Migraines impact over a billion people globally, and women are three times as likely than males to suffer from them.[ref] That’s a lot of people who have experienced the pain, mental fogginess, sensitivity to light, and overwhelming desire to crawl into a dark hole and hide from the world.
This article explores current research on why migraines happen and how genetics influences your risk of migraines. Understanding your genetic susceptibility can help you target solutions to try. The article ends with Lifehacks, a section on research-backed solutions combined with genetic connections. My hope is that you can use this information to find relief from the misery of migraines.
What is a migraine and why does it happen?
Migraine symptoms generally include:
- headache (usually lasting 4 to 72 hours)
- sensitivity to light, sounds, and smells
- nausea or vomiting
- sensory disturbances, aura (sometimes)
Somehow that list of symptoms doesn’t really do migraines justice.
For many, migraines are more than a headache — and, usually, the pain isn’t even the worst part. Instead, it’s the altered ability to think, irritability, nausea, slowed reflexes, and body temperature fluctuations.
The different types of migraines:
- migraine with aura (about 1/3 of people get auras)
- migraine without aura
- hemiplegic migraines (rare numbness/tingling on one side of the body)
Some people get premonitory or prodromal symptoms, which may appear up to a day or two before the migraine. Irritability, fatigue, food cravings, stiff neck, sensitivity to sounds, and yawning are some of the warning signs. On a PET scan, these symptoms accompany an increased blood flow to the hypothalamus.[ref]
Chronic migraines affect around 2% of the population. When you have more than 8 migraine days each month, your migraines are considered chronic.[ref]
What is going on in your brain when you have a migraine?
In the 1960s, researchers found that people with migraines had higher levels of a serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in their urine. This has prompted a lot of research over the past five decades into the relationship between the serotonergic system and migraines.
More recently, researchers have also investigated how CGRP (calcitonin gene-related peptide), neuroinflammation, and altered ion levels impact migraines.[ref]
Brain electrical storm: Migraines are often described as an excitatory state in the brain – also known as a state of hypersynchrony. Other researchers describe migraines as the brain over-responding to stimulus.[ref]
Long story short, research provides a lot of competing theories but no simple answers…
Migraine research breaks down into three paths:
- vascular causes (intracranial constriction and vasodilation of blood vessels)
- neural events (hyperexcitability and cortical spreading depression)
- nociceptive causes (pain pathways, activation of the trigeminal nerve, neuropeptides)
How serotonin plays a role in migraines:
Part of what happens in your brain during a migraine suggests vasodilation, which is the widening of blood vessels in your brain. Vasodilation causes decreased blood pressure. The vasodilation reaction results from an initial period of vasoconstriction; however, this may not be something that occurs in the rest of the body. The blood vessels inside the cranium don’t always act in the same manner as the rest of the body.[ref]
These vascular (blood vessel) causes may be due, at least in part, to serotonin signaling.
Serotonin (a.k.a. 5-hydroxytryptamine; 5-HTP) is a neurotransmitter that causes the signal to flow from one neuron to the next. It is found in abundance in both the digestive system and the brain.
Brain morphology, the way the neurons in the brain are shaped and formed, is also affected by serotonin. Keep in mind that serotonin is the signal, and it needs a receptor to cause an effect. There are different serotonin receptors found throughout the brain and intestinal tract, causing diverse effects of serotonin.[ref]
Genetic studies show a link between migraine susceptibility and a type of genetic variant known as a variable number tandem repeat in a serotonin transporter gene.[ref]
One big link between migraines and serotonin is that triptans, the most commonly used migraine prescription medication, work by amplifying the serotonin signal. Triptans act on the serotonin receptors (5-HT1B) in the blood vessels of the brain, constricting them and inhibiting the release of neuropeptides.[ref]
Using PET scans on people who had been migraine-free for at least 48 hours, researchers have begun studying the 5-HT1B (serotonin) receptor in the brain. These scans showed migraine patients with lower 5-HT1B binding than those without migraines.
