Entry
- %157300 - MIGRAINE WITH OR WITHOUT AURA, SUSCEPTIBILITY TO, 1
- OMIM
- (OMIM.ORG)
%157300
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ICD+
157300
MIGRAINE WITH OR WITHOUT AURA, SUSCEPTIBILITY TO, 1
Alternative titles; symbols
MGR1
MGAU; MA
MIGRAINE
Cytogenetic location:
4q24
Genomic coordinates
(GRCh38)
4:100,100,001-106,700,000
Gene-Phenotype Relationships
Location
Phenotype
Phenotype
MIM number
Inheritance
Phenotype
mapping key
4q24
{Migraine with or without aura, susceptibility to, 1}
157300
AD
Clinical Synopsis
Phenotypic Series
Linear
Radial
INHERITANCE
- Autosomal dominant
[SNOMEDCT:
771269000
263681008
[UMLS:
C0443147
C1867440
HPO:
HP:0000006
[HPO:
HP:0000006
ABDOMEN
Gastrointestinal
- Nausea
[SNOMEDCT:
422587007
[ICD10CM:
R11.0
[UMLS:
C4255480
C0027497
HPO:
HP:0002018
[HPO:
HP:0002018
Vomiting
[SNOMEDCT:
422400008
300359004
249497008
[ICD10CM:
R11.1
R11.10
[UMLS:
C0042963
HPO:
HP:0002013
[HPO:
HP:0002013
NEUROLOGIC
Central Nervous System
- Migraine with aura
[SNOMEDCT:
4473006
[ICD10CM:
G43.109
G43.1
[ICD9CM:
346.0
[UMLS:
C0154723
HPO:
HP:0002077
[HPO:
HP:0002077
Migraine without aura
[SNOMEDCT:
56097005
[ICD10CM:
G43.0
G43.009
[ICD9CM:
346.1
[UMLS:
C0338480
HPO:
HP:0002083
[HPO:
HP:0002083
Headache is unilateral
[UMLS:
C1834873
Photophobia
[SNOMEDCT:
409668002
246622003
[ICD10CM:
H53.14
[UMLS:
C0085636
HPO:
HP:0000613
[HPO:
HP:0000613
Phonophobia
[SNOMEDCT:
313387002
[UMLS:
C0751466
HPO:
HP:0002183
[HPO:
HP:0002183
Pulsating quality
[UMLS:
C1834874
MISCELLANEOUS
- Headache duration 4-72 hours
Aggravated by physical activity
Genetic heterogeneity, see, e.g., MGR2 (
300125
), MGR3 (
607498
), MGR4 (
607501
), MGR5 (
607508
), MGR6 (
607516
▲ Close
Migraine with or without aura, susceptibility to
PS157300
- 17 Entries
Location
Phenotype
Inheritance
Phenotype
mapping key
Phenotype
MIM number
Gene/Locus
Gene/Locus
MIM number
1q31
{Migraine, familial hemiplegic, 4}
AD
607516
MGR6
607516
1q31
{Migraine with or without aura, susceptibility to, 6}
AD
607516
MGR6
607516
4q24
{Migraine with or without aura, susceptibility to, 1}
AD
157300
MGR1
157300
4q31.22-q31.23
{Migraine, resistance to}
AD
157300
EDNRA
131243
5q21
{Migraine, susceptibility to, 8}
609570
MGR8
609570
6p21.33
{Migraine without aura, susceptibility to}
AD
157300
TNF
191160
6p21.1-p12.2
{Migraine with or without aura, susceptibility to, 3}
AD
607498
MGR3
607498
6q25.1-q25.2
{Migraine, susceptibility to}
AD
157300
ESR1
133430
10q22-q23
{Migraine, with or without aura, susceptibility to, 12}
AD
611706
MGR12
611706
10q25.3
{Migraine, with or without aura, susceptibility to, 13}
AD
613656
KCNK18
613655
11q24
{Migraine with aura, susceptibility to, 9}
609670
MGR9
609670
14q21.2-q22.3
{Migraine without aura, susceptibility to, 4}
AD
607501
MGR4
607501
15q11.2-q12
{Migraine with aura, susceptibility to, 7}
609179
MGR7
609179
17p13.1
{Migraine with or without aura, susceptibility to, 10}
AD
610208
MGR10
610208
18q12.1
{Migraine with or without aura, susceptibility to, 11}
AD
610209
MGR11
610209
19p13
{Migraine with or without aura, susceptibility to, 5}
AD
607508
MGR5
607508
Xq
{Migraine, familial typical, susceptibility to, 2}
XL
300125
MGR2
300125
▲ Close
TEXT
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
).
