1D) and 5-HT(2C) receptor gene and the human serotonin transporter (hSERT) gene polymorphisms in 18 unrelated families with multiple affected members. METHOD: Two polymorphisms in the 5-HT(1B/1D) receptor gene and one polymorphism in the 5-HT(2C) receptor gene were studied by restriction fragment length polymorphism analysis. Allelic variation of the hSERT, with 9, 10, and 12 copies of a "repetitive element," was studied by polymerase chain reaction amplification of the variable number tandem repeat region. RESULTS: Allelic distribution of 5-HT(1B/1D) and 5-HT(2C) receptor gene polymorphisms in affected patients did not differ in either of the control groups (unaffected relatives or unrelated healthy individuals). A trend toward a significant effect of the 12-repeat hSERT allele as a risk factor for migraine with aura versus unrelated controls was observed. CONCLUSION: Our data do not support the involvement of 5-HT(1B/1D) and 5-HT(2C) receptor gene polymorphisms in migraine with aura, yet do suggest a possible role for a locus at or near the hSERT gene in the susceptibility to migraine with aura. [Abstract]

Juhasz G, Zsombok T, Laszik A, Gonda X, Sotonyi P, Faludi G, Bagdy G
Association analysis of 5-HTTLPR variants, 5-HT2a receptor gene 102T/C polymorphism and migraine.
J Neurogenet. 2003 Apr-Sep;17(2-3):231-40.
It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. There is evidence to suggest that serotonin-related genes participate in the pathogenesis of migraine. Previous studies have shown that gender differences influence the serotonergic neurotransmission and, in addition, the migraine prevalence is higher in females than males. Therefore, we investigated the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the 102T/C polymorphism of the 5-HT2A receptor gene in the Hungarian female population. These genes were analysed in 126 migraine sufferers (with or without aura)and 101 unrelated healthy controls using case control design. A borderline association (chi2 = 3.84, df = 1, p = 0.049; OR = 1.45, 95% CI = 1.00-2.12) between 5-HTTLPR short (S) allele and migraine was found. No significant difference between migraine sufferers and controls was observed for the 102T/C polymorphism of 5-HT2A receptor gene. Furthermore, there was no significant interaction between5-HTTLPR and 102T/C polymorphisms in our study population. In conclusion, our results support that the genetic susceptibility of migraine may be associated with a locus at or near the 5-HT transporter gene. [Abstract]

Juhasz G, Zsombok T, Laszik A, Jakus R, Faludi G, Sotonyi P, Bagdy G
Despite the general correlation of the serotonin transporter gene regulatory region polymorphism (5-HTTLPR) and platelet serotonin concentration, lower platelet serotonin concentration in migraine patients is independent of the 5-HTTLPR variants.
Neurosci Lett. 2003 Oct 16;350(1):56-60.
Platelet serotonin (5-HT) concentrations in a headache-free period during the mid-follicular phase and the serotonin transporter gene regulatory region polymorphism (5-HTTLPR) were measured in female migraine patients without aura (n = 64) and healthy controls (n = 42). High-pressure liquid chromatography (HPLC) was used to determine the platelet 5-HT concentration and genetic polymorphism was determined by polymerase chain reaction. Significantly lower platelet 5-HT concentrations were found in migraine patients compared to controls. Concerning the 5-HTTLPR polymorphism, the S/S genotype was associated with a significantly higher platelet 5-HT concentration (P = 0.027) in the whole study population. This association between the 5-HTTLPR genotypes and platelet 5-HT concentrations was independent of the diagnosis. In addition, the platelet 5-HT concentration was lower in migraineurs in all genotypes (S/S, S/L, L/L). In conclusion, 5-HTTLPR variants may have an effect on the platelet 5-HT concentrations, but the lower 5-HT concentrations in migraine patients seem to be determined by other factors. [Abstract]

Kotani K, Shimomura T, Shimomura F, Ikawa S, Nanba E
A polymorphism in the serotonin transporter gene regulatory region and frequency of migraine attacks.
Headache. 2002 Oct;42(9):893-5.
BACKGROUND: The serotonergic system has been thought to play an important part in the pathophysiology of migraine. OBJECTIVE: To study an association between the polymorphism of serotonin (5-hydroxytryptamine [5-HT]) transporter gene-linked polymorphic region (5-HTTLPR) and migraine. Method.-We compared 151 patients with migraine with 190 healthy unrelated control subjects. The 5-HTTLPR polymorphism was detected using polymerase chain reaction. Migraine patients were interviewed regarding attack frequency in the last 6 months. RESULTS: We denoted the products of the 484-base pair (bp) fragments as the short (s) and those of 528 bp as the long (l) allele according to the previously reported manner. Migraine patients with s/s genotype were compared with those with l/s and l/l genotype. We did not find significant differences in the genotype and allele frequencies of 5-HTTLPR between patients with migraine and control subjects. Among patients with migraine, those with s/s type had significantly more frequent attacks than those with the l/s or l/l type. CONCLUSIONS: This polymorphism does not appear to be involved in a genetic predisposition to the disease but may affect the frequency of attacks in patients with migraine. These findings may contribute to our understanding of factors that influence the clinical severity of migraine. [Abstract]

Yilmaz M, Erdal ME, Herken H, Cataloluk O, Barlas O YA
Significance of serotonin transporter gene polymorphism in migraine.
J Neurol Sci. 2001 May 1;186(1-2):27-30.
OBJECTIVE: To elucidate significance of the serotonin transporter gene (STG) polymorphism in migraine, and to address the polymorphic patterns of STG, both in the migraineurs and healthy people in this country. STUDY DESIGN: A PCR study of STG in 52 migraineurs and 80 healthy controls. METHODS: Using the PCR technique, STG polymorphism was studied in the DNA obtained from leukocytes of the patients and healthy controls. Polymorphism of the two regions (VNTR and 5-HTTLPR) of STG was assessed. RESULTS: VNTR STin 2.10 and STin 2.12 alleles were detected in migraineurs and healthy controls. Both homozygous and heterozygous STin 2.10 allele predominated in the migraine group (p=0.01), while STin 2.12 allele was more frequent in the healthy controls (p=0.02). There was no relationship between the migraine type, family history of migraine and STG polymorphism. CONCLUSION: STin 2.10 and STin 2.12 alleles of VNTR are frequent in this country. While the presence of STin 2.10 allele increases the risk of migraine, 5-HTTLPR polymorphism is not associated with this risk. [Abstract]

Ogilvie AD, Russell MB, Dhall P, Battersby S, Ulrich V, Smith CA, Goodwin GM, Harmar AJ, Olesen J
Altered allelic distributions of the serotonin transporter gene in migraine without aura and migraine with aura.
Cephalalgia. 1998 Jan;18(1):23-6.
Allelic variation of the human serotonin transporter gene (HSERT), a highly plausible candidate gene for susceptibility to migraine, was investigated in 266 individuals with migraine, including 173 having migraine without aura (MO), 94 having migraine with aura (MA), 18 with co-occurrence of MO and MA, plus 133 unaffected controls. The distribution of a polymorphism with different forms of a variable tandem number repeat (VNTR) in intron 2 were compared. The MO group had an over-representation of genotypes with two twelve repeat alleles (STin2.12) and a reduction of genotypes containing one ten repeat (STin2.10) compared to controls. The MA group showed a similar pattern, but also a trend towards an increase in genotypes containing the nine repeat allele of the VNTR (STin2.9). Genotypes containing this allele were found in 6.4% of the MA group compared to 2.3% of controls. The group with co-occurrence of MO and MA had a significantly different pattern of overall allele frequency distribution from controls, reflecting a reduction in genotypes containing the STin2.10 allele and a shift both to STin2.9 carriers and to STin2.12 homozygosity. These results support the view that susceptibility to MO and MA has a genetic component, that these disorders are distinct, and that genetic susceptibility may in some cases be associated with a locus at or near the serotonin transporter gene. [Abstract]

Mochi M, Cevoli S, Cortelli P, Pierangeli G, Soriani S, Scapoli C, Montagna P
A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes.
Neurol Sci. 2003 Feb;23(6):301-5.
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. [Abstract]

Lea RA, Dohy A, Jordan K, Quinlan S, Brimage PJ, Griffiths LR
Evidence for allelic association of the dopamine beta-hydroxylase gene (DBH) with susceptibility to typical migraine.
Neurogenetics. 2000 Sep;3(1):35-40.
Migraine is a debilitating neurological disorder characterized by recurrent attacks of severe headache. The disorder is highly prevalent, affecting approximately 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. However, the calcium channel gene, CACNA1A, on chromosome 19 contains mutations responsible for familial hemiplegic migraine, a rare and severe subtype of migraine. There is also evidence to suggest that serotonin- and dopamine-related genes may be involved in the pathogenesis of migraine. This study employed a linkage and association approach to investigate neurotransmitter-related migraine candidate genes. Polymorphisms within the dopamine beta-hydroxylase (DBH) gene, serotonin transporter gene (SERT), and dopamine receptor gene (DRD2) were tested in 177 unrelated Caucasian migraineurs and 182 control individuals. In addition, an independent sample of 82 families affected with migraine was examined. Unrelated case-control association analysis of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution between migraine and control groups (chi2 = 16.53, P=0.019). Furthermore, the transmission/disequilibrium test, which was implemented on the family data, also indicated distortion of allele transmission for the same DBH marker (chi2 = 4.44, P=0.035). Together, these results provide evidence for allelic association of the DBH gene with typical migraine susceptibility (Fisher's combined P value =0.006) and indicate that further research into the role of the DBH gene in the etiology of migraine is warranted. [Abstract]

Emin Erdal M, Herken H, Yilmaz M, Bayazit YA
Significance of the catechol-O-methyltransferase gene polymorphism in migraine.
Brain Res Mol Brain Res. 2001 Oct 19;94(1-2):193-6.
The objective was to assess the significance of the catechol-o-methyltransferase (COMT) enzyme polymorphism in migraine. For this reason, 62 migraineurs and 64 healthy volunteers were included in the study. The analysis of COMT polymorphism was performed using PCR. The H/H genotype was more frequent in the control group than in the patients group (P=0.032). The homozygous or heterozygous L allele was over represented in the migraineurs compared with the controls (P=0.013). The L/L genotype was over represented in the migraineurs who also had a family history of migraine (P=0.003). There was no relationship between aura and COMT genotypes. In conclusion, the COMT polymorphism may be of potential pharmacological importance regarding the individual differences in the metabolism of catechol drugs in migraineurs. Although altered catecholamine activity due to polymorphism of COMT gene may be one of the mechanisms involved in the pathogenesis of migraine, these mechanisms are not related to presence or absence of aura. [Abstract]

