Genetics in primary headaches
© Springer-Verlag Italia 2007
Received: 7 February 2007
Accepted: 8 March 2007
Published: 11 June 2007
This tutorial describes different methods and results of genetic studies of primary headaches. A positive family history is imprecise, because it does not specify the number of affected, family size or relation to the proband. Nor does it include an interview of the possibly affected family members. Calculation of the familial aggregation after confirmation of the diagnosis by a physician is more precise. Compared to the general population, first-degree relatives of probands with migraine without aura, migraine with aura, chronic tension-type headache and cluster headache has a significantly increased risk of the proband’s disorder. These data are confirmed in twin studies. The primary headaches are caused by a combination of genetic and environmental factors. A major breakthrough was identification of 3 different genes all causing the rare autosomal dominant inherited familial hemiplegic migraine. The genes encode ion channels. So far no genes have been identified to cause the more common types of primary headaches.
KeywordsMigraine cluster headache tension-type headache genetics primary headache
The diagnosis of primary headaches relies on the headache history and exclusion of secondary causes. The lack of an objective marker applicable for usual clinical practice makes case definition a challenge. The International Classification of Headache Disorder provides explicit diagnostic criteria in order to minimise the diagnostic variability . Genetic studies of primary headaches are further complicated by the high prevalence of migraine and tension-type headache [2, 3].
This tutorial describes different methods and results of genetic studies of primary headache.
Co-occurrence of primary headaches
Co-occurrence of migraine and tension-type headache is frequent, and both the prevalence and the frequency of tension-type headache are higher in those with than without migraine . This confounding factor should be dealt with in genetic studies of migraine and tension-type headache. The prevalence of migraine in those with cluster headache corresponds to the prevalence of migraine in the general population, indicating that migraine and cluster headache are distinct primary headaches [2, 4].
A positive family history is imprecise, because it does not specify number of affected, family size or relation to the proband. An example: the lifetime prevalence of migraine is 16% in the general population . This causes a positive family history simply by chance in >65% of the families, if the proband has six first-degree relatives (parents, siblings and children), and one or both parents are affected in >30% of the families. Furthermore, a positive family history does not include an interview of the relatives by a physician. This adds to the imprecision as probands only identify about half of their affected first-degree relatives with migraine .
The most precise calculation of familial occurrence can be assessed by estimating the population’s relative risk of the disease in specified groups of relatives . The risk is calculated according to the following equation:
Prob(Relative is affected|Proband is affected)
A family aggregation is implied when this risk ratio significantly exceeds 1.
As the prevalence of the different primary headaches depends on age and gender, the value of the denominator is adjusted according to the distribution of age and gender in the group of relatives studied. Hence, this standardised population relative risk is estimated by dividing the observed number of affected first-degree relatives by the expected number according to the prevalence rates in the population. The expected number is calculated by adding the products of the current age- and gender-specific rates and the number of relatives within each corresponding age-gender category. Some studies calculate the familial aggregation by comparing the families of probands with and without disease.
Genetic epidemiological surveys
Age and gender standardised risk of migraine without aura (MO), migraine with aura (MA), cluster headache (CH) and chronic tension-type headache (CTTH). The population relative risk is calculated by available data from the original articles by the author. The revised population relative risks on CH were calculated assuming the prevalence of cluster headache is 200 per 100.000 inhabitants . CI denotes confidence intervals
Disease in proband
Disease in first-degree relative
No. of affected relatives Expected
Population relative risk (95% CI)
Migraine without aura
Mochi et al. 
Russell and Olesen 
Stewart et al. 
Migraine with aura
Mochi et al. 
Russell and Olesen 
Kalfakis et al. 
Stewart et al. 
Chronic tension-type headache
Øtergaard et al. 
Russell et al. 
Kudrow and Kudrow 
Leone et al. 
El Amrani et al. 
An increased familial risk can be caused by genetic as well as environmental factors. The risk among spouses can be used to evaluate this relation, because probands and spouses in part share a common environment, but differ in genetic constitution. Spouses to probands with migraine without aura had a slightly increased risk of migraine without aura, while spouses to probands with migraine with aura had no increased risk of migraine with aura . Spouses to probands with chronic tension-type headache had no increased risk of chronic tension-type headache . Thus, the epidemiological surveys of migraine without aura, migraine with aura and chronic tension-type headache suggest the importance of genetic factors. The increased familial risk of cluster headache strongly suggests a genetic cause. Theoretically, a shared environment can produce relative risks of the magnitude observed for cluster headache only under extreme conditions .