See also familial hemiplegic migraine-1 (FHM1;
141500
), a subtype of autosomal dominant migraine with aura (MA).
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
Associations Pending Confirmation
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
).
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.
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.
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Full Text
Ulrich, V., Gervil, M., Kyvik, K. O., Olesen, J., Russell, M. B.
Evidence of a genetic factor in migraine with aura: a population-based Danish twin study.
Ann. Neurol. 45: 242-246, 1999.
[PubMed:
9989627
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Ulrich, V., Russell, M. B., Ostergaard, S., Olesen, J.
Analysis of 31 families with an apparently autosomal-dominant transmission of migraine with aura in the nuclear family.
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[PubMed:
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Wessman, M., Kallela, M., Kaunisto, M. A., Marttila, P., Sobel, E., Hartiala, J., Oswell, G., Leal, S. M., Papp, J. C., Hamalainen, E., Broas, P., Joslyn, G., and 11 others.
A susceptibility locus for migraine with aura, on chromosome 4q24.
Am. J. Hum. Genet. 70: 652-662, 2002.
[PubMed:
11836652
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Contributors:
Ada Hamosh - updated : 01/23/2014
Ada Hamosh - updated : 5/7/2013
Cassandra L. Kniffin - updated : 5/11/2010
Victor A. McKusick - updated : 6/16/2006
Cassandra L. Kniffin - updated : 5/1/2006
Cassandra L. Kniffin - updated : 4/13/2006
Cassandra L. Kniffin - updated : 4/10/2006
Victor A. McKusick - updated : 1/28/2005
Cassandra L. Kniffin - updated : 1/5/2005
Cassandra L. Kniffin - updated : 3/16/2004
Cassandra L. Kniffin - updated : 9/22/2003
Cassandra L. Kniffin - updated : 2/5/2003
Cassandra L. Kniffin - reorganized : 2/3/2003
Victor A. McKusick - updated : 3/21/2002
Orest Hurko - updated : 11/1/1999
Orest Hurko - updated : 4/2/1999
Victor A. McKusick - updated : 1/25/1999
Orest Hurko - updated : 11/9/1998
Victor A. McKusick - updated : 8/27/1997
Orest Hurko - updated : 11/22/1996
Creation Date:
Victor A. McKusick : 6/2/1986
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157300
MIGRAINE WITH OR WITHOUT AURA, SUSCEPTIBILITY TO, 1
Alternative titles; symbols
MGR1
MGAU; MA
MIGRAINE
SNOMEDCT:
37796009;
ICD10CM:
G43, G43.9, G43.909;
ICD9CM:
346, 346.9;
DO:
6364;
MONDO:
0008000;
Cytogenetic location: 4q24
Genomic coordinates
(GRCh38)
: 4:100,100,001-106,700,000
Gene-Phenotype Relationships
Location
Phenotype
Phenotype
MIM number
Inheritance
Phenotype
mapping key
4q24
{Migraine with or without aura, susceptibility to, 1}
157300
Autosomal dominant
TEXT
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).
See also familial hemiplegic migraine-1 (FHM1; 141500), a subtype of autosomal dominant migraine with aura (MA).
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
Associations Pending Confirmation
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).
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.
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.
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Ulrich, V., Gervil, M., Kyvik, K. O., Olesen, J., Russell, M. B.
Evidence of a genetic factor in migraine with aura: a population-based Danish twin study.
Ann. Neurol. 45: 242-246, 1999.
[PubMed: 9989627]
[Full Text: https://doi.org/10.1002/1531-8249(199902)45:2<242::aid-ana15>3.0.co;2-1]
Ulrich, V., Russell, M. B., 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. 74: 395-397, 1997.