Rebaudengo N, Rainero I, Parziale A, Rosina F, Pavanelli E, Rubino E, Mazza C, Ostacoli L, Furlan PM
Lack of interaction between a polymorphism in the dopamine D2 receptor gene and the clinical features of migraine.
Cephalalgia. 2004 Jun;24(6):503-7.
The purpose of this study was to evaluate whether a particular genotype of the dopamine D2 receptor (DRD2) gene would affect the clinical features of migraine. In a group of 118 migraineurs (55 migraine with aura and 63 migraine without aura patients), we tested the association of the biallelic C/T NcoI DRD2 polymorphism with several characteristics of the disease. Genotype and allele frequencies resulted similarly distributed in migraine with aura and migraine without aura patients (chi2 = 1.58, P = 0.45 and chi2 = 0.09, P = 0.77, respectively). The different DRD2 genotypes (C/C, C/T and T/T) had no significant effects on age at onset of migraine, presence of premonitory phenomena, frequency of headache attacks, associated symptoms, psychological features and quality of life of our migraine patients. The results of our study do not support a role for the DRD2 gene in modifying the clinical features of migraine. [Abstract]

Maude S, Curtin J, Breen G, Collier D, Russell G, Shaw D, Clair DS
The -141C Ins/Del polymorphism of the dopamine D2 receptor gene is not associated with either migraine or Parkinson's disease.
Psychiatr Genet. 2001 Mar;11(1):49-52.
Abnormalities in dopamine neurotransmission at the dopamine D2 receptor (DRD2) have been implicated in both migraine and Parkinson's disease. Positive associations have also been found between polymorphisms within the DRD2 gene and both of these conditions. The -141C Ins/Del polymorphism in the DRD2 receptor gene is a putative functional polymorphism. The purpose of this study was to determine whether it and any genes in linkage disequilibrium with this marker are involved in either of these conditions. We have compared the genotype and allele frequencies of the -141C Ins/Del polymorphism in 200 migraineurs and 260 Parkinson's disease cases with 464 controls. We have found no association between the receptor gene and either condition (P = 0.89 and P = 0.56 respectively). Our findings do not support the hypothesis that this polymorphism is involved in the aetiology of migraine or Parkinson's disease. [Abstract]

Dichgans M, Förderreuther S, Deiterich M, Pfaffenrath V, Gasser T
The D2 receptor NcoI allele: absence of allelic association with migraine with aura.
Neurology. 1998 Sep;51(3):928.
[Abstract]

Peroutka SJ, Wilhoit T, Jones K
Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles.
Neurology. 1997 Jul;49(1):201-6.
Migraine has a major genetic component. Although most recent scientific studies have focused on the role of 5-hydroxytryptamine and neuropeptides in migraine, dopaminergic systems are also implicated in the pathogenesis. Therefore, the dopamine D2 receptor (DRD2) was analyzed as a candidate gene since antagonists of this receptor have been reported to be effective in the acute treatment of migraine. Individuals with migraine with aura (n = 52) have an increased frequency (0.84) of the DRD2 NcoI C allele (chi-square = 6.47; p < 0.005) compared with control individuals (n = 121; C allele frequency = 0.71). Individuals with migraine without aura (n = 77) showed the same DRD2 T allele frequency (0.70) as the control group. Migraine with aura was present in 27% of the C/C individuals, 16% of the C/T individuals, and 5.2% of the T/T individuals. These data suggest that activation of the DRD2 receptor plays a modifying role in the pathophysiology of migraine with aura. As a result, these data provide a molecular rationale for the documented efficacy of DRD2 antagonists in the treatment of migraine with aura. [Abstract]

Shepherd AG, Lea RA, Hutchins C, Jordan KL, Brimage PJ, Griffiths LR
Dopamine receptor genes and migraine with and without aura: an association study.
Headache. 2002 May;42(5):346-51.
OBJECTIVE: To investigate the role of the dopamine receptor genes, DRD1, DRD3, and DRD5 in the pathogenesis of migraine. BACKGROUND: Migraine is a chronic debilitating disorder affecting approximately 12% of the white population. The disease shows strong familial aggregation and presumably has a genetic basis, but at present, the type and number of genes involved is unclear. The study of candidate genes can prove useful in the identification of genes involved in complex diseases such as migraine, especially if the contribution of the gene to phenotypic expression is minor. Genes coding for proteins involved in dopamine metabolism have been implicated in a number of neurologic conditions and may play a contributory role in migraine. Hence, genes that code for enzymes and receptors modulating dopaminergic activity are good candidates for investigation of the molecular genetic basis of migraine. METHODS: We tested 275 migraineurs and 275 age- and sex-matched individuals free of migraine. Genotypic results were determined by restriction endonuclease digestion of polymerase chain reaction products to detect DRD1 and DRD3 alleles and by Genescan analysis after polymerase chain reaction using fluorescently labelled oligonucleotide primers for the DRD5 marker. RESULTS: Results of chi-square statistical analyses indicated that the allele distribution for migraine cases compared to controls was not significantly different for any of the three tested gene markers (chi2 = 0.1, P =.74 for DRD1; chi2 = 1.8, P =.18 for DRD3; and chi2 = 20.3, P =.08 for DRD5). CONCLUSIONS: These findings offer no evidence for allelic association between the tested dopamine receptor gene polymorphisms and the more prevalent forms of migraine and, therefore, do not support a role for these genes in the pathogenesis of the disorder. [Abstract]

Del Zompo M, Cherchi A, Palmas MA, Ponti M, Bocchetta A, Gessa GL, Piccardi MP
Association between dopamine receptor genes and migraine without aura in a Sardinian sample.
Neurology. 1998 Sep;51(3):781-6.
BACKGROUND: Migraine seems to be caused by a combination of environmental and genetic factors. Clinical and pharmacologic evidence supports the hypothesis that dopaminergic transmission is involved in the pathogenesis of migraine. OBJECTIVE: The current report concerns a genetic study to test the involvement of genes for dopamine (DA) receptors D2 (DRD2), D3 (DRD3), and D4 (DRD4) in migraine without aura, particularly in a subgroup with enhanced DA sensitivity. METHODS: For the first time, a family-based association method--the Transmission Disequilibrium Test (TDT)--was used to examine an isolated population, such as Sardinians. We studied 50 nuclear families of patients affected by migraine without aura. The subgroup of dopaminergic migraineurs was selected based on the presence of both nausea and yawning immediately before or during the pain phase of migraine. RESULTS: No association was detected using the TDT between DRD3, DRD4, and migraine without aura either in the overall sample or in the subgroup. No difference was observed in DRD2 allelic distribution in the overall sample, although the allelic distribution at the DRD2 locus differed significantly in the subgroup of dopaminergic migraineurs (p = 0.004). Allele 1 of the TG dinucleotide intronic noncoding polymorphism of the DRD2 locus was the individual allele that appeared to be in disequilibrium with migraine without aura (p = 0.02). CONCLUSIONS: Our data suggest that a genetic approach could be useful in providing molecular support to the hypothesis that hypersensitivity of the dopaminergic system may represent the pathophysiologic basis of migraine, at least in a subgroup of patients. [Abstract]

Stochino ME, Asuni C, Congiu D, Del Zompo M, Severino G
Association study between the phenotype migraine without aura-panic disorder and dopaminergic receptor genes.
Pharmacol Res. 2003 Nov;48(5):531-4.
Clinical and epidemiological evidence suggests that migraine often co-occurs with psychopathological conditions. Several longitudinal and population-based studies have suggested that migraine and panic disorder might share a common predisposition. An abnormal dopaminergic function has been hypothesized to be involved as etiological factor in panic disorder as well as in migraine. Epidemiological and molecular data suggest the role of genetic factors in the pathogenesis of both migraine and panic attack disorder. We assessed the presence of panic disorder in 100 probands suffering from migraine without aura and the present study was designed to analyse the possible association of the migraine-panic phenotype with dopaminergic genes. In our sample, 17 out of 100 migraineurs were affected by panic disorder and were thus considered for the genetic association study. The allele frequencies of DRD1, DRD3, DRD5, DRD2 in probands did not differ from that of parental non-transmitted chromosomes.This result does not seem to support, in our limited sample, a common pathological basis, with regard to the dopaminergic system, between migraine and panic. Should migraine and panic disorder share some common mechanisms, these could be sought in neuro-chemical systems other than the dopaminergic one. [Abstract]

Marziniak M, Mössner R, Benninghoff J, Syagailo YV, Lesch KP, Sommer C
Association analysis of the functional monoamine oxidase A gene promotor polymorphism in migraine.
J Neural Transm. 2004 May;111(5):603-9.
Migraine affects about 15% of the adult population. Serotonergic and dopaminergic systems are believed to be involved in its pathophysiology. One of the key enzymes in the degradation of serotonin and to a lesser extent of dopamine is monoamine oxidase A (MAO-A). In this study we investigated a functionally relevant gene-linked polymorphic repetitive sequence (LPR) located approximately 1.2 kb upstream of the ATG codon in the MAO-A-promotor gene. 119 patients with migraine and 229 controls were tested. The allelic distribution of the controls and the migraine patients did not show significant differences with respect to the low- and high-activity alleles. Moreover, effectiveness of the potent serotonergic antimigraine agents, triptans, which are metabolized by MAO-A, was clinically not affected by the MAO-A-LPR in our patients. These findings thus indicate that there is no association between the functional MAO-A-LPR and susceptibility to migraine. [Abstract]

Maassen VanDenBrink A, Vergouwe MN, Ophoff RA, Naylor SL, Dauwerse HG, Saxena PR, Ferrari MD, Frants RR
Chromosomal localization of the 5-HT1F receptor gene: no evidence for involvement in response to sumatriptan in migraine patients.
Am J Med Genet. 1998 Jun 5;77(5):415-20.
The 5-HT1F receptor, which is present in both human vascular and neuronal tissue, may mediate the therapeutic effect and/or side-effects of sumatriptan. We investigated the chromosomal localization of the 5-HT1F receptor gene and the relation between eventually existing polymorphisms and the clinical response to sumatriptan in migraine patients. The 5-HT1F receptor gene was localized using a monochromosomal mapping panel, followed by a radiation-reduced hybrid mapping and fluorescent in situ hybridization. The results of these techniques show that the 5-HT1F receptor gene is localized at 3p12. We investigated the presence of polymorphisms by single strand conformation polymorphism analysis in 14 migraine patients who consistently responded well to sumatriptan, 12 patients who consistently experienced recurrence of the headache after initial relief, 12 patients with no response to sumatriptan, and in 13 patients who consistently experienced chest symptoms after use of sumatriptan. No polymorphisms were detected in any of the patients. We therefore conclude that genetic diversity of the 5-HT1F receptor gene is most probably not responsible for the variable clinical response to sumatriptan. [Abstract]

