Around 1 in 4 women and 1 in 12 men suffer from migraine headaches. Many sufferers find that certain foods trigger migraines. For others, migraines may be triggered by loud noise, certain smells, stress, and other environmental and lifestyle factors. Why is it, though, that some people are affected by these triggers and others aren’t? Might migraines be all in your… genes? A wide range of research suggests that genetics and migraines are closely intertwined.
Indeed, while migraine is a complex multifactorial disorder, research suggests that up to 50% of your risk could be genetic.1
Familial migraines and genetic variants
The first genetic studies of migraine focused on the rare subtype of migraine: familial hemiplegic migraine (FHM). FHM is characterized by migraine with aura, commonly shortened to MA in medical texts (MO is migraine without aura). FHM was first described in 1910 as affecting four generations of a family in the United Kingdom. The symptoms of FHM, during aura, include:
- Hemiparesis (weakness in half of the body)
- Temporary visual symptoms including:
- blind spots (scotomas)
- zig-zagging lines
- double vision
- flashing lights.
FHM also tends to be associated with a longer aura than other types of migraine.
Early research involving families with FHM identified three causative genes: CACNA1A, ATP1A2 and SCNA1A.2 These genes code for proteins that regulate ion transports across neuronal and glial cell membranes in the brain. Subsequent research has identified other genes that may be involved in FHM, including:3
Not all migraines are FHM, but at least one of the genes seemingly involved in FHM, namely HCRTR1, appears to affect the likelihood of aura in other migraineurs due to its interactions with serotonin in the brain.4
Hypocretin-1, serotonin, and migraines
Serotonin is a neurotransmitter involved in regulating mood and appetite. Serotonin also constricts nerve endings and blood vessels, which influences nociceptive pain, i.e. the kind of pain resulting from damage or potential damage to the body.
In the 1960s, scientists found that migraineurs had high levels of a urinary metabolite called 5-hydroxyindoleacetic acid (5-HIAA). 5-HIAA is the main metabolite of serotonin. This led researchers to suggest that an inborn mutation in serotonin metabolism might play a role in migraines.5
In short, too little serotonin (or a poor response to serotonin) might trigger a migraine by dilating blood vessels and making you more sensitive to pain. This increase in pain perception may itself be influenced by the hypocretin system. This system controls pain modulation, regulation of the autonomic system, and stress response, in part due to its interactions with serotonin.
The hypocretin system also involves the receptors HCRTR1 and HCRTR2, and activating HCRTR1 may help reduce vasodilation in the brain. Certain genetic variants in the HCRTR1 gene have been linked to increased migraine risk, including the polymorphism rs2271933 (G1222A). People with the AA genotype have a two-fold increased risk of migraine without aura compared to carriers of the GG genotype. In Europe, around 37% of the population has the A allele, compared to more than 70% of the population in Asia and Africa. 8
In simple terms, hypocretin-1 appears to have an analgesic (painkilling) effect, which makes it an exciting target for research into migraine treatment.
Boosting serotonin to beat migraines
Current migraine treatments also include oral contraceptives. Why? In part because ovarian hormones influence levels of serotonin. This may go some way towards explaining why women experience migraines at a much higher rate than men. It may also offer a reason for the so-called “menstrual migraine.” If this sounds familiar, you may want to talk to your physician about managing migraines with estrogen therapy.
For migraineurs in general, though, what’s the takeaway from the hypocretin/serotonin research? For now, the smart move for migraineurs may be to ensure a good intake of nutrients that support healthy serotonin synthesis. This means getting enough of the amino acid tryptophan, which the body converts into serotonin, as well as co-factors in serotonin synthesis, such as vitamin B6.
Although it may seem counterintuitive at first, increasing protein consumption does not increase serotonin levels in the brain. This is because tryptophan is one of the least-abundant amino acids in food, and the other amino acids out compete tryptophan for transport across the blood-brain barrier. For more on natural ways to increase serotonin levels, see John’s post on increasing serotonin with food and supplements.
Other genes and migraines
In addition to genes affecting hypocretin-1, serotonin, and pain transmission, several other genes appear to influence migraine susceptibility. These genes affect immune response and oxidative stress, among other things. They exert their effects through:
Genetic variations affecting AOC1 and HNMT genes seem to play a role in migraine susceptibility, due to their effects on histamine. Mutations in the MTHFR gene, which affects homocysteine metabolism, have also been linked to migraine susceptibility. People with the ‘T’ allele of C667T experience more frequent and severe migraines.
In one study, 20.3% of migraine sufferers had the homozygous transition (T/T) compared to just 9.6% of people without migraines. What’s more, the T/T variation was identified in a staggering 40.9% of people with migraine with aura. 9
In a pilot study, migraineurs with a genetic variation affecting MTHFR activity were given supplements providing folate, vitamin B6, and vitamin B12 for six months. Their migraine symptoms improved, and this improvement corresponded with a decrease in homocysteine levels. 10
SNPs to watch out for
Five single-nucleotide polymorphisms (SNPs) have been identified as playing a role in migraine susceptibility in Western populations:
- rs4379368, in the succinic HMG coenzyme A transferase (C7orf10) gene
- rs10504861, near the matrix metallopeptidase 16 (MMP16) gene
- rs10915437, near the adherens junctions associated protein 1 (AJAP1) gene
- rs12134493, upstream of the tetraspanin 2 (TSPAN2) gene
- rs13208321, within the four and a half LIM domains protein 5 (FHL5) gene
These SNPs are not associated with an overall increase in migraine incidence in Han Chinese or She Chinese peoples, but certain SNPs are strongly associated with particular types of migraine, i.e migraine with aura (MA) or without aura (MO): 11
- The CT genotype of rs4379368 – identified in 75% of patients with MA vs. 47.9% of patients with MO vs. 48.5% of non-migraineurs.
- The TT genotype of rs1050486 – identified in 8.3% of patients with MA vs. 0.5% of controls
- The CC genotype of rs12134493 – identified in 80.6% of patients with MO vs. 88% of controls.
Another study looked at She Chinese people with migraine and found the following:12
- Most migraineurs (58.7%) had the rs4379368 T allele compared to the C allele
- Migraineurs were more likely to have the CT (54%) or TT (31.7%) genotypes compared to non-migraineurs (48.0% for CT and 28.7% for TT)
- Female migraineurs were more likely to have the CT (53.8%) and TT (30.9%) genotypes compared to females without migraines (46.7% for CT and 27.6% for TT).
The CC genotype of rs4379368 and AA or AG genotype of rs13208321 were associated with a reduced risk of migraine in this population.
Practical steps for migraineurs
There are reasons why migraines tend to run in families. If you have a first-degree relative who suffers from migraines, you are almost twice as likely as average to experience migraines. This genetic component to the disease is far from straightforward, however, making it hard to identify specific actions migraineurs can take to prevent migraine attacks and reduce symptoms.
What we know so far is that many of the genetic mutations linked to migraines appear to affect how the body handles certain nutrients. Looking to your genotype could, therefore, offer clues as to how to help prevent migraines or reduce symptom severity.
If you need help getting started, Aaron wrote an excellent post on the types of DNA tests out there and how to choose one that works for you: Finding the best DNA test: Should I genotype or sequence? After you receive your results, this blog, along with our Genetics and Nutrition Guide, are excellent resources to keep handy during the next steps of your health-improvement journey.