Genetics of migraine headaches

Migraines are often hereditary. It is estimated that 60% of migraine cases are caused by genetics.[1] The role of natural selection in the development of migraines is not known. Fitness-impairing disorders, including migraines, tend to disappear as a result of natural selection, and their frequency decreases to near the rate of spontaneous mutation.[unreliable medical source?][2] However, it is estimated that migraines affect 15-20% of the population and is increasing.[1] This could suggest that a central nervous system (CNS) susceptible to severe, intermittent headache has been linked to an important survival or reproductive advantage. Five possible evolutionary explanations exist: i) migraine as a defence mechanism, ii) migraine as a result of conflicts with other organisms, iii) migraine as a result of novel environmental factors, iv) migraine as a compromise between genetic harms and benefits, and v) headache as a design constraint.[3] These considerations allow the treatment and prevention of migraine to be approached from an evolutionary medicine perspective.[medical citation needed]

## Heritability[edit]

Studies of twins indicate a 34% to 51% genetic influence on the likelihood to develop migraine headaches.[4] This genetic relationship is stronger for migraines with aura than for migraines without aura.[medical citation needed][5] A number of specific variants of genes increase the risk by a small to moderate amount.[6]

Single gene disorders that result in migraines are rare.[6] One of these is known as familial hemiplegic migraine, a type of migraine with aura, which is inherited in an autosomal dominant fashion.[7][8] Four genes have been shown to be involved in familial hemiplegic migraine.[9] Three of these genes are involved in ion transport.[9] The fourth is an axonal protein associated with the exocytosis complex.[9] Another genetic disorder associated with migraine is CADASIL syndrome or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.[10]

## Evolution[edit]

### Defence mechanism[edit]

The tendency to develop head pain when faced with a stressor or strong sensory stimuli can be explained in two ways. First, it may be a side effect of other CNS processes that provide important evolutionary advantages. One example is counteracting the dilation of cranial arteries to counteract dangerous vasoconstriction in the brain.[unreliable medical source?][11] Second, migraine may be an example of how pain has evolved to encourage organisms to avoid potentially harmful situations. Olfactory-induced migraines (migraines stimulated by strong smells) have been explained as an attempt to interrupt the entry of toxins into the brain via the olfactory nerve.[unreliable medical source?][12] Similarly, the low threshold for nausea and vomiting may be a mechanism to enhance the elimination of ingested toxins in food. Migraineurs have a lower prevalence of malignant neoplasms in the brain than controls, suggesting that migraines are protective against tumours. However, the mechanism responsible for this difference is unknown.[unreliable medical source?][13]

### Conflicts with other organisms[edit]

A headache-prone CNS may have resulted from interactions with other organisms in two ways. The first possibility is that migraine offers an advantage to the organism in fighting infection by increasing blood flow to the brain.[3] The second possibility is that certain pathogens evolved to cause headaches as a way of speeding their transmission to other organisms.[3] Finally, migraine may benefit neither the host nor the pathogen, but may simply be the result of certain infections.[14] This last explanation is concordant with the apparent negative impact of migraine on human fitness.[original research?]

### Novel environmental factors[edit]

Modern environmental factors, with an increased sensory overload, may be especially permissive of the expression of genes that predispose to the disorder. If so, natural selection may not have had a chance to eliminate these genes yet. The increasing prevalence of migraine is easily a result of increased known triggers, such as bright light, loud noise, altered sleep/wake patterns, and emotional stress. This is an example of mismatch theory, which states that the current environment differs from the evolutionary environment of a particular trait.[3]

### Genetic harms and benefits[edit]

Migraine is influenced on a polygenetic level (controlled by multiple genes). Therefore, researchers have theorized that migraine is a trade-off and that it exists as a spectrum of susceptibility, with the majority of the population falling in the "heterozygous" zone between the two extremes of experiencing no headache and experiencing frequent, incapacitating headache. While it is not known for certain how or whether mild forms of the disorder would enhance survival, there is evidence of enhanced visual sensitivity in family members of migraineurs.[unreliable medical source?][15] Additionally, this compromise theory may explain the higher prevalence among women, especially pregnant women and women of reproductive age (25-40). The avoidance of threatening environments is historically more important to the reproductive success of women.[unreliable medical source?][16] The compromise between genetic harms and benefits is commonly seen in other disorders, such as cystic fibrosis and sickle cell anemia.

### Headache as a design construct[edit]

Finally, migraine may be a component of imperfect central nervous system design. Evidence has suggested a dysfunction of pain-inhibitory pathways in migraine and discordant interaction between the ancient brain stem design and the more evolved neocortex.[unreliable medical source?][17] The brain stem may be unable to suppress excessive input from higher brain centres.