MaassenVanDenBrink A, Vergouwe MN, Ophoff RA, Saxena PR, Ferrari MD, Frants RR
5-HT1B receptor polymorphism and clinical response to sumatriptan.
Headache. 1998 Apr;38(4):288-91.
The 5-HT1 receptor agonist, sumatriptan, is highly effective in the treatment of migraine. Some patients, however, do not respond or experience recurrence of the headache. In addition, some patients report chest symptoms after sumatriptan. We investigated whether these different responses could be attributed to genetic diversity of the 5-HT1B receptor, which most likely mediates the therapeutic action and the coronary side effects of sumatriptan. Allele frequencies of two polymorphisms in the 5-HT1B receptor gene (G861C and T-261G) were investigated in migraine patients with consistently good response to sumatriptan (n = 14), with no response (n = 12), with recurrence of the headache (n = 12), with chest symptoms (n = 13), and in patients without chest symptoms (n = 27). Allele frequencies (G:0.74; C:0.26 at nt 861 and T:0.39; G:0.61 at nt -261) did not differ between patient groups, indicating that genetic diversity of the 5-HT1B receptor does not seem to be involved in the different clinical responses to sumatriptan. [Abstract]

Peroutka SJ, Price SC, Jones KW
The comorbid association of migraine with osteoarthritis and hypertension: complement C3F and Berkson's bias.
Cephalalgia. 1997 Feb;17(1):23-6.
Migraine is known to have a major genetic component and has been associated with a wide variety of comorbid disorders including arthritis and heart disease. Since migraine and some of its comorbid disorders involve inflammation, complement C3, a protein involved in acute inflammation, was selected for analysis as a candidate gene in an ongoing study of the genetic basis of migraine. Polymorphism frequencies for complement C3F (0.19) and C3S (0.81) in a sample of 137 unrelated migraineurs were found to be consistent with a control group as well as previous population studies, indicating that this common polymorphism has no association with migraine susceptibility. However, C3F positive individuals with migraine were found to have an increased incidence of osteoarthritis (Chi square = 10.06; p < 0.0008) and hypertension (Chi square = 5.18; p < 0.01). Therefore, the data in the present study indicate that certain migraine comorbidities that have been reported in the literature may result from Berkson's bias as opposed to a shared pathophysiological variation in the C3 gene. [Abstract]

Griffiths LR, Nyholt DR, Curtain RP, Goadsby PJ, Brimage PJ
Migraine association and linkage studies of an endothelial nitric oxide synthase (NOS3) gene polymorphism.
Neurology. 1997 Aug;49(2):614-7.
Migraine shows strong familial aggregation. However, the number of genes involved in the disorder is unknown and not identified. Nitric oxide is involved in the central processing of pain stimuli and plays an important role in the regulation of basal or stimulated vasodilation. Nitric oxide synthase, which controls the synthesis of nitric oxide, could possibly be a cause, or candidate gene, in migraine etiology. In this study, we detected a polymorphism for endothelial nitric oxide synthase by polymerase chain reaction and tested this for association and linkage to migraine. Results from the study did not show an association of the nitric oxide synthase microsatellite when tested in 91 affected and 85 unaffected individuals. Using the FASTLINK program for parametric linkage analysis, the polymorphism did not show significant linkage to migraine when tested in four migraine pedigrees composed of 116 individuals, 52 affected. Total LOD scores excluded linkage up to 8.5 cM between the nitric oxide synthase polymorphism and migraine. Results using the nonparametric affected pedigree member form of analysis also did not support a role for this gene in migraine etiology. [Abstract]

Iniesta JA, Corral J, González-Conejero R, Rivera J, Vicente V
Prothrombotic genetic risk factors in patients with coexisting migraine and ischemic cerebrovascular disease.
Headache. 1999 Jul-Aug;39(7):486-9.
The role of hemostatic elements in stroke has been clearly defined but several prothrombotic polymorphisms of hemostatic factors, important for other thromboembolic disorders, seem not to be very significant in stroke. Recently, the high prevalence of factor V Leiden in patients with stroke and a history of migraine has suggested an association between migraine and prothrombotic genetic risk factors. Stroke being a multifactorial disease, the aim of this study was to test whether prothrombotic tendencies increase the risk of stroke in patients with migraine. We determined the prevalence of four prothrombotic genetic risk factors (factor V R/Q 506, factor II 20210 G/A, decanucleotide insertion/deletion in the factor VII promoter, and the platelet HPA-1 alloantigen system) in 17 patients with coexisting ischemic cerebrovascular disease and migraine, 107 patients with ischemic cerebrovascular disease, 106 patients with migraine, and 202 control subjects. Genotyping for all polymorphisms analyzed in our study were performed after specific genomic polymerase chain reaction, and confirmed by single-strain conformation polymorphism analysis. In the group of patients with coexisting ischemic cerebrovascular disease and migraine, the prevalence of prothrombotic genotypes (factor V Leiden, 5.8%; factor II 20210 A, 0%; factor VII A1, 70.6%; and HPA-1b, 35.3%) was similar to that obtained in all other groups. We can conclude that the studied polymorphisms do not seem to be associated with the development of ischemic cerebrovascular disease in those patients with migraine. [Abstract]

Corral J, Iniesta JA, González-Conejero R, Lozano ML, Rivera J, Vicente V
Migraine and prothrombotic genetic risk factors.
Cephalalgia. 1998 Jun;18(5):257-60.
It has been suggested that during attacks of migraine both platelet activation and plasma coagulability are increased. We investigated the prevalence of several prothrombotic genetic risk factors in patients with migraine: factor V R/Q 506, factor II 20210 G/A, decanucleotide insertion/deletion in the factor VII promoter, and the platelet HPA-1 and HPA-2 alloantigenic systems, by genotypic identification in an age- and sex-matched case-control study including 106 patients with migraine (49 with aura, and 57 without aura). The prevalence of all genotypes was similar among case patients and controls. No association in relation to the type of migraine was detected in the factor II, factor VII, HPA-1, or HPA-2 polymorphisms. Our results showed a high prevalence of factor V Leiden in those patients with migraine with aura (6.1%), though that association was not statistically significant. The studied prothrombotic genetic factors do not seem to be associated with the development of migraine and, therefore, are not likely relevant in the previously reported hypercoagulability and platelet hyperaggregability in this disease. [Abstract]

McCarthy LC, Hosford DA, Riley JH, Bird MI, White NJ, Hewett DR, Peroutka SJ, Griffiths LR, Boyd PR, Lea RA, Bhatti SM, Hosking LK, Hood CM, Jones KW, Handley AR, Rallan R, Lewis KF, Yeo AJ, Williams PM, Priest RC, Khan P, Donnelly C, Lumsden SM, O'Sullivan J, See CG, Smart DH, Shaw-Hawkins S, Patel J, Langrish TC, Feniuk W, Knowles RG, Thomas M, Libri V, Montgomery DS, Manasco PK, Xu CF, Dykes C, Humphrey PP, Roses AD, Purvis IJ
Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine.
Genomics. 2001 Dec;78(3):135-49.
We have identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of which we genotyped 24 in a Caucasian population comprising 827 unrelated cases and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor gene showed significant association with migraine. This association was independently replicated in a case-control population collected separately. We used experiments with insulin receptor RNA and protein to investigate functionality for the migraine-associated single-nucleotide polymorphisms. We suggest possible functions for the insulin receptor in migraine pathogenesis. [Abstract]

Mochi M, Cevoli S, Cortelli P, Pierangeli G, Scapoli C, Soriani S, Montagna P
Investigation of an LDLR gene polymorphism (19p13.2) in susceptibility to migraine without aura.
J Neurol Sci. 2003 Sep 15;213(1-2):7-10.
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. [Abstract]

Jones KW, Ehm MG, Pericak-Vance MA, Haines JL, Boyd PR, Peroutka SJ
Migraine with aura susceptibility locus on chromosome 19p13 is distinct from the familial hemiplegic migraine locus.
Genomics. 2001 Dec;78(3):150-4.
Migraine is a common neurological disease with a major genetic component. Recently, it has been proposed that a single locus on chromosome 19p13 contributes to the genetic susceptibility of both rare familial hemiplegic migraine (FHM) and more common types of migraine, migraine with aura and migraine without aura. We analyzed 16 families for co-segregation of migraine with aura and chromosome 19p13 markers. Using multipoint model-free linkage analysis, we obtained a lod score of 4.28 near D19S592. Using an affecteds-only model of linkage, we observed a lod score of 4.79 near D19S592. We were able to provide statistical evidence that this locus on chromosome 19p13 is most likely not the gene CACNA1A, mutations in which cause FHM. These data indicate that chromosome 19p13 contains a locus which contributes to the genetic susceptibility of migraine with aura that is distinct from the FHM locus. [Abstract]

Jen JC, Kim GW, Dudding KA, Baloh RW
No mutations in CACNA1A and ATP1A2 in probands with common types of migraine.
Arch Neurol. 2004 Jun;61(6):926-8.
BACKGROUND: Mutations in CACNA1A, encoding a neuronal calcium channel subunit, and ATP1A2, encoding a catalytic subunit of a sodium-potassium-ATPase, have been found in some families with dominantly inherited hemiplegic migraine. OBJECTIVE: To determine the prevalence of mutations in these genes in individuals with different migraine syndromes. DESIGN: Prospective screening study. SETTING: University outpatient neurology clinic.Subjects Probands of 19 families with hemiplegic migraine, 7 with basilar migraine, 25 with migraine without aura, and 18 with migraine with aura, as well as 40 unaffected relatives of probands. INTERVENTIONS: All known exons and flanking introns of CACNA1A and ATP1A2 were subjected to denaturing high-performance liquid chromatography analysis of polymerase chain reaction-amplified genomic DNA. Exons with atypical elution patterns were sequenced by standard techniques. MAIN OUTCOME MEASURES: Presence of mutations in CACNA1A and ATP1A2. RESULTS: A single mutation (T666M) was found in CACNA1A in a patient with hemiplegic migraine and ataxia. No other mutation was identified in either gene. The frequency of a previously reported intronic insertion in ATP1A2 was not significantly different between patients with migraine and control subjects. CONCLUSION: These 2 genes are not associated with more common migraine syndromes and are not the most common hemiplegic migraine genes. [Abstract]

Noble-Topham SE, Dyment DA, Cader MZ, Ganapathy R, Brown JD, Rice GP, Ebers GC
Migraine with aura is not linked to the FHM gene CACNA1A or the chromosomal region, 19p13.
Neurology. 2002 Oct 8;59(7):1099-101.
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. [Abstract]

