Migraine With Or Without Aura, Susceptibility To, 1

Description

Migraine is the most common type of chronic, episodic headache, as summarized by Featherstone (1985).

One locus for migraine with or without aura (MGR1) has been identified on chromosome 4q24. Other loci for migraine have been identified on 6p21.1-p12.2 (MGR3; 607498), 14q21.2-q22.3 (MGR4; 607501), 19p13 (MGR5; 607508), 1q31 (MGR6; 607516), 15q11-q13 (MGR7; 609179), 5q21 (with or without aura, MGR8, 609570; with aura, MGR9, 609670), 17p13 (MGR10; 610208), 18q12 (MGR11; 610209), 10q22-q23 (MGR12; 611706), and the X chromosome (MGR2; 300125).

Mutation in the KCNK18 gene (613655) on chromosome 10q25 causes migraine with aura (MGR13; 613656).

A subtype of autosomal dominant migraine with aura (MA), familial hemiplegic migraine (FHM; see 141500), is caused by mutation in the CACNA1A gene (601011) on chromosome 19p13 (FHM1; 141500), by mutation in the ATP1A2 gene (182340) on chromosome 1q21 (FHM2; 602481), or by mutation in the SCN1A gene (182389) on chromosome 2q24 (FHM3; 609634). Another locus for FHM has been mapped to chromosome 1q31 (FHM4; see 607516).

There is evidence that a polymorphism in the estrogen receptor gene (ESR1; 133430.0005) and a polymorphism in the TNF gene (191160.0004) may confer susceptibility to migraine. A polymorphism in the endothelin receptor type A gene (EDNRA; 131243.0001) may confer resistance to migraine.

Clinical Features

Most cases of migraine are of the mild rather than the classic type, which has prodromal neurologic deficit and severe, focal head pain. Since no biochemical marker for migraine has been found, migraine and its variants remain a clinical diagnosis (Featherstone, 1985). Refsum (1968), Raskin (1988), and Miller (1991) provided extensive reviews of all aspects of migraine.

In a study of 532 persons with migraine, Stewart et al. (2006) found that the relative risk (RR) of migraine in first-degree relatives was significantly increased (RR of 1.88) compared to controls. The RR of migraine was even higher for relatives of probands with onset before age 16 years (RR of 2.50) and with more severe pain (RR of 2.38). The results suggested higher levels of familial aggregation of migraines in those with earlier onset and more severe pain scores.

In a population-based case-control study of 140 Icelandic children with seizures and 180 controls, Ludvigsson et al. (2006) found that migraine with aura conferred an odds ratio of 8.1 for subsequent development of unprovoked seizures (see, e.g., idiopathic generalized epilepsy, EIG; 600669). Migraine without aura did not increase the risk for seizures. The prevalence of both types of migraine was 20.2% in children with seizures and 6.9% in controls. The findings were consistent with the hypothesis that migraine with aura and migraine without aura are separate disease entities, and suggested that migraine with aura and seizures may share a common pathogenesis.

Other Features

In 209 patients with migraine without aura (MO) and 151 patients with migraine with aura (MA) and 617 controls, all of whom were from a genetically isolated Dutch population, Stam et al. (2010) found a significant association between migraine with aura and depression (608516) (p less than 0.001; OR, 1.70). Heritability estimates were significant for all migraine (0.56), MO (0.77), and MA (0.96) patients, and decreased somewhat after adjustment for depression, especially in MA. The findings indicated a bidirectional association between depression and migraine, in particular migraine with aura, which may be partly due to shared genetic factors.

Diagnosis

The Headache Classification Committee of the International Headache Society (1988) proposed a classification for headache disorders which provided operational diagnostic criteria for all varieties of facial pain and headache, including migraine.