The results of the study suggest two possibilities:[ref]
- One, is that lower serotonin receptors may either be causal (low serotonin causing migraines);
- or, two, that serotonin receptors decrease over time because of repeated exposure to migraines.
Melatonin and migraines:
Researchers also found low melatonin levels in people with chronic migraines when compared to a control population. It is notable, especially because serotonin is needed for the reaction in the pineal gland that produces melatonin.[ref]
tryptophan -> serotonin -> melatonin
One study explains that serotonin levels are low between migraine attacks, but are shown to increase at the beginning of a migraine. This initial surge of serotonin causes vasoconstriction and is thought to be part of the aura phase. When serotonin then breaks down (which happens pretty quickly), serotonin levels drop, causing vasodilation and headache pain.[ref]
Related article: Serotonin: How your genes affect this neurotransmitter
How does CGRP affect migraines?
Another key player in vasodilation during a migraine is the vasodilator CGRP. CGRP stands for calcitonin gene-related peptide and is released from the trigeminovascular system.
The trigeminovascular system includes both the trigeminal nerve neurons and the cerebral blood vessels.
The trigeminal nerve is the largest cranial nerve. It branches to the eyes and the jaw.
Time for a picture:
Notice how the trigeminal nerve goes to the root of the teeth. My teeth often hurt during a migraine…
The sensory nerve fibers of the trigeminal nerve can activate the release of neuropeptides, including CGRP, substance P, and neurokinin A. CGRP is a potent vasodilator making it important for both migraines and normal blood pressure regulation in the body. It is also thought to influence the pain portion of migraines.[ref][ref]
CGRP, mast cells, and neuroinflammation in migraines:
The release of CGRP seems to activate receptors on several different cell types, including mast cells.
The activated mast cells can degranulate, releasing histamine and pro-inflammatory compounds. This degranulation of mast cells causes a “prolonged state of excitation in meningeal nociceptors”. The meninges line the skull, and nociceptors are pain receptors.[ref][ref]
Here is an image of the meninges, which includes three layers surrounding the brain (dura mater, arachnoid, and pia mater).
The brain itself doesn’t have pain receptors, but there are pain receptors and blood vessels throughout the meninges.
So what exactly are mast cells, and could they cause migraines?
Mast cells are part of the body’s immune system and are found in all of our body tissues. They stand ready to release a payload of histamine, serotonin, and inflammatory cytokines when activated by a pathogen, allergic reaction, or other signaling molecules (such as CGRP).[ref]
Some researchers theorize that mast cells and neuroinflammation are at the root of migraine pathology.
- Histamine, released when mast cells degranulate, is elevated during migraine attacks.[ref]
- Tryptase is also released during degranulation and is thought to sensitize pain receptors.[ref]
Other researchers theorize that central sensitization is at the root of migraines. Central sensitization involves enhanced signaling through pain pathways and is caused by overexcited pain receptors and decreased inhibition. This term applies to various pain-related conditions such as peripheral neuropathy, IBS, and migraines.[ref]
Related article: Mast cells: MCAS, genetics, and solutions
Can an electrolyte imbalance cause migraines?
Another observation of researchers is that ion levels are often altered in migraineurs.
Sodium, potassium, calcium, and chloride ions are integral parts of how neurons fire. Neurons send signals to other neurons by transmitting electrical impulses carried by positive and negative ions.
A recent study found that sodium (Na) levels were higher in the cerebrospinal fluid (CSF) of people with migraines compared with a control group. It backs up previous work that also showed an increase in CSF sodium levels during a migraine. The other ion levels – calcium, potassium, and magnesium – did not change, nor did the sodium levels in the plasma.[ref][ref]
There have been large studies trying to determine if sodium intake affects migraine risk. One study found that for women with low BMI and men at any BMI, a low sodium intake slightly increased the risk of headaches and migraines.[ref]
Another study found that people who have migraines have, on average, lower magnesium levels than a healthy control group.[ref]
What causes the aura in migraines?