Terwindt GM, Ophoff RA, van Eijk R, Vergouwe MN, Haan J, Frants RR, Sandkuijl LA, Ferrari MD
Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura.
Neurology. 2001 Apr 24;56(8):1028-32.
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. [Abstract]

Nyholt DR, Lea RA, Goadsby PJ, Brimage PJ, Griffiths LR
Familial typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity.
Neurology. 1998 May;50(5):1428-32.
Migraine is a frequent familial disorder that, in common with most multifactorial disorders, has an unknown etiology. The authors identified several families with multiple individuals affected by typical migraine using a single set of diagnostic criteria and studied these families for cosegregation between the disorder and markers on chromosome 19, the location of a mutation that causes a rare form of familial hemiplegic migraine (FHM). One large tested family showed both cosegregation and significant allele sharing for markers situated within or adjacent to the FHM locus. Multipoint GENEHUNTER results indicated significant excess allele sharing across a 12.6-cM region containing the FHM Ca2+ channel gene, CACNL1A4 (maximum nonparametric linkage Z score = 6.64, p = 0.0026), with a maximum parametric lod score of 1.92 obtained for a (CAG)n triplet repeat polymorphism situated in exon 47 of this gene. The CAG expansion did not, however, appear to be the cause of migraine in this pedigree. Other tested families showed neither cosegregation nor excess allele sharing to chromosome 19 markers. HOMOG analysis indicated heterogeneity, generating a maximum HLOD score of 3.6. It was concluded that Chr19 mutations either in the CACNL1A4 gene or a closely linked gene are implicated in some pedigrees with familial typical migraine, and that the disorder is genetically heterogeneous. [Abstract]

Wieser T, Mueller C, Evers S, Zierz S, Deufel T
Absence of known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients with common migraine: implications for genetic testing.
Clin Chem Lab Med. 2003 Mar;41(3):272-5.
Mutations in the gene CACNA1A have been known to cause familial hemiplegic migraine (FHM); it has been suggested, based on indirect genetic studies, that this gene may also be involved in common forms of migraine. To obtain data from direct gene analysis to test this hypothesis, we investigated 143 patients with common migraine, irrespective of their family history, for the presence of mutations known to result in the FHM phenotype; the mutations V714A, R192Q, R583Q, T666M, V1457L, and 11811L were absent in our patient sample. Furthermore, exons 4, 16, 17, and 36 were completely screened by single-strand conformation polymorphism (SSCP), and no other, hitherto unknown, mutations were detected. Bearing in mind that, in particular, the T666M mutation contributes to a large proportion of FHM linked to chromosome 19, we conclude that common migraine is distinct from FHM in its molecular basis and, therefore, most likely also in its pathophysiology. The possibility, however, of the existence of allelic disorders, with mutations located in other regions of the CACNA1A gene, cannot be ruled out. Molecular testing, therefore, is at present not a feasible option for the diagnosis and classification of migraine. [Abstract]

Haan J, van Vliet JA, Kors EE, Terwindt GM, Vermeulen FL, van den Maagdenberg AM, Frants RR, Ferrari MD
No involvement of the calcium channel gene (CACNA1A) in a family with cluster headache.
Cephalalgia. 2001 Dec;21(10):959-62.
It is very likely that genetic factors play a role in the pathophysiology of cluster headache (CH). As CH shares its paroxysmal character with migraine, and migraine has been described in coexistence with CH in some families, we hypothesized that both diseases might share a genetic aetiology. In this study, we tested whether the migraine CACNA1A gene on chromosome 19 is involved in CH in an extended pedigree. Haplotype analysis did not reveal an obvious disease haplotype, and SSCP analysis of all 47 exons of the CACNA1A gene did not reveal a causative mutation. CH in this family is not caused by mutations in the CACNA1A gene. [Abstract]

Sjöstrand C, Giedratis V, Ekbom K, Waldenlind E, Hillert J
CACNA1A gene polymorphisms in cluster headache.
Cephalalgia. 2001 Dec;21(10):953-8.
Cluster headache (CH) is a primary headache disorder where the aetiological and pathophysiological mechanisms still are largely unknown. An increased risk of CH in first- and second-degree relatives suggests the importance of genetic factors. Mutations of the P/Q type calcium channel alpha 1 subunit (CACNA1A) gene on chromosome 19p13 have been shown to cause several neurological disorders with a wide clinical spectrum, mainly episodic diseases. Missense mutations of the gene cause familial hemiplegic migraine (FHM) and it is also likely to be involved in the more common forms of migraine. The CACNA1A gene is thus a promising candidate gene for CH. In this study we performed an association analysis of an intragenic polymorphic (CA)n-repeat with marker D19S1150 and a (CAG)n-repeat in the 3'UTR region, in 75 patients with CH according to IHS criteria and 108 matched controls. Genotypes and allele frequencies were similarly distributed in patients and controls. Linkage disequilibrium between the two markers was similar in patients and controls. We conclude that an importance of the CACNA1A gene in sporadic CH is unlikely. [Abstract]

Wessman M, Kallela M, Kaunisto MA, Marttila P, Sobel E, Hartiala J, Oswell G, Leal SM, Papp JC, Hämäläinen E, Broas P, Joslyn G, Hovatta I, Hiekkalinna T, Kaprio J, Ott J, Cantor RM, Zwart JA, Ilmavirta M, Havanka H, Färkkilä M, Peltonen L, Palotie A
A susceptibility locus for migraine with aura, on chromosome 4q24.
Am J Hum Genet. 2002 Mar;70(3):652-62.
Migraine is a complex neurovascular disorder with substantial evidence supporting a genetic contribution. Prior attempts to localize susceptibility loci for common forms of migraine have not produced conclusive evidence of linkage or association. To date, no genomewide screen for migraine has been published. We report results from a genomewide screen of 50 multigenerational, clinically well-defined Finnish families showing intergenerational transmission of migraine with aura (MA). The families were screened using 350 polymorphic microsatellite markers, with an average intermarker distance of 11 cM. Significant evidence of linkage was found between the MA phenotype and marker D4S1647 on 4q24. Using parametric two-point linkage analysis and assuming a dominant mode of inheritance, we found for this marker a maximum LOD score of 4.20 under locus homogeneity (P=.000006) or locus heterogeneity (P=.000011). Multipoint parametric (HLOD = 4.45; P=.0000058) and nonparametric (NPL(all) = 3.43; P=.0007) analyses support linkage in this region. Statistically significant linkage was not observed in any other chromosomal region. [Abstract]

Reuter U, Chiarugi A, Bolay H, Moskowitz MA.
Nuclear factor-kappaB as a molecular target for migraine therapy.
Ann Neurol. 2002 Apr;51(4):507-16.
Nitric oxide (NO) generated from inducible NO synthase (iNOS) participates in immune and inflammatory responses in many tissues. The NO donor glyceryl trinitrate (GTN) provokes delayed migraine attacks when infused into migraineurs and also causes iNOS expression and delayed inflammation within rodent dura mater. Sodium nitroprusside, an NO donor as well, also increases iNOS expression. Because inflammation and iNOS are potential therapeutic targets, we examined transcriptional regulation of iNOS following GTN infusion and the consequences of its inhibition within dura mater. We show that intravenous GTN increases NO production within macrophages. L-N(6)-(1-iminoethyl)lysine, a selective iNOS inhibitor, attenuates the NO signal, emphasizing the importance of enzymatic activity to delayed NO production. iNOS expression is preceded by significant nuclear factor kappa B (NF-kappaB) activity, as reflected by a reduction in the inhibitory protein-kappa-Balpha (IkappaBalpha) and activation of NF-kappaB after GTN infusion. IkappaBalpha degradation, NF-kappaB activation, and iNOS expression were attenuated by parthenolide (3mg/kg), the active constituent of feverfew, an anti-inflammatory drug used for migraine treatment. These findings suggest that GTN promotes NF-kappaB activity and inflammation with a time course consistent with migraine attacks in susceptible individuals. We conclude, based on results with this animal model, that blockade of NF-kappaB activity provides a novel transcriptional target for the development of anti-migraine drugs.[Abstract]

OMIM - Online Mendelian Inheritance in Man: Nuclear factor-kappaB subunit 1
[The NFKB1 gene has been located at 4q23-q24]

Björnsson A, Gudmundsson G, Gudfinnsson E, Hrafnsdóttir M, Benedikz J, Skúladóttir S, Kristjánsson K, Frigge ML, Kong A, Stefánsson K, Gulcher JR
Localization of a gene for migraine without aura to chromosome 4q21.
Am J Hum Genet. 2003 Nov;73(5):986-93.
Migraine is a common form of headache and has a significant genetic component. Here, we report linkage results from a study in Iceland of migraine without aura (MO). The study group comprised patients with migraine recruited by neurologists and from the registry of the Icelandic Migraine Society, as well as through the use of a questionnaire sent to a random sample of 20,000 Icelanders. Migraine diagnoses were made and confirmed using diagnostic criteria established by the International Headache Society. A genome-wide scan with multipoint allele-sharing methods was performed on 289 patients suffering from MO. Linkage was observed to a locus on chromosome 4q21 (LOD=2.05; P=.001). The locus reported here overlaps a locus (MGR1) reported elsewhere for patients with migraine with aura (MA) in the Finnish population. This replication of the MGR1 locus in families with MO indicates that the gene we have mapped may contribute to both MA and MO. Further analysis indicates that the linkage evidence improves for affected females and, especially, with a slightly relaxed definition of MO (LOD=4.08; P=7.2 x 10(-6)). [Abstract]

Cader ZM, Noble-Topham S, Dyment DA, Cherny SS, Brown JD, Rice GP, Ebers GC
Significant linkage to migraine with aura on chromosome 11q24.
Hum Mol Genet. 2003 Oct 1;12(19):2511-7.
Migraine with aura (MA) is a prevalent neurological condition with strong evidence for a genetic basis. Familial hemiplegic migraine, a rare Mendelian form of MA, can be caused by mutations in the calcium channel gene, CACNA1A or in the ATP1A2 gene, a Na+/K+ pump. Susceptibility genes for the more prevalent forms of migraine have yet to be identified despite several reports of linkage including loci on 4q24, 1q31, 19p13 and Xq24-28. We have undertaken a genome-wide screen of 43 Canadian families, segregating MA with families chosen for an apparent autosomal dominant pattern of transmission. Diagnosis was based upon International Headache Society Criteria. Parametric linkage analysis revealed a novel locus on 11q24 with a two-point LOD score of 4.2 and a multi-point parametric LOD score of 5.6. We did not find any support for linkage at previously reported loci. The lack of consensus amongst linkage studies, including this study, is probably an indication of the heterogeneity that is inherent for MA. Nevertheless, the finding of a highly significant locus with a LOD score of 5.6 is powerful evidence that a gene increasing susceptibility to MA resides on 11q24. Several candidate genes map to this region of the genome including a number of ion channel genes such as GRIK4, SCNB2, KCNJ5 and KCNJ1. [Abstract]

