Timothy C. Hain, MD • Page last modified: March 6, 2021
The common dogma is that 50% of patients with migraine have first degree family member with migraine (Persico et al, 2015). This not such a great feat of course, as with a condition that affects 15% of the population, it would seem difficult NOT to have a family member. Lets see -- mother, father -- thats a 30% chance right there. A sibling -- we are now up to 45%.
Now that the human genome has been sequenced, one would think that we could figure out what gene(s) cause migraine. This presumes that "migraine" IS a disease, which seems rather unlikely now in view of recent genetic findings. The number of single gene variants of migraine are very few, and instead the risk of checking off the right answers on the IHS questionnaire seems to be distributed over a LARGE number of genes.. Lets take a look at what the review articles say.
Ducros (2013) stated that "Since 2010, three large genome-wide association studies (GWAS) have identified six genetic variants associated with migraine. Each variant has only a modest contribution to the overall genetic risk of migraine, suggesting a marked genetic heterogeneity." -- "The vast majority of the migraine genes are still to be identified."
More recently, Nyholt and van den Maagedenberg (2016) stated that "Genome-wide association studies (GWAS) have revealed over a dozen genetic factors robustly associated with the common forms of migraine. " OK -- we went from 6 to 12 in 3 years. Trolner et al (2015) stated that "Common forms of migraine (both with and without an aura), instead, are thought to have a polygenic makeup". Moving on to 2019, de Boer et al (2019) reported that "Genome-wide association studies have identified approximately 40 genetic loci associated with migraine."
Persico et al (2015) stated that "Common variants identified by GWAS collectively contribute to migraine pathogenesis each exerting a small effect size, with ORs below 1.3 as typically occurs in complex disorders".
Gormley and many many others (2018) recently published "Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families". They stated "Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71–1.81, p = 1.7 × 10−109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25–1.38, p = 7.2 × 10−17). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine."
Vgontzas and Renthal (2019) reported that most of the migraine genes are expressed somewhere other than the nervous system. "Fifty-four putative migraine-associated genes were expressed in the central nervous system, peripheral nervous system or neurovascular cell types analyzed. Six genes (11.1%) were selectively enriched in central nervous system cell types, three (5.5%) in neurovascular cell types, and two (3.7%) in peripheral nervous system cell types. The remaining genes were expressed in multiple cell types. " That would seem to indicate -- 11 genes in the nervous system. 43 genes outside the nervous system.
Knol et al (2020) stated that "Recent genome-wide association studies have identified 44 genetic variants in 38 genetic loci that affect the risk of migraine". Now we are up to 44-54.
Lets think about this for a second - - 40-50+ genes. Each one, either present or absent. That provides at least 2 to the 40th possible genetic patterns -- more than a trillion. Some of these genes might be for headache, some for photophobia, some for vertigo .. lots of possibilities here.
If we accept that migraine is polygenetic, and that genes can be selected for in the population, it would seem logical that at least some of these migraine genes must be good for something that keeps them from being selected out. One idea about this derives from a recent report that being diagnosed as having migraine lowers women's risk for type 2 diabetes (Fagherazzi et al, 2019) .This is an association, not a cause. Still, perhaps one of these genes lowers diabetes risk and increases migraine risk. Gelfand and Loder offer other ideas about how Migraine might have positive effects (2019).
So it looks that as genetic research progresses, things are rapidly going from simple to complex- -we are not finding the "migraine gene", we are finding a cloud of genes, each of which contributes slightly to the probability that someone will be diagnosed as "migraine". As they say, the devil is in the details.
There are a small number of exceptions to the general rule that migraine is polygenetic. These are good candidates for "splitting" them out from "migraine" into other entities. In general, it is unproductive to test patients with migraine for these disorders, because they are so extremely rare. Of course, studies attempting to link these single genes to the larger population of migraine have all failed, as the GWAS studies noted above demostrate that the collection of symptoms termed "migraine" is actually polygenetic.
Familial Hemiplegic Migraine: This is a rare condition, considered to be a "subtype" of migraine (Silberstein and Dodick, 2013). It shares the trait of headache with migraine, but differs because of the very pronounced stroke symptoms or strokes themselves. These patients do not "blend" into the general migraine population. Reasonably, one might rebrand them as "Familial Hemiplegic Headache".
CADASIL is another genetic disorder -- it stands for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. This is extremely uncommon. The NOTCH3 gene is responsible. (Takeshima and Nakasnima, 2005). We see no reason to call "CADASIL" migraine at all. Studies attempting to link NOTCH3 mutations with the larger population of migraine have failed (e.g. Borroni et al, 2006; Schwaag et al, 2006)
MELAS -- mitochondrial encephalopathy with lactic acidosis and stroke is another exceedingly rare genetic disorder, in this instance involving the mitochondria, with stroke. Most studies attempting to link MELAS mutations with the larger population of migraine have failed. (e.g. Klopstock et al, 1996; Di Gennaro et al, 2000) Again, we see no reason to call MELAS "migraine" at all.
It seems to us that the core problem is that Migraine is just a set of symptoms -- defined by the International Headache Society. This is not at all the same as diabetes (defined basically by persistent high blood sugar), brain cancer (abnormal MRI), or infections (organisms detected). In other words, "migraine" may be actually a collection of genetic traits, lumped together. The lumping is not all that simple, as the IHS document on headache now extends to about 165 pages.
The genetic data would suggest that we do not really have a "disease" in migraine - - rather we have a list of symptoms that often occur in clusters, and that also are sometimes modified by medications. Perhaps we have "spectrum". Or perhaps we just have several distinct conditions lumped under one title and a cloud of genetic variants. For the most part, prevention medications that "work" seem to be ones that reduce sensory input (such as triptans), or quiet down irritable neurons (such as anticonvulsants).
It is important that many headaches are alleviated by triptans, or perhaps prevented by various antidepressants, seizure medications, or blood pressure medications. On the other hand, given that "migraine" appears to be a chance collection of genetic risk factors, suggesting that this or that medication will always work for "migraine" seems naive. Rather, it seems right now that we have a trial/error process.
To make progress with migraine treatment in the future, it seems likely that we will have to start splitting up "migraine" into smaller collections of symptoms, hopefully that can be associated with response to treatments. Treatment for head pain is fairly well advanced, but treatment for sensory problems such as photophobia, phonophobia, allodynia, etc, is very scanty.