The probandwise concordance rates in monozygotic (MZ) and same gender dizygotic (DZ) twin pairs with migraine without aura, migraine with aura and tension-type headache without co-occurrence of migraine. The concordance rates are in percentage and the 95% confidence intervals are in parenthesis. n.s. denotes not significant
Migraine without aura
Gervil et al. 
15 (‒19 to 49)
Migraine with aura
Ulrich et al. 
Tension-type headache No
Russell et al. 
Russell et al. 
Russell et al. 
Russell et al. 
15 (‒52 to 83)
12 (‒50 to 73)
10 (‒47 to 67)
9 (‒45 to 63)
Mode of inheritance
A classical segregation analysis analyses for Mendelian inheritance, while a complex segregation analysis also analyses for multifactorial inheritance, as well as transmissible and non transmissible environmental factors . A complex segregation analysis of migraine without aura, migraine with aura and chronic tension-type headache suggested multifactorial inheritance [24, 25]. An analysis of cluster headache suggested that an autosomal dominant gene has a role in some families . An analysis of a single Italian pedigree suggested autosomal recessive inheritance in that particular family .
Molecular genetic studies
Sporadic and familial hemiplegic migraine are rare subtypes of migraine with aura, the latter having autosomal dominant inheritance [28, 29]. At present three different genes have been identified to cause familial hemiplegic migraine, i.e., locus heterogeneity [30–32]. The genes all encode ion channels, which makes good sense due to the paroxysmal nature of migraine. At present these genes have not been shown to be involved in the common types of migraine, nor have other genes causing migraine been identified. However, it is likely that migraine without aura and migraine with aura also are ion channel disorders. So far no genes have been identified for tension-type headache or cluster headache. The migraine and cluster headache literature provides information on several linkage and association studies. So far it is not possible to draw firm conclusion about the results, and many of the association studies suffer from lack of power as well as contradictory results .
The variability of therapeutic effect and adverse events depend on both environmental and genetic factors. An example is the intraindividual variability of migraine with aura attacks, which is likely to be caused by environmental factors as the genetic constitution remains the same . The efficacy and adverse events both show intra- and interindividual variability, even though the medication is given subcutaneously. Intraindividual variability is likely to be caused mainly by environmental factors, while interindividual variability is likely to be caused by a combination of genetic and environmental factors. Most primary headaches have multifactorial inheritance and a precise description of the pathogenesis is lacking. This constitutes a major challenge for future pharmacogenetic research, a research field that hopefully will expand in the future for the benefit of patients.
Our knowledge about genetics in primary headache disorders has improved rapidly since linkage was first demonstrated in familial hemiplegic migraine at the International Headache Society congress in Paris 1993 . The genetics of migraine without aura, migraine with aura, tension-type headache and cluster headache are considered to be complex and identification of genes is anticipated to be a difficult task. So we still have a long way to go before we can fully elucidate the aetiology in the more common types of primary headache.