Adams BS, Leung K, Meltzer PS, Lewis KA, Wagner-McPherson C, Evans GA, Nabel GJ.
Localization of the gene encoding R kappa B (NFRKB), a tissue-specific DNA binding protein, to chromosome 11q24-q25.
Genomics. 1992 Oct;14(2):270-4.
Although NF (nuclear factor)-kappa B binds in vitro to several of the kappa B regulatory elements found in cellular and viral genes, another DNA binding protein, R kappa B, also binds to a related variant of the kappa B site that regulates interleukin-2 receptor alpha-chain gene expression, a critical event in T cell activation. Southern blot analysis of a human-mouse somatic cell hybrid panel and in situ hybridization using a fluorescent genomic R kappa B probe have allowed assignment of the R kappa B gene (NFRKB) to 11q24-q25. The NFRKB locus is in close proximity to the chromosomal breakpoint implicated in Ewing sarcoma, but it does not appear to span this region. Nonetheless, NFRKB may be particularly useful as the most telomeric marker thus far assigned to 11q.[Abstract]

Martelletti P.
T cells expressing IL-2 receptor in migraine.
Acta Neurol (Napoli). 1991 Oct;13(5):448-56.
We studied a group of migraine patients for circulating immune complexes, lymphocyte subpopulations, IgG4 and anti-IgG antibodies, before, after 4 hours and after 72 hours a specific challenge test. We found an increased incidence of circulating immune complexes. Total T cells showed a marked increase after challenge test. The most important finding was the presence of T-activated cells. Also K and NK cells showed an early increase after the challenge. In commenting the outcomes of this investigation, it must be stressed that the evidence of an early lymphocyte activation after the challenge test indicates an involvement of interleukin-2 related receptor in food-induced migraine. The results have reinforced the idea of immune mechanism involvement in food-induced migraine, but it seems to be localized at different step from that until now hypothesized, with the involvement of the complex cytokines network.[Abstract]

Soragna D, Vettori A, Carraro G, Marchioni E, Vazza G, Bellini S, Tupler R, Savoldi F, Mostacciuolo ML
A locus for migraine without aura maps on chromosome 14q21.2-q22.3.
Am J Hum Genet. 2003 Jan;72(1):161-7.
Migraine is a common and disabling neurological disease of unknown origin characterized by a remarkable clinical variability. It shows strong familial aggregation, suggesting that genetic factors are involved in its pathogenesis. Different approaches have been used to elucidate this hereditary component, but a unique transmission model and causative gene(s) have not yet been identified. We report clinical and molecular data from a large Italian pedigree in which migraine without aura (MO) segregates as an autosomal dominant trait. After exclusion of any association between MO and the known familial hemiplegic migraine and migraine with aura loci, we performed a genomewide linkage analysis using 482 polymorphic microsatellite markers. We obtained significant evidence of linkage between the MO phenotype and the marker D14S978 on 14q22.1 (maximum two-point LOD score of 3.70, at a recombination fraction of 0.01). Multipoint parametric analysis (maximum LOD score of 5.25 between markers D14S976 and D14S978) and haplotype construction showed strong evidence of linkage in a region of 10 cM flanked by markers D14S1027 and D14S980 on chromosome 14q21.2-q22.3. These results indicate the first evidence of a genetic locus associated with MO on chromosome 14. [Abstract]

Jenkins DW, Feniuk W, Humphrey PP.
Characterization of the prostanoid receptor types involved in mediating calcitonin gene-related peptide release from cultured rat trigeminal neurones.
Br J Pharmacol. 2001 Nov;134(6):1296-302.
"1. Prostaglandins and the vasodilator neuropeptide, calcitonin-gene related peptide (CGRP), have both been implicated in the pathogenesis of migraine headache. We have used primary cultures of adult rat trigeminal neurones to examine the effects of prostanoids on CGRP release in vitro. 2. CGRP release was stimulated by prostaglandin E2 (PGE2) and the IP receptor agonist, carbaprostacyclin (cPGI2). These responses were extracellular calcium-dependent, and the PGE2-induced CGRP release was unaltered by inhibition of nitric oxide synthase (NOS), ATP receptor blockade, or the addition of adenosine deaminase. 3. Increases in CGRP levels were also observed in response to prostaglandin D2 (PGD2), and the EP2 receptor selective agonist, butaprost. No increases in CGRP release were observed in response to prostaglandin F2alpha (PGF2alpha) or the TP receptor selective agonist, U46619, or the EP3 receptor selective agonist, GR63799X. 4. The selective DP receptor antagonist, BWA868C, antagonized the PGD2-, but not PGE2- or cPGI2-induced release. Furthermore, the EP1 selective antagonist, ZM325802, failed to antagonize the PGE2-induced CGRP release from these cells. 5. These data indicate that activation of DP, EP and IP receptors can each cause CGRP release from trigeminal neurones, and suggest that the predominant EP receptor subtype involved may be the EP2 receptor. Together with evidence that the cyclo-oxygenase inhibitor, aspirin, particularly when administered intravenously is effective in treating acute migraine, these findings further suggest a role for prostaglandins in migraine pathophysiology." [Abstract]

Anderson JA.
Mechanisms in adverse reactions to food. The brain.
Allergy. 1995;50(20 Suppl):78-81.
"Specific chemical mediator release such as histamine and the prostaglandins (PG2a or PGD2) associated with headaches has been found in a few patients who were repeatedly challenged with specific foods, using DBPCFC techniques." [Abstract]

On Site Link: Prostaglandins in Migraine

OMIM - Online Mendelian Inheritance in Man: Prostaglandin E Receptor 2 (EP2)
[The PTGER2 gene has been located at 14q22]

OMIM - Online Mendelian Inheritance in Man: Prostaglandin D2 synthase
[The PGDS gene has been located at 14q21-q22]

Carlsson A, Forsgren L, Nylander PO, Hellman U, Forsman-Semb K, Holmgren G, Holmberg D, Holmberg M
Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1.
Neurology. 2002 Dec 10;59(11):1804-7.
Migraine is the most common type of chronic episodic headache. To find novel susceptibility genes for familial migraine with and without aura, a genomewide screen was performed in a large family from northern Sweden. Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of 5.41 for marker D6S452. The patients with migraine shared a common haplotype of 10 Mb between markers D6S1650 and D6S1960. [Abstract]

Choudhuri R, Cui L, Yong C, Bowyer S, Klein RM, Welch KM, Berman NE.
Cortical spreading depression and gene regulation: relevance to migraine.
Ann Neurol. 2002 Apr;51(4):499-506.
Cortical spreading depression (CSD) may be the underlying mechanism of migraine aura. The role of CSD in initiating a migraine headache remains to be determined, but it might involve specific changes in gene expression in the brain. To examine these changes, four episodes of CSD at 5-minute intervals were induced in the mouse brain by application of 300mM KCl, and gene expression was examined 2 hours later using cDNA array and reverse transcriptase-polymerase chain reaction. Controls consisted of groups that received anesthesia only, attachment of recording electrodes only, and application of 0.9% NaCl. Of the over 1,180 genes examined in our experiments, those consistently regulated by CSD included vasoactive peptides; the vasodilator atrial natriuretic peptide was induced by CSD, while the vasoconstrictor neuropeptide Y was downregulated. Other genes specifically regulated by CSD were involved in oxidative stress responses (major prion protein, glutathione-S-transferase-5, and apolipoprotein E). L-type calcium channel mRNA was upregulated. In summary, CSD regulates genes that are intrinsic to its propagation, that identify accompanying vascular responses as a potential source of pain, and that protect against its potential pathological consequences. We believe these observations have strong relevance to the mechanisms of migraine and its outcomes. [Abstract]

OMIM - Online Mendelian Inheritance in Man: Glutathione S-transferase alpha-5
[The Glutathione S-transferase alpha-5 gene has been located at 6p12.2]

Martelletti P, Lulli P, Morellini M, Mariani B, Pennesi G, Cappellacci S, Brioli G, Giacovazzo M, Trabace S
Chromosome 6p-encoded HLA-DR2 determination discriminates migraine without aura from migraine with aura.
Hum Immunol. 1999 Jan;60(1):69-74.
Segregation analysis indicates that migraine without aura (MWoA) and migraine with aura (MWA) have multifactorial inheritance, but involved genetic and environmental factors are largely unknown. A controlled study was performed to assess the HLA-driven liability to migraine and to verify if the heterogeneity between MWoA and MWA is HLA-linked. Forty-five migraine patients (31 MWoA, 14 MWA) and 53 healthy blood donors as controls, coming from the same geographic area, were studied. Tissue typing was performed using the standard complement-dependent microlymphocytotoxicity technique for HLA Class I and by PCR-SSP (Sequences Specific Primers) typing for HLA Class II. Data emerging from the present study showed no altered distribution for HLA Class I A, B, C antigen frequency in migraine (MWoA, MWA) if compared to the control group. HLA Class II DR2 antigen showed a decreased frequency in MWA group if compared with both MWoA (p = 0.01) and control group (p = 0.039, RR = 0.21). These results seem to support the hypothesis of a protective role of DR2 antigen in MWA and provide additional basis for the proposed difference within MWoA and MWA. [Abstract]

Lea RA, Shepherd AG, Curtain RP, Nyholt DR, Quinlan S, Brimage PJ, Griffiths LR
A typical migraine susceptibility region localizes to chromosome 1q31.
Neurogenetics. 2002 Mar;4(1):17-22.
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 Chrlq31 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 chi2 (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 Chrlq3l, and reinforce the idea that an FHM gene in this genomic region may also contribute to susceptibility to the more common forms of migraine. [Abstract]

Gardner K, Barmada MM, Ptacek LJ, Hoffman EP.
A new locus for hemiplegic migraine maps to chromosome 1q31.
Neurology. 1997 Nov;49(5):1231-8.
"A single familial hemiplegic migraine locus has been previously mapped to 19p13.1 and associated with mutations in a calcium channel gene (CACNL1A4). We describe a new 39-member four-generation family from Wyoming of German-Native American descent with autosomal dominant familial hemiplegic migraine that is not linked to the chromosome 19p locus. Affected individuals showed a stereotypic pattern of migrainous headache associated with hemisensory and hemiparetic attacks, without other headache types. Eighty-three percent reported minor head trauma as a trigger for individual attacks. Seventy-two percent reported other typical migraine triggers for the attacks. Attack frequency decreased with age and the overall course was benign. Genetic linkage studies of this family found strong evidence for the disease gene in this family being located at chromosome 1q31. Multipoint analysis showed lod scores > 3 in a 44-cm region flanked by D1S158 and D1S2781, using 80% penetrance and a phenocopy rate of 1/50. Haplotype and multipoint analysis, including flanking markers, suggested incomplete penetrance and variable expressivity of the disease. A single affected patient who reports atypical symptoms including daily headaches likely represents a phenocopy. This new locus for hemiplegic migraine suggests that mutations of additional calcium channels in the region may cause the disease." [Abstract]