Inheritance

Familial aggregation for migraine is undoubted. Allan (1928) favored dominant inheritance. Among 500 patients, at least 1 parent was affected in 91%. Among offspring of affected by affected matings, 83.3% had migraine; affected by unaffected matings, 61%; and unaffected by unaffected matings, 3.7%. Goodell et al. (1954) found values of 69%, 44%, and 29% in the 3 types of matings and favored recessive inheritance with about 70% penetrance. Dalsgaard-Nielsen (1965) found that 90 of 100 women with migraine had affected first-degree relatives. Subsequent authors, e.g., Devoto et al. (1986), reported inconclusive patterns of inheritance, suggesting genetic heterogeneity, but lack of ascertainment of mild cases is a major methodologic problem. Studies of twins (e.g., Lucas, 1977) have not clarified the issue. Alonso Vilatela et al. (1992) found a frequency of migraine in first-degree relatives in Mexico that supported a strong hereditary factor in migraine; familial occurrence was found in 52.7% of urban patients and 38.7% of rural patients. Because of a deficiency of affected sibs, they considered autosomal dominant inheritance very unlikely unless the penetrance of the gene is very low. Russell et al. (1993) studied 121 patients with migraine without aura (MO) and 72 probands with migraine with aura (MA), diagnosed according to criteria of the International Headache Society and selected from 35 general practices in Denmark. On the basis of an interview with the probands concerning the presence of MO and MA among their first-degree relatives, Russell et al. (1993) reported that, compared with the general population, the first-degree relatives of probands with MO had a 3-fold increase of MO, and only 1 first-degree relative of 1 proband with MO had MA. First-degree relatives of probands with MA had a 2-fold increase of both MA and MO. Compared with the general population, few spouses had MO and MA.

Russell et al. (1995) analyzed the mode of inheritance in the 2 main types of migraine, migraine without aura and migraine with aura, by complex segregation analysis using a computer program POINTER. The study included 126 probands with MO and 127 probands with MA from the general population. First-degree relatives and spouses were blindly interviewed by a neurology research fellow. The analysis indicated to the authors that both forms have multifactorial inheritance.

In a study of 77 pairs of monozygotic (MZ) twins and 134 pairs of dizygotic (DZ) twins in which at least one twin had migraine with aura, Ulrich et al. (1999) found that the pairwise concordance rate was significantly higher in MZ twins (34%) than in DZ twins (12%). The recurrence risk of migraine with aura was 50% in MZ twins and 21% in DZ twins. The authors concluded that both genetic and environmental factors are important in migraine with aura. Gervil et al. (1999) surveyed 2,680 Danish twin pairs for migraine without aura, finding a pairwise concordance rate of 28% in MZ twin pairs and 18% in DZ twin pairs.

Ulrich et al. (1997) analyzed 31 families selected for an apparently autosomal dominant mode of inheritance of migraine with aura in the nuclear family. They found that both first- and second-degree relatives outside the nuclear families had a statistically significant lower risk of migraine with aura than expected on the basis of autosomal dominant inheritance. Autosomal recessive inheritance was also considered unlikely because of the unequal sex distribution. Mitochondrial and X-linked inheritance were likewise excluded because of paternal transmission. They concluded that migraine with aura most likely has a multifactorial inheritance.

Mapping

Wessman et al. (2002) reported results from a genomewide screen of 50 multigenerational, clinically well-defined Finnish families showing intergenerational transmission of migraine with aura. 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 migraine with aura phenotype and marker D4S1647 on 4q24. Using parametric 2-point linkage analysis and assuming a dominant mode of inheritance, they found for this marker a maximum lod score of 4.20 under locus homogeneity or locus heterogeneity. Multipoint parametric and nonparametric analyses likewise supported linkage in this region. Statistically significant linkage was not observed in any other chromosomal region.

Bjornsson et al. (2003) reported results from a genomewide screen of 289 patients from 103 Icelandic families with MO. Linkage to a locus on chromosome 4q21 was observed (lod = 2.05 at marker D4S1534). When only females were considered, with a slightly relaxed criteria for MO, the lod score increased to 4.08 at marker D4S2409. The authors noted that this region overlaps the region reported by Wessman et al. (2002) for MA, and suggested that the MGR1 locus may contribute to both MA and MO.

Anttila et al. (2006) suggested that the commonly used 'end diagnosis' phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of the disease. This is likely to be the case for common types of migraine. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society (IHS) classification as phenotypes. Anttila et al. (2006) introduced an alternative strategy, the use of trait components (individual clinical symptoms of migraine) to determine affection status in genomewide linkage analysis of migraine-affected families. They identified linkage between several traits and markers on 4q24, with highest lod score under locus heterogeneity (hlod) of 4.52, a locus Wessman et al. (2002) had previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 (MGR10; 610208). Additionally, a trait combination phenotype revealed a locus on 18q12 (MGR11; 610209), and the age-at-onset trait revealed a locus at 4q28 (hlod 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to 4 additional loci was observed with the traits phonophobia (10q22) and aggravation by physical exercise (12q21, 15q14, and Xp21); these loci had been linked to migraine in previous studies. The findings suggested that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.

