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 g