Nyholt DR, Curtain RP, Griffiths LR
Familial typical migraine: significant linkage and localization of a gene to Xq24-28.
Hum Genet. 2000 Jul;107(1):18-23.
In a previous study we found evidence for an X-linked genetic component for familial typical migraine in two large Australian white pedigrees, designated MF7 and MF14. Significant excess allele sharing was indicated by nonparametric linkage (NPL) analysis using GENEHUNTER (P=0.031 and P=0.012, respectively), with a combined analysis of the two pedigrees showing further increased evidence for linkage, producing a maximum NPL score of 2.87 (P=0.011 ) at DXS 1123 on Xq27. The present study was aimed at refining the localization of the migraine X-chromosomal component by typing additional markers, performing haplotype analysis and applying a more powerful technique in the analysis of linkage data from these two pedigrees. Results from the haplotype analyses, coupled with linkage analyses that produced a peak GENEHUNTER-PLUS LOD* score of 2.388 (P=0.0005), provide compelling evidence for the presence of a migraine susceptibility locus on chromosome Xq24-28. [Abstract]

Nyholt DR, Dawkins JL, Brimage PJ, Goadsby PJ, Nicholson GA, Griffiths LR
Evidence for an X-linked genetic component in familial typical migraine.
Hum Mol Genet. 1998 Mar;7(3):459-63.
Migraine is a common complex disorder that shows strong familial aggregation. There is a general increased prevalence of migraine in females compared with males, with recent studies indicating that migraine affects 18% of females compared with 6% of males. This preponderance of females among migraine sufferers coupled with evidence of an increased risk of migraine in first degree relatives of male probands but not in relatives of female probands suggests the possibility of an X-linked dominant gene. We report here the localization of a typical migraine susceptibility locus to the X chromosome. Of three large multigenerational migraine pedigrees two families showed significant excess allele sharing to Xq markers (P = 0.031 and P = 0.012). Overall analysis of data from all three pedigrees gave significant evidence in support of linkage and heterogeneity (HLOD = 3.1). These findings provide conclusive evidence that familial typical migraine is a heterogeneous disorder. We suggest that the localization of a migraine susceptibility locus to the X chromosome could in part explain the increased risk of migraine in relatives of male probands and may be involved in the increased female prevalence of this disorder. [Abstract]

Mulder EJ, Van Baal C, Gaist D, Kallela M, Kaprio J, Svensson DA, Nyholt DR, Martin NG, MacGregor AJ, Cherkas LF, Boomsma DI, Palotie A
Genetic and environmental influences on migraine: a twin study across six countries.
Twin Res. 2003 Oct;6(5):422-31.
Migraine is a common neurovascular brain disorder that is manifested in recurrent episodes of disabling headache. The aim of the present study was to compare the prevalence and heritability of migraine across six of the countries that participate in GenomEUtwin project including a total number of 29,717 twin pairs. Migraine was assessed by questionnaires that differed between most countries. It was most prevalent in Danish and Dutch females (32% and 34%, respectively), whereas the lowest prevalence was found in the younger and older Finnish cohorts (13% and 10%, respectively). The estimated genetic variance (heritability) was significant and the same between sexes in all countries. Heritability ranged from 34% to 57%, with lowest estimates in Australia, and highest estimates in the older cohort of Finland, the Netherlands, and Denmark. There was some indication that part of the genetic variance was non-additive, but this was significant in Sweden only. In addition to genetic factors, environmental effects that are non-shared between members of a twin pair contributed to the liability of migraine. After migraine definitions are homogenized among the participating countries, the GenomEUtwin project will provide a powerful resource to identify the genes involved in migraine. [Abstract]

Ulrich V, Gervil M, Kyvik KO, Olesen J, Russell MB
The inheritance of migraine with aura estimated by means of structural equation modelling.
J Med Genet. 1999 Mar;36(3):225-7.
Studies of migraine with aura (MA) have shown familial aggregation of the disorder, which cannot be explained by simple mendelian inheritance. The interest in a genetic basis for the disorder has increased after identification of three genetic loci for familial hemiplegic migraine (FHM), which is a rare subtype of MA with autosomal dominant inheritance. Both genetic and environmental factors seem to be important in the expression of MA. To elucidate the molecular pathogenesis of MA, knowledge of the relative role of genetic and environmental factors is essential. Twin studies are a classic way to analyse this. We applied structural equation modelling on MA with twin data obtained from a population based twin register in order to evaluate the effects of genes and environment. The correlation in liability of MA was 0.68 in monozygotic (MZ) and 0.22 in dizygotic (DZ) twin pairs, indicating a high degree of genetic determination in the total variance of liability. The best fitting model combined additive genetic effects and environmental effects that were not shared by the twins. The estimate of heritability was 0.65 and similar in males and females. [Abstract]

Gervil M, Ulrich V, Kyvik KO, Olesen J, Russell MB
Migraine without aura: a population-based twin study.
Ann Neurol. 1999 Oct;46(4):606-11.
To investigate the importance of genetic and environmental factors to the etiology of migraine without aura and to compare the symptomatology of migraine without aura in monozygotic and dizygotic twins, 2,680 twin pairs were recruited from the population-based Danish Twin Registry. Monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs, where at least one twin had self-reported migraine or self-reported severe headache with accompanying symptoms, were telephone interviewed by a physician. The participation rate in the telephone interview was 90%. The pairwise concordance rate was significantly higher in MZ than in DZ twin pairs (28% vs 18%). The probandwise concordance rate was 40% (95% CI, 33-48%) in MZ and 28% (95% CI, 23-33%) in DZ twin pairs. The pairwise concordance rates for the different pain characteristics and accompanying symptoms were not significantly different in MZ and DZ twin pairs. However, comparing all of the pairwise concordance rates of pain characteristics and accompanying symptoms together, MZ twin pairs were significantly more concordant than DZ twin pairs. Our data demonstrate a significant genetic factor in migraine without aura. The size of this factor is modest and the demonstration of susceptibility genes is predicted to be laborious and difficult. [Abstract]

Ulrich V, Russell MB, Ostergaard S, Olesen J
Analysis of 31 families with an apparently autosomal-dominant transmission of migraine with aura in the nuclear family.
Am J Med Genet. 1997 Jul 25;74(4):395-7.
We analyzed 31 families selected for an apparently autosomal-dominant mode of inheritance of migraine with aura (MA) in the nuclear family. The nuclear families were expanded with first- and second-degree relatives. All interviews were made by physicians experienced in headache diagnoses. The criteria of the International Headache Society were used. The population relative risk among children in nuclear families was similar to the estimated population relative risk of MA assuming an autosomal-dominant mode of inheritance. The population relative risk tended to decrease among first-degree relatives outside nuclear families and further among second-degree relatives. Both first- and second-degree relatives outside the nuclear families had a statistically significant lower risk of MA than expected. Thus, autosomal-dominant inheritance with or without reduced penetrance was unlikely. Autosomal-recessive inheritance was unlikely because of the unequal sex distribution. Other modes of inheritance were considered as well. Mitochondrial and X-linked inheritance were excluded because of paternal transmission. The female preponderance was too low to explain sex-influenced inheritance. We conclude that MA most likely has a multifactorial inheritance even in high-risk families with MA. [Abstract]

Russell MB, Iselius L, Olesen J
Migraine without aura and migraine with aura are inherited disorders.
Cephalalgia. 1996 Aug;16(5):305-9.
The familial occurrence and mode of inheritance were analysed in families with migraine without aura (MO) and migraine with aura (MA). The probands were found among 4000 persons from the general population. All persons with MA were included as probands, and an equivalent number of probands with MO was selected as a random sample among those with MO. Spouses and first-degree relatives were blindly interviewed. All interviews were performed by one neurological research fellow. The distinct familial patterns indicate that MO and MA have a different aetiology. Compared with the general population, the first-degree relatives of probands with MO had a 1.9-fold increased risk of MO while spouses had a 1.5-fold increased risk of MO, indicating that both genetic and environmental factors are important in MO. The first-degree relatives of probands with MA had a four-fold increased risk of MA while spouses had no increased risk of MA, indicating that MA is determined largely by genetic factors. The complex segregation analysis indicated that both MO and MA have multifactorial inheritance without generational difference. [Abstract]

Lea RA, Hilton DA, MacMillian JC, Griffiths LR
An analysis of clinical characteristics in genetically linked migraine-affected pedigrees.
Cephalalgia. 2003 Oct;23(8):808-13.
Migraine is a common complex disorder characterized by severe recurrent headache and usually accompanied by nausea and vomiting. Previous studies in our laboratory have utilized three large multigenerational Australian pedigrees affected with migraine to indicate that the disease is genetically heterogeneous, with linkage results implicating genomic susceptibility regions on both chromosomes 19p and Xq. The present study explores the possibility of a correlation between genetic and clinical heterogeneity in these affected pedigrees. Specifically, the clinical characteristics of migraine including subtype, age of onset, frequency, duration, and disease symptoms were compared between the migraine pedigrees, and gender differences were also assessed. Our exploratory analyses revealed no significant differences in any of the clinical characteristics tested between the chromosome 19-linked family and the two X-linked families. Also, we did not detect any differences in male vs. female clinical features for these pedigrees. In conclusion, migraine is considered to be a clinically and genetically heterogeneous disorder; however, our study provided no conclusive evidence that variation in genomic susceptibility region is related to heterogeneity at the clinical level in these migraine-affected pedigrees. [Abstract]