[PubMed: 9259375]
[Full Text: https://doi.org/10.1002/(sici)1096-8628(19970725)74:4<395::aid-ajmg10>3.0.co;2-d]
Wessman, M., Kallela, M., Kaunisto, M. A., Marttila, P., Sobel, E., Hartiala, J., Oswell, G., Leal, S. M., Papp, J. C., Hamalainen, E., Broas, P., Joslyn, G., and 11 others.
A susceptibility locus for migraine with aura, on chromosome 4q24.
Am. J. Hum. Genet. 70: 652-662, 2002.
[PubMed: 11836652]
[Full Text: https://doi.org/10.1086/339078]
Contributors:
Ada Hamosh - updated : 01/23/2014
Ada Hamosh - updated : 5/7/2013
Cassandra L. Kniffin - updated : 5/11/2010
Victor A. McKusick - updated : 6/16/2006
Cassandra L. Kniffin - updated : 5/1/2006
Cassandra L. Kniffin - updated : 4/13/2006
Cassandra L. Kniffin - updated : 4/10/2006
Victor A. McKusick - updated : 1/28/2005
Cassandra L. Kniffin - updated : 1/5/2005
Cassandra L. Kniffin - updated : 3/16/2004
Cassandra L. Kniffin - updated : 9/22/2003
Cassandra L. Kniffin - updated : 2/5/2003
Cassandra L. Kniffin - reorganized : 2/3/2003
Victor A. McKusick - updated : 3/21/2002
Orest Hurko - updated : 11/1/1999
Orest Hurko - updated : 4/2/1999
Victor A. McKusick - updated : 1/25/1999
Orest Hurko - updated : 11/9/1998
Victor A. McKusick - updated : 8/27/1997
Orest Hurko - updated : 11/22/1996
Creation Date:
Victor A. McKusick : 6/2/1986
Edit History:
carol : 01/26/2024
carol : 10/02/2023
carol : 09/29/2023
carol : 01/21/2023
carol : 03/11/2022
carol : 06/27/2019
carol : 06/02/2017
carol : 08/11/2016
alopez : 01/23/2014
alopez : 5/7/2013
terry : 10/2/2012
wwang : 12/6/2010
ckniffin : 11/23/2010
wwang : 5/14/2010
ckniffin : 5/11/2010
terry : 6/3/2009
wwang : 5/30/2008
ckniffin : 5/23/2008
alopez : 6/29/2007
wwang : 9/7/2006
alopez : 6/23/2006
terry : 6/16/2006
wwang : 5/3/2006
ckniffin : 5/1/2006
wwang : 4/19/2006
ckniffin : 4/13/2006
wwang : 4/11/2006
ckniffin : 4/10/2006
wwang : 11/14/2005
carol : 3/8/2005
wwang : 2/2/2005
wwang : 1/28/2005
tkritzer : 1/5/2005
tkritzer : 1/5/2005
ckniffin : 1/5/2005
joanna : 3/19/2004
carol : 3/16/2004
ckniffin : 3/16/2004
tkritzer : 11/14/2003
ckniffin : 10/30/2003
carol : 9/25/2003
ckniffin : 9/22/2003
carol : 2/14/2003
ckniffin : 2/5/2003
carol : 2/3/2003
ckniffin : 1/27/2003
alopez : 3/27/2002
terry : 3/21/2002
carol : 11/1/1999
carol : 4/2/1999
terry : 1/25/1999
terry : 1/25/1999
carol : 12/3/1998
terry : 11/9/1998
terry : 7/31/1998
terry : 8/27/1997
mark : 11/22/1996
terry : 10/22/1996
mark : 1/10/1996
mark : 1/4/1996
terry : 12/14/1994
mimadm : 11/6/1994
davew : 7/27/1994
carol : 3/14/1994
warfield : 3/3/1994
carol : 9/14/1993
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OMIM
and Online Mendelian Inheritance in Man
are registered trademarks of the Johns Hopkins University.
1966-2026 Johns Hopkins University.
NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM
and Online Mendelian Inheritance in Man
are registered trademarks of the Johns Hopkins University.
1966-2026 Johns Hopkins University.
Printed: April 24, 2026
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