Anttila et al. (2013) reported the results of a metaanalysis across 29 genomewide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls, and identified 12 loci associated with migraine susceptibility (P less than 5 x 10(-8)). Five loci were novel, and 3 were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggested potential functional candidate genes at 4 loci: APOA1BP (608862), TBC1D7 (612655), FUT9 (606865), STAT6 (601512), and ATP5B (102910).

Pathogenesis

Glover et al. (1983) reported that dietary monoamines, tyramine and phenylethylamine, found in chocolate, aged cheeses, and citrus fruits, trigger migraine attacks in some patients who have low levels of phenolsulfotransferase P. See phenolsulfotransferase (171150). See glutamate monosodium sensitivity (231630), which has migraine-like headache as a feature.

Hiner et al. (1986) reported that most antimigraine drugs bind to the 5-hydroxytryptamine 1A receptor (5HT1A; 109760), which suggests its importance in the pathogenesis of migraine.

Nitric oxide (NO) generated from inducible NO synthase (NOS2A; 163730) participates in inflammatory responses and has been implicated in migraine based on pharmacologic evidence in animals and humans. In a rat model, Reuter et al. (2002) showed that the NO donor glyceryl trinitrate (GTN) caused NOS2A expression in macrophages, mediated by increased activity of the nuclear transcription factor kappa-B (NFKB1; 164011), resulting in generation of NO within rodent dura mater 6 hours later. Parthenolide, a lactone found in the medical herb feverfew which has been used successfully in the treatment of inflammatory conditions and migraine, blocked NOS2A expression in dura mater by inhibiting NFKB1. Reuter et al. (2002) concluded that NFKB1 plays a major role in the expression of proinflammatory proteins that lead to increased blood vessel permeability, tissue edema, and pain sensitization that underlie the pathogenesis of migraine, and that blockade of NFKB1 could be a transcriptional target of antimigraine drugs.

In patients with migraine headache, Goadsby et al. (1990) found a substantial elevation of the calcitonin-related peptide (CGRP; 114130) in the external jugular vein. In 9 patients with a history of migraine without aura, Lassen et al. (2002) found that intravenous infusion of CGRP resulted in a headache during the following 11 hours, as compared to 1 of 9 patients who received placebo. In 3 patients who had the infusion, the delayed headache fulfilled the International Headache Society criteria for migraine without aura. The authors suggested a causative role for CGRP in migraine headache. Olesen et al. (2004) presented evidence suggesting that a CGRP receptor (114190) antagonist may be effective in the treatment of a subgroup of patients with migraine.

Karatas et al. (2013) described a signaling pathway between stressed neurons and trigeminal afferents during cortical spreading depression (CSD), the putative cause of migraine aura and headache. CSD caused neuronal pannexin-1 (PANX1; 608420) megachannel opening and caspase-1 (CASP1; 147678) activation followed by high mobility group box-1 (HMGB1; 163905) release from neurons and nuclear factor kappa-B (NFKB; see 164011) activation in astrocytes. Suppression of this cascade abolished CSD-induced trigeminovascular activation, dural mast cell degranulation, and headache. CSD-induced neuronal megachannel opening may promote sustained activation of trigeminal afferents via parenchymal inflammatory cascades reaching glia limitans. Karatas et al. (2013) suggested that this pathway may function to alarm an organism with headache when neurons are stressed.

Molecular Genetics

In different populations, Kowa et al. (2000), Oterino et al. (2004), and Scher et al. (2006) found associations between migraine with aura and a 677CT polymorphism in the MTHFR gene (607093.0003).

Population Genetics

This very frequent and sometimes incapacitating condition affects about 4% of children, 6% of men, and 18% of women (Stewart et al., 1992). In a random-digit dialing prevalence study of migraine as diagnosed by the International Headache Society Criteria, Stewart et al. (1996) found a prevalence of 20.4% in Caucasian women, 16.2% in African American women, and 9.2% in Asian American women; 8.6% of Caucasian men, 7.2% of African American men, and 4.2% of Asian American men are affected.