Russell MB, Ulrich V, Gervil M, Olesen J
Migraine without aura and migraine with aura are distinct disorders. A population-based twin survey.
Headache. 2002 May;42(5):332-6.
OBJECTIVE: To investigate the co-occurrence of migraine without aura (MWOA) and migraine with aura (MWA) in a population-based twin survey. BACKGROUND: Migraine without aura and MWA are multifactorial disorders. If MWOA and MWA share common genes, co-occurrence should be observed more frequently than expected, ie, the product of the prevalence in the general population. MATERIAL AND METHODS: The study population included all living Danish monozygotic (MZ) and same-gender dizygotic (DZ) twin pairs born between 1953 and 1960: 5360 twins (2026 MZ, 3334 DZ). The sample included 2840 men and 2520 women. All received a posted questionnaire, and those with possible migraine were interviewed via telephone by trained physicians (V.U. or M.G.). Twins who did not respond to the questionnaire and who had a co-twin with possible migraine were contacted by telephone. The questionnaire response rate was 87% (4660 of 5360), and the telephone interview was participated in by 90% (2035 of 2272). The physician interviewers were unaware of questionnaire answers, zygosity, and the clinical diagnosis of the co-twin. The criteria of the International Headache Society were used to establish a diagnosis of migraine. RESULTS: Lifetime prevalence in the twin sample: 7% of men and 19% of women had MWOA, while 7% of men and 8% of women had MWA. Lifetime prevalence of MWA in twin pairs with MWOA: MZ men, 2% (1 of 47); MZ women, 6% (5 of 90); DZ men, 9% (7 of 75); and DZ women, 10% (19 of 182). Lifetime prevalence of MWOA in twin pairs with MWA: MZ men, 3% (1 of 33); MZ women, 5% (3 of 58); DZ men, 9% (4 of 44); and DZ women, 13% (10 of 76). The observed and the expected numbers of twins with co-occurrence of MWOA and MWA based on the prevalence in the general population were not significantly different in either men or women (men, P=.1 and women, P=.5). CONCLUSION: The results strongly suggest that MWOA and MWA are distinct disorders, and identification of common genes for MWOA and MWA, thus, should not be expected to result from future genetic research. [Abstract]

Kallela M, Wessman M, Havanka H, Palotie A, Färkkilä M
Familial migraine with and without aura: clinical characteristics and co-occurrence.
Eur J Neurol. 2001 Sep;8(5):441-9.
Migraine with aura (MwA) and migraine without aura (MwoA) are the two common forms of migraine. Many migraine patients suffer from both kinds of attacks. In a questionnaire-based study using the current International Headache Society (IHS) criteria we determined the clinical characteristics and occurrence of MwA + MwoA in 1000 migraine patients belonging to 210 Finnish migraine families. Nine hundred and six patients were able to indicate whether they suffered from MwA (but not MwoA), migraine aura without headache (migraine equivalent) (but not MwA) or MwA and MwoA. Of these patients, 3.2% had experienced MwoA, 11.1% MwA, 40.6% MwA + MwoA, 23.5% MwoA and 20.3% MwA-like symptoms not meeting the IHS criteria. The high prevalence of MwA attacks in the families studied supports the belief that aura has a strong hereditary component. The MwA + MwoA patients had significantly more severe attacks, more typical headache and more prodromal symptoms than the MwA and MwoA subjects. Therefore, it is possible that there is a continuum with pure MwA at the neural and pure MwoA at the headache end of the spectrum, and MwA + MwoA lying in between the two. The MwA + MwoA patients would thus be liable to both types of migraine, making their attacks more characteristic and more severe. This would also explain why the co-occurrence of MwA and MwoA is more common in the clinic compared with population based epidemiological studies. These findings have consequences for future research on liability genes for migraine. [Abstract]

Kallela M, Wessman M, Färkkilä M, Palotie A, Koskenvuo M, Honkasalo ML, Kaprio J
Clinical characteristics of migraine in a population-based twin sample: similarities and differences between migraine with and without aura.
Cephalalgia. 1999 Apr;19(3):151-8.
OBJECTIVE: To look into clinical differences between migraine with and without aura in a population-based sample of migraineurs. BACKGROUND: Migraine presents in two major forms, migraine with and migraine without aura. With the exception of the aura phase, the clinical characteristics of these entities are very similar. Despite this, however, the recent epidemiological data underline differences between migraine with and without aura. We tried to examine whether other features besides the aura differ between these two major forms of migraine. METHODS: We studied 321 twins suffering from migraine with aura and 166 twins with migraine without aura from the population-based Finnish Twin Cohort. Migraine was diagnosed according to the criteria of the International Headache Society (IHS). Analysis was based on the combination of a mailed questionnaire and a telephone interview by a neurologist. Special attention was paid to differences between migraine with and without aura. RESULTS: Some qualities of headaches differed between IHS defined migraine with and without aura. Unilateral headache (Chi-squared p = 0.039) and photophobia (Chi-squared p = 0.010) were more typical for migraine with aura, while nausea was more typical for migraine without aura (Chi-squared p = 0.002). Duration of headache in migraine without aura was also longer than in migraine with aura (Mann-Whitney U-test 0.007). CONCLUSIONS: There are clinical differences between IHS defined migraine with and without aura; even the headache phase between the two entities differs. It is worthwhile distinguishing between them when looking for the elusive genes for these more common forms of migraine. [Abstract]

Nyholt DR, Gillespie NG, Heath AC, Merikangas KR, Duffy DL, Martin NG
Latent class and genetic analysis does not support migraine with aura and migraine without aura as separate entities.
Genet Epidemiol. 2004 Apr;26(3):231-44.
Latent class and genetic analyses were used to identify subgroups of migraine sufferers in a community sample of 6,265 Australian twins (55% female) aged 25-36 who had completed an interview based on International Headache Society (IHS) criteria. Consistent with prevalence rates from other population-based studies, 703 (20%) female and 250 (9%) male twins satisfied the IHS criteria for migraine without aura (MO), and of these, 432 (13%) female and 166 (6%) male twins satisfied the criteria for migraine with aura (MA) as indicated by visual symptoms. Latent class analysis (LCA) of IHS symptoms identified three major symptomatic classes, representing 1) a mild form of recurrent nonmigrainous headache, 2) a moderately severe form of migraine, typically without visual aura symptoms (although 40% of individuals in this class were positive for aura), and 3) a severe form of migraine typically with visual aura symptoms (although 24% of individuals were negative for aura). Using the LCA classification, many more individuals were considered affected to some degree than when using IHS criteria (35% vs. 13%). Furthermore, genetic model fitting indicated a greater genetic contribution to migraine using the LCA classification (heritability, h(2)=0.40; 95% CI, 0.29-0.46) compared with the IHS classification (h(2)=0.36; 95% CI, 0.22-0.42). Exploratory latent class modeling, fitting up to 10 classes, did not identify classes corresponding to either the IHS MO or MA classification. Our data indicate the existence of a continuum of severity, with MA more severe but not etiologically distinct from MO. In searching for predisposing genes, we should therefore expect to find some genes that may underlie all major recurrent headache subtypes, with modifying genetic or environmental factors that may lead to differential expression of the liability for migraine. [Abstract]

Ulrich V, Gervil M, Olesen J
The relative influence of environment and genes in episodic tension-type headache.
Neurology. 2004 Jun 8;62(11):2065-9.
OBJECTIVE: To examine the relative importance of genetic and environmental influence for the development of tension-type headache by analyses of twins. METHODS: The authors screened by questionnaire a population of 5,360 twins born during 1953 to 1960 from the general population for migraine and headache symptoms. The response rate of the questionnaire was 87%. All twin pairs with at least one twin of the pair reporting migraine or headache symptoms were interviewed by telephone by a physician. Correlation of liability and structural equation modeling were applied on tension-type headache. RESULTS: A total of 1,417 subjects had tension-type headache equivalent to a 1-year prevalence of 62%. The male: female ratio was 1:1.24. Chronic tension-type headache was found in 49 twins corresponding to a prevalence of 2% with a male:female ratio of 1:1.21. The prevalence, pain characteristics, frequency, and duration of tension-type headache were similar to what has been found in the general Danish population. The correlation of liability of tension-type headache was low and not significantly different in monozygotic and dizygotic twin pairs: 0.21 (0.03 to 0.39), 0.08 (0 to 0.24). The best fitting model of phenotypic variation consisted of 81% non-shared environmental effects and of 19% additive genetic effects. CONCLUSIONS: Environmental influence is of major importance for episodic tension-type headache and a genetic factor, if it exits, is minor. In chronic tension-type headache the genetic factor may be more important. These data clearly separate episodic tension-type headache from migraine without aura where the phenotypic variation consists of non-shared environmental effects of 39% and of 61% additive genetic effects. [Abstract]

Monari L, Mochi M, Valentino ML, Arnaldi C, Cortelli P, De Monte A, Pierangeli G, Prologo G, Scapoli C, Soriani S, Montagna P
Searching for migraine genes: exclusion of 290 cM out of the whole human genome.
Ital J Neurol Sci. 1997 Oct;18(5):277-82.
A linkage and association analysis was made on 14 Italian families with recurrent migraine. We analyzed five chromosomal regions surrounding the candidate genes 5HT1D (1p36.3-34.3), 5HT1B (6q13), 5HT2A (13q14-21), 5HT transporter (17q11.2-12), CACNLB1 (17q11.2-22) and FHM (19p13), using 29 DNA polymorphic markers. All two-point lod scores were negative, and the chi 2 sib-pair analyses were not significant, thus indicating the probable exclusion of these regions as sites of migraine genes in our population. [Abstract]

Rainero I, Salani G, Valfrè W, Savi L, Rivoiro C, Ferrero M, Pinessi L, Grimaldi LM
Absence of linkage between the interleukin-6 gene (-174 G/C) polymorphism and migraine.
Neurosci Lett. 2003 Jun 12;343(3):155-8.
To assess the role of interleukin-6 (IL-6) in migraine, we analyzed the -174 G/C IL-6 gene polymorphism in 268 patients with migraine and 305 controls. No significant difference in the distribution of IL-6 genotypes (chi(2)=0.601, P=0.74) and allelic frequencies (chi(2)=0.024, P=0.876) was found. When patients were subdivided into subgroups (migraine with aura, migraine without aura and mixed headaches), IL-6 alleles were similarly distributed. Comparison of the clinical features of the disease with the -174 G/C IL-6 genotypes showed no significant difference. In conclusion, we found no significant association between the -174 G/C IL-6 polymorphism and the occurrence or the clinical features of migraine. [Abstract]

Takeshima T, Fukuhara Y, Adachi Y, Ishizaki K, Kusumi M, Kowa H, Iigaya M, Sakai F, Nakashima K
Leukocyte mitochondrial DNA A to G polymorphism at 11084 is not a risk factor for Japanese migraineurs.
Cephalalgia. 2001 Dec;21(10):987-9.
Mitochondrial dysfunction has been reported in patients with migraine. We investigated leukocyte mitochondrial DNA 11084 A to G polymorphism in 166 Japanese migraineurs and 483 Japanese controls. The migraine group consisted of 43 patients suffering from migraine with aura (MWA) and 123 from migraine without aura (MOA). The frequency of the transition was 7.2% (12/166) in the migraine group and 7.3% (35/483) in the controls. The frequency of the transition was 4.7% in MWA and 8.1% in MOA. There was no significant difference among the groups (chi-square test). The mitochondrial DNA 11084 A to G transition was more common in Japanese subjects than reported in Caucasians; however, this polymorphism is not a genetic risk factor for migraine in Japanese patients. [Abstract]