## References[edit]

1. ^ a b Bron, Charlene; Sutherland, Heidi G.; Griffiths, Lyn R. (2021-04-22). "Exploring the Hereditary Nature of Migraine". Neuropsychiatric Disease and Treatment. 17: 1183–1194. doi:10.2147/NDT.S282562. PMC 8075356. PMID 33911866.
2. ^ [unreliable medical source?]Nesse, RM; Williams, GC (November 1998). "Evolution and the origins of disease". Scientific American. 279 (5): 86–93. Bibcode:1998SciAm.279e..86N. doi:10.1038/scientificamerican1198-86. PMID 9796548. Erratum in Sci Am 1999 Mar;280(3):14.
3. ^ a b c d Loder, E (1 October 2002). "What is the evolutionary advantage of migraine?". Cephalalgia (Review). 22 (8): 624–632. doi:10.1046/j.1468-2982.2002.00437.x. PMID 12383059. S2CID 1781214.
4. ^ Piane, M; Lulli, P; Farinelli, I; Simeoni, S; De Filippis, S; Patacchioli, FR; Martelletti, P (December 2007). "Genetics of migraine and pharmacogenomics: some considerations". The Journal of Headache and Pain (Review). 8 (6): 334–9. doi:10.1007/s10194-007-0427-2. PMC 2779399. PMID 18058067.
5. ^ [full citation needed]The Headaches, Pg 232-233
6. ^ a b Schürks, M (January 2012). "Genetics of migraine in the age of genome-wide association studies". The Journal of Headache and Pain (Review). 13 (1): 1–9. doi:10.1007/s10194-011-0399-0. PMC 3253157. PMID 22072275.
7. ^ de Vries, B; Frants, RR; Ferrari, MD; van den Maagdenberg, AM (July 2009). "Molecular genetics of migraine". Human Genetics (Review). 126 (1): 115–32. doi:10.1007/s00439-009-0684-z. PMID 19455354. S2CID 20119237.
8. ^ Montagna, P (September 2008). "Migraine genetics". Expert Review of Neurotherapeutics (Review). 8 (9): 1321–30. doi:10.1586/14737175.8.9.1321. PMID 18759544. S2CID 207195127.
9. ^ a b c Ducros, A (Apr 22, 2013). "[Genetics of migraine]". Revue neurologique. 169 (5): 360–71. doi:10.1016/j.neurol.2012.11.010. PMID 23618705.
10. ^ Aminoff, Roger P. Simon, David A. Greenberg, Michael J. (2009). Clinical neurology (7 ed.). New York, N.Y: Lange Medical Books/McGraw-Hill. pp. 85–88. ISBN 9780071664332.`{{cite book}}`: CS1 maint: multiple names: authors list (link)
11. ^ [unreliable medical source?]Edvinsson, L.; Olesen, I. J.; Kingman, T.; McCulloch, J.; Uddman, R. (1 October 1995). "Modification of vasoconstrictor responses in cerebral blood vessels by lesioning of the trigeminal nerve: possible involvement of CGRP". Cephalalgia. 15 (5): 373–383. doi:10.1046/j.1468-2982.1995.1505373.x. PMID 8536296. S2CID 6338356.
12. ^ [unreliable medical source?]Covelli, Vito; Massari, Franco; Ďandrea, Lucia; Cervo, M. Augusta; Buscaino, Giuseppe Andrea; Jirillo, Emilio (1 January 1994). "Could migraine be a "protective factor" against tumors?". International Journal of Neuroscience. 75 (1–2): 139–143. doi:10.3109/00207459408986297. PMID 8050847.
13. ^ [unreliable medical source?]Snyder, RD; Drummond, PD (1 November 1997). "Olfaction in migraine". Cephalalgia (Clinical trial). 17 (7): 729–732. doi:10.1046/j.1468-2982.1997.1707729.x. PMID 9399001. S2CID 21617632.
14. ^ Cochran, Gregory M; Ewald, Paul W; Cochran, Kyle D (1 January 2000). "Infectious causation of disease: an evolutionary perspective". Perspectives in Biology and Medicine (Historical article). 43 (3): 406–448. CiteSeerX 10.1.1.182.5521. doi:10.1353/pbm.2000.0016. PMID 10893730. S2CID 5908583.
15. ^ [unreliable medical source?]Puca, F.; de Tommaso, M.; Tota, T.; Sciruicchio, V. (1 June 1996). "Photic driving in migraine: correlations with clinical features". Cephalalgia. 16 (4): 246–250. doi:10.1046/j.1468-2982.1996.1604246.x. PMID 8792036. S2CID 23967616.
16. ^ [unreliable medical source?]Stewart, Walter F. (1 January 1992). "Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors". JAMA: The Journal of the American Medical Association. 267 (1): 64–9. doi:10.1001/jama.1992.03480010072027. PMID 1727198.
17. ^ [unreliable medical source?]Weiller, C; May, A; Limmroth, V; Jüptner, M; Kaube, H; Schayck, RV; Coenen, HH; Diener, HC (July 1995). "Brain stem activation in spontaneous human migraine attacks". Nature Medicine. 1 (7): 658–60. doi:10.1038/nm0795-658. PMID 7585147. S2CID 20878130.