- Headache Classification Subcommittee of the International Headache Society (2004) The International Classification of Headache Disorders. Cephalalgia 24[Suppl 1]:9–160Google Scholar
- Russell MB (1997) Genetic epidemiology of migraine and cluster headache. University of Copenhagen. Cephalalgia 17:683–701, 10.1046/j.1468-2982.1997.1706683.x, 1:STN:280:DyaK1c%2FhtFCktA%3D%3D, 9350392View ArticlePubMedGoogle Scholar
- Russell MB (2005) Tension-type headache in 40-year-olds: a Danish population-based sample of 4000. J Headache Pain 6:441–447, 10.1007/s10194-005-0253-3, 16388338PubMed CentralView ArticlePubMedGoogle Scholar
- Rasmussen BK, Jensen R, Schroll M, Olesen J (1991) Epidemiology of headache in a general population — a prevalence study. J Clin Epidemiol 44:1147–1157, 10.1016/0895-4356(91)90147-2, 1:STN:280:DyaK38%2FksVKlsw%3D%3D, 1941010View ArticlePubMedGoogle Scholar
- Russell MB, Fenger K, Olesen J (1996) The family history of migraine. Direct versus indirect information. Cephalalgia 16:156–160, 10.1046/j.1468-2982.1996.1603156.x, 1:STN:280:DyaK28zhslSgug%3D%3D, 8734766View ArticlePubMedGoogle Scholar
- Weiss KM, Chakraborty R, Majumder PP, Smouse PE (1982) Problems in the assessment of relative risk of affected individuals. J Chronic Dis 35:539–551, 10.1016/0021-9681(82)90073-X, 1:STN:280:DyaL383hsVeltQ%3D%3D, 7085846View ArticlePubMedGoogle Scholar
- Mochi M, Sangiorgi S, Cortelli P et al (1993) Testing models for genetic determination in migraine. Cephalalgia 13:389–394, 10.1046/j.1468-2982.1993.1306389.x, 1:STN:280:DyaK2c7kslCrtA%3D%3D, 8313452View ArticlePubMedGoogle Scholar
- Russell MB, Olesen J (1995) Increased familial risk and evidence of genetic factor in migraine. Br Med J 311:541–544, 1:STN:280:DyaK2Mzpt1amsw%3D%3DView ArticleGoogle Scholar
- Kalfakis N, Panas M, Vassilopoulos D, Malliara Loulakaki S (1996) Migraine with aura: segregation analysis and heritability estimation. Headache 36:320–322, 10.1046/j.1526-4610.1996.3605320.x, 1:STN:280:DyaK283mslOruw%3D%3D, 8682675View ArticlePubMedGoogle Scholar
- Stewart WF, Staffa J, Lipton RB, Ottman R (1997) Familial risk of migraine: a population based study. Ann Neurol 41:166–172, 10.1002/ana.410410207, 1:STN:280:DyaK2s7otVyntQ%3D%3D, 9029065View ArticlePubMedGoogle Scholar
- Østergaard S, Russell MB, Bendtsen L, Olesen J (1997) Comparison of first degree relatives and spouses of people with chronic tension type headache. Br Med J 314:1092–1093View ArticleGoogle Scholar
- Russell MB, Andersson PG, Thomsen LL (1995) Familial occurrence of cluster headache. J Neurol Neurosurg Psychiatry 58:341–343, 10.1136/jnnp.58.3.341, 1:STN:280:DyaK2M3gsFWmtQ%3D%3D, 7897418PubMed CentralView ArticlePubMedGoogle Scholar
- Kudrow L, Kudrow DB (1994) Inheritance of cluster headache and its possible link to migraine. Headache 34:400–407, 10.1111/j.1526-4610.1994.hed3407400.x, 1:STN:280:DyaK2M%2Fhtlejsw%3D%3D, 7928324View ArticlePubMedGoogle Scholar
- Leone M, Russell MB, Rigamonti A et al (2001) Familial risk of cluster headache: a study of Italian families. Neurology 56:1233–1236, 1:STN:280:DC%2BD3MzntFalsg%3D%3D, 11342697View ArticlePubMedGoogle Scholar
- El Amrani M, Ducros A, Boulan P et al (2002) Familial cluster headache: a series of 186 index patients. Headache 42:974–977, 10.1046/j.1526-4610.2002.02226.x, 12453028View ArticlePubMedGoogle Scholar
- Russell MB (2004) Epidemiology and genetics of cluster headache. Lancet Neurol 3:279–283, 10.1016/S1474-4422(04)00735-5, 15099542View ArticlePubMedGoogle Scholar
- Khoury MJ, Beaty TH, Liang K-Y (1988) Can familial aggregation of diseases be explained by familial aggregation of environmental risk factors? Am J Epidemiol 127:674–683, 1:STN:280:DyaL1c7jtV2qsw%3D%3D, 3341366PubMedGoogle Scholar