Rainero I, Grimaldi LM, Salani G, Valfrè W, Savi L, Rivoiro C, Gentile S, Pinessi L
Apolipoprotein E gene polymorphisms in patients with migraine.
Neurosci Lett. 2002 Jan 11;317(2):111-3.
To investigate the role of apolipoprotein E (APOE) polymorphisms in migraine, we analyzed the APOE genotypes of 241 migraine patients and 587 controls. The results of a Chi-square analysis indicated that APOE alleles were similarly distributed (chi(2)=2.89, P=0.24) between cases and controls. However, we found a significant (P<0.001) increase of the varepsilon2-varepsilon4 genotype in the group of migraine patients. Patients were divided into three subgroups: migraine with aura; migraine without aura; and mixed headaches (migraine associated with tension-type headache). Subgroup analysis showed that the varepsilon2-varepsilon4 genotype was significantly increased only in patients with mixed headaches. The stratification of patients by APOE status did not reveal significant associations with the clinical features of the disease. In conclusion, we observed no significant association between APOE polymorphisms and migraine. The association between the APOE varepsilon2-varepsilon4 genotype and the tension-type headache deserves further evaluation. [Abstract]

Iniesta JA, Corral J, González-Conejero R, Díaz Ortuño A, Martínez Navarro ML, Vicente V
Role of factor XIII Val 34 Leu polymorphism in patients with migraine.
Cephalalgia. 2001 Oct;21(8):837-41.
At present, it is contradictory to determine if the combination of certain prothrombotic polymorphisms and migraine increases the risk to develop ischaemic cerebrovascular disease. Recently, the common Val34Leu polymorphism of the A-chain factor XIII gene, associated with variations in factor XIII activity, has been suggested to play a significant role in the development of arterial and venous thrombotic disorders. We analysed the prevalence of this polymorphism in 17 patients with coexisting ischaemic cerebrovascular disease and migraine (5 with aura, and 12 without aura), 89 patients with migraine (43 with aura, and 46 without aura), 116 patients with ischaemic cerebrovascular disease, and 467 healthy Caucasian controls from the South of Spain. Genomic PCR amplification, using a mutated oligonucleotide, and allele-specific restriction assays were used for genotyping. The factor XIII Leu 34 variant was present in 47.1; 40.5; 34.9; and 35.1% of patients with coexisting ischaemic cerebrovascular disease and migraine, ischaemic cerebrovascular disease, migraine, and control subjects, respectively. These data suggest that the factor XIII Leu 34 allele does not play a protective role against these disorders in our population. [Abstract]

Lea RA, Curtain RP, Shepherd AG, Brimage PJ, Griffiths LR
No evidence for involvement of the human inducible nitric oxide synthase (iNOS) gene in susceptibility to typical migraine.
Am J Med Genet. 2001 Jan 8;105(1):110-3.
Migraine is a debilitating disorder affecting approximately 12% of Caucasian populations. The disease has a large genetic component, although at present the type and number of genes involved is unclear. Candidate gene studies may be useful strategies for identifying genes involved in complex diseases such as migraine, especially if the gene being examined contributes only a minor effect to the overall phenotype. Nitric oxide (NO) is emerging as a key molecule affecting the pain associated with migraine. Since NO synthase (NOS) enzymes catalyze the synthesis of NO, the genes that code for these enzymes are good candidates for migraine molecular genetic analysis. This study investigated the role of a functionally relevant bi-allelic tetranucleotide polymorphism located in the promoter region of the human inducible nitric oxide synthase (iNOS) gene in migraine etiology. A large group of migraine affected individuals (n = 261) were genotyped and compared with an age- and sex-matched group of unaffected controls (n = 252). Results of a chi-squared analysis indicated that allele distributions for both migraine cases and controls were not significantly different (chi2 = 1.93, P = 0.16). These findings offer no evidence for an allelic association of the tested iNOS polymorphism with the common forms of the disease and therefore do not support a role for this gene in migraine pathogenesis. [Abstract]

Di Gennaro G, Buzzi MG, Ciccarelli O, Santorelli FM, Pierelli F, Fortini D, D'Onofrio M, Costa A, Nappi G, Casali C
Assessing the relative incidence of mitochondrial DNA A3243G in migraine without aura with maternal inheritance.
Headache. 2000 Jul-Aug;40(7):568-71.
OBJECTIVE: To determine whether patients with migraine without aura with maternal "inheritance" are affected by a monosymptomatic form of the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) or carry the most common mitochondrial DNA (mtDNA) mutation associated with MELAS, namely the A3243G transition in the transfer RNA (tRNA)Leu(UUR) gene. BACKGROUND: The association between migraine and abnormal mitochondrial function has been suggested on clinical, biochemical, and neuroradiological grounds. Migraine attacks with vomiting and cerebral infarctions, most often in the posterior cerebral regions, which are reminiscent of complicated migraine, are typical features of MELAS. The observation that migrainous patients have affected mothers more often than affected fathers suggests a possible role for maternally transmitted genetic factors. METHODS: We studied 25 patients with migraine with aura whose mothers were also affected. A sensitive polymerase chain reaction restriction fragment length polymorphism analysis was used to detect mutated genomes. CONCLUSIONS: We failed to detect the MELAS mutation, but migraine may still be associated with point mutations of mtDNA other than A3243G or with as-yet-unidentified nuclear DNA factors related to mitochondrial function. [Abstract]

Haan J, Terwindt GM, Maassen JA, Hart LM, Frants RR, Ferrari MD
Search for mitochondrial DNA mutations in migraine subgroups.
Cephalalgia. 1999 Jan;19(1):20-2.
It has been suggested that mitochondrial mutations cause migraine(-like) symptoms. The presence of mtDNA mutations (3243, 3271, 11084, and deletions) was investigated in three migraine subgroups (maternally transmitted migraine with and without aura, migrainous infarction, and nonfamilial hemiplegic migraine). No mutations were found. These mutations and deletions probably are not involved in the migraine subgroups studied, although an investigation of other material (e.g., muscle tissue) would have shown this with more certainty. [Abstract]

Russell MB, Diamant M, Nørby S
Genetic heterogeneity of migraine with and without aura in Danes cannot be explained by mutation in mtDNA nucleotide pair 11084.
Acta Neurol Scand. 1997 Sep;96(3):171-3.
INTRODUCTION: Migraine is a genetic heterogeneous disorder. The 11084 A to G base substitution is in the gene for the ND4 subunit of the respiratory complex I, and leads to a Thr to Ala amino acid replacement. This mutation had been found in 25% of Japanese migraineurs, while tension-type headache sufferers and non-migraineurs did not have it. MATERIAL AND METHODS: We investigated the importance of this mutation in Danish migraineurs without aura, migraineurs with aura and non-migraineurs from the general population. RESULTS: We did not detect this mutation in Danes. CONCLUSION: Our result excludes a significant role of this mutation in the etiology of migraine in Denmark, and its absence in non-migraineurs supports that this mutation is rare in non-Japanese populations. [Abstract]

Klopstock T, May A, Seibel P, Papagiannuli E, Diener HC, Reichmann H
Mitochondrial DNA in migraine with aura.
Neurology. 1996 Jun;46(6):1735-8.
Migraine and the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome have some clinical features in common. First, cerebral infarctions, most often in the posterior cerebral regions, which are a main symptom of MELAS, may complicate migraine. Second, migrainous headache with vomiting is also a characteristic feature of the MELAS syndrome. Less frequently, hemicranial headache is present in another mitochondrial disease, myoclonic epilepsy with ragged-red fibers (MERRF). Moreover, there is a mild bias toward maternal transmission in migraine. Apart from clinical resemblance, there is some experimental evidence for mitochondrial dysfunction in migraine. There may be depression of respiratory chain enzyme activity in muscle and platelets, and magnetic resonance spectroscopy has revealed a defective energy metabolism in brain and muscle of migraine patients. There has not been a systematic study of mitochondrial DNA in migraine, however. We therefore analyzed the mitochondrial DNA in lymphocytes of 23 migraine patients with aura. Southern blot and polymerase chain reaction analysis of mitochondrial DNA failed to detect any large-scale deletions or point mutations at base pair 3243 (MELAS) and base pair 8344 (MERRF). Our data show that deletions of mitochondrial DNA and the most frequent point mutations of MELAS and MERRF syndromes are not common in migraine with aura. In particular, these data do not support the hypothesis that some cases of migraine may be monosymptomatic forms of a MELAS syndrome. We cannot exclude, however, that migraine may be associated with different point mutations of mitochondrial DNA or with mutations of autosomally coded respiratory chain subunit genes. [Abstract]

Mattsson P, Bjelfman C, Lundberg PO, Rane A
Cytochrome P450 2D6 and glutathione S-transferase M1 genotypes and migraine.
Eur J Clin Invest. 2000 Apr;30(4):367-71.
BACKGROUND: Migraine is thought to be a disease of the brain and trigeminovascular system. Migraine patients often claim that stress, food, and beverages trigger their attacks. Chemical substances in these foodstuffs with the property of triggering migraine attacks have not yet been characterised. Cytochrome P450 2D6 (CYP2D6) and glutathione S-transferase M1 (GSTM1) are thought to be present in the brain. They metabolise numerous environmental compounds. The genes exhibit genetic polymorphism that is associated with altered enzyme activity. The aim of this study was to determine if the genotypes of these two enzymes are associated with migraine. MATERIALS AND METHODS: The study included 100 female patients and 245 female controls from the general population. Genomic DNA was isolated from whole blood. Allele specific PCR methods were used to identify the normal CYP2D6*1 allele and the mutated CYP2D6*3 and CYP2D6*4 alleles. Initially all samples were genotyped only for GSTM1 plus (+) and GSTM1 null (-) variants. All samples positive for GSTM1 were further analysed for the presence of allelic variants GSTM1*A and GSTM1*B. RESULTS: None of the CYP2D6 and GSTM1 genotypes was associated with migraine. We observed an odds ratio (OR) for the poor metaboliser genotype of CYP2D6 of 1.4 (95% CI = 0.5-3.6) and for the GSTM1 null genotype of 1.0 (95% CI = 0.6-1.5). CONCLUSION: The results of this study indicate that deficient metabolism because of mutated CYP2D6 alleles or GSTM1 allele variants is not important in the aetiology of migraine. [Abstract]