- Ulrich V, Gervil M, Kyvik KO et al (1999) Evidence of a genetic factor in migraine with aura: a population-based Danish twin study. Ann Neurol 45:242–246, 10.1002/1531-8249(199902)45:2<242::AID-ANA15>3.0.CO;2-1, 1:STN:280:DyaK1M7kt1OgsQ%3D%3D, 9989627View ArticlePubMedGoogle Scholar
- Gervil M, Ulrich V, Kyvik KO et al (1999) Migraine without aura: A population based twin study. Ann Neurol 46:606–611, 10.1002/1531-8249(199910)46:4<606::AID-ANA8>3.0.CO;2-O, 1:STN:280:DyaK1Mvkt1amtw%3D%3D, 10514097View ArticlePubMedGoogle Scholar
- Motulsky AG (1978) Biased ascertainment and the natural history of diseases. N Engl J Med 298:1196–1197, 1:STN:280:DyaE1c7nslShtw%3D%3D, 651950, 10.1056/NEJM197805252982111View ArticlePubMedGoogle Scholar
- Svensson D, Ekbom K, Pedersen NL et al (2003) A note on cluster headache in a population-based twin registry. Cephalalgia 5:376–380, 10.1046/j.1468-2982.2003.00521.xView ArticleGoogle Scholar
- Russell MB, Saltyte-Benth J, Levi N (2006) Are infrequent episodic, frequent episodic and chronic tension-type headache inherited? A population-based study of 11 199 twin pairs. J Headache Pain 7:119–126, 10.1007/s10194-006-0299-x, 16767531PubMed CentralView ArticlePubMedGoogle Scholar
- Lalouel JM, Morton NE (1981) Complex segregation analysis with pointers. Hum Hered 31:312–321, 10.1159/000153231, 1:STN:280:DyaL387ktVOgsA%3D%3D, 7333620View ArticlePubMedGoogle Scholar
- Russell MB, Iselius L, Olesen J (1995) Investigation of inheritance of migraine by complex segregation analysis. Hum Genet 96:726–730, 10.1007/BF00210307, 1:STN:280:DyaK287gtF2jsA%3D%3D, 8522335View ArticlePubMedGoogle Scholar
- Russell MB, Iselius L, Østergaard S, Olesen J (1998) A complex segregation analysis of chronic tension-type headache. Hum Genet 102:138–140, 10.1007/s004390050666, 1:STN:280:DyaK1c7otVyktQ%3D%3D, 9521579View ArticlePubMedGoogle Scholar
- Russell MB, Andersson PG, Thomsen LL, Iselius L (1995) Cluster headache is an autosomal dominant inherited disorder in some families. A complex segregation analysis. J Med Genet 32:954–956, 10.1136/jmg.32.12.954, 1:STN:280:DyaK28vitlehsA%3D%3D, 8825923PubMed CentralView ArticlePubMedGoogle Scholar
- De Simone R, Fiorillo C, Bonuso S, Castaldo G (2003) A cluster headache family with possible autosomal recessive inheritance. Neurology 61:578–579, 12939449View ArticlePubMedGoogle Scholar
- Ducros A, Tournier-Lasserve E, Bousser MG (2002) The genetics of migraine. Lancet Neurol 1:285–293, 10.1016/S1474-4422(02)00134-5, 1:CAS:528:DC%2BD3sXkvFOgsLk%3D, 12849426View ArticlePubMedGoogle Scholar
- Thomsen LL, Ostergaard E, Romer SF et al (2003) Evidence for a separate type of migraine with aura: sporadic hemiplegic migraine. Neurology 60:595–601, 12601098View ArticlePubMedGoogle Scholar
- Ophoff RA, Terwindt GM, Vergouwe MN et al (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543–552, 10.1016/S0092-8674(00)81373-2, 1:CAS:528:DyaK28XmvVOqt78%3D, 8898206View ArticlePubMedGoogle Scholar
- De Fusco M, Marconi R, Silvestri L et al (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33:192–196, 10.1038/ng1081, 12539047, 1:CAS:528:DC%2BD3sXnsFSktA%3D%3DView ArticlePubMedGoogle Scholar
- Dichgans M, Freilinger T, Eckstein G et al (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366:371–377, 10.1016/S0140-6736(05)66786-4, 1:CAS:528:DC%2BD2MXmvVWmsbY%3D, 16054936View ArticlePubMedGoogle Scholar
- Russell MB, Olesen J (1996) A nosographic analysis of the migraine aura in the general population. Brain 119:355–361, 10.1093/brain/119.2.355, 8800932View ArticlePubMedGoogle Scholar
- Joutel A, Bousser MG, Biousse V (1993) A gene for familial hemiplegic migraine maps to chromosome 19. Nat Genet 5:40–45, 10.1038/ng0993-40, 1:CAS:528:DyaK3sXlvFOjtL8%3D, 8220421View ArticlePubMedGoogle Scholar