A migraine aura is the altered sensory perception, such as visual alterations like sparkles and the waviness of images.
The Mayo Clinic explains that “A visual aura is like an electrical or chemical wave that moves across the visual cortex of your brain. The visual cortex is part of your brain that processes visual signals. As the wave spreads, you might have visual hallucinations.” Sensory auras may also cause tingling and problems with speaking.
The aura is thought to result from cortical spreading depression (CSD). CSD is a massive depolarization of neurons that occurs in the brain. A wave of hyperexcitability of the neurons is followed by a wave of inhibition. This depolarization causes the release of potassium, hydrogen, nitric oxide, and glutamate ions, as well as arachidonic acid.[ref]
Here is a visual:
This cortical-spreading depression causes the pain receptors in the meninges to start firing after a bit of a delay. The firing of the pain receptors continues for a long while. Animal studies show that inducing CSD by various means caused the pain receptors to start firing about 14 minutes later.[ref]
Bringing the various research studies together:
Sometimes when reading a bunch of research studies on a topic, I feel like the analogy of the blind men describing different parts of an elephant.
To recap, here’s what research shows on migraines:
- We have the involvement of the serotonin system that can cause changes in blood vessel dilation.
- The trigeminal neurovascular system releases CGRP, which is a vasodilator that also acts on mast cells.
- Activation of mast cells causes sterile neuroinflammation. Mast cells release histamine, tryptase, and other inflammatory cytokines.
- The inflammation acts on the meninges, the lining of the cranium, causing pain.
- If the migraine is preceded by an aura, the cortical spreading depression may be what is triggering the nociceptors (pain receptors) in the meninges to fire.
Migraine triggers:
People often identify various triggers for their migraines. Traveling, foods, stress, hormones, odors, sleep deprivation, and flashing/bright lights often top the list.
One problem with identifying migraine triggers is that the premonitory or prodromal symptoms (up to a day or two ahead of the migraine) may overlap with what people identify as triggers.
- Food cravings are one prodromal symptom, and various food triggers are often blamed. Thus, it is hard to separate the food craving due to prodromal symptoms from the unusual food that may seem like a trigger.
- Altered sleep patterns are another thing identified as a trigger which could be a prodromal symptom. Instead of altered sleep causing a migraine, the prodromal migraine causes altered sleep.
- Bright light sensitivity could also fall into this conundrum.
While sometimes difficult to pin down, it does seem that there are specific triggers for some people. These include certain foods, scents, hormonal changes, and weather changes.
Which foods trigger migraines?
A lot of people have identified specific foods as being likely to cause migraines for them. Some of these include gluten, wine, cheese, and chocolate.
Genetics may come into play here:
- Some people are likely to be intolerant to suddenly consume a lot of foods with high tyramine levels. (Read more about tyramines increasing blood pressure)
- Genetic variants also link histamine intolerance to an increased risk of chronic migraines. (Read more about genes related to histamine intolerance.)
- Other top triggers for migraines include MSG and beer.[ref][ref]
Studies show, though, that ‘overall dietary patterns’ don’t relate to migraine risk. Dietary patterns refer to the big picture of your diet – vegetarian, carnivore, keto, fruitarian, etc. One study did show that women with migraines eat a slightly higher amount of fat and a slightly lower amount of protein on average.[ref][ref]
Why do scents trigger migraines?
Some people are sensitive to odors and find that certain smells (floral, perfumes, strong cleaning chemicals, paint, gasoline, plastics) can trigger migraines.[ref]
It isn’t just all in your head (pun intended). A small study looked at cerebral blood flow in people with migraines vs. a control group. The migraineurs had altered blood flow in certain areas of the brain when stimulated with odors.[ref]
What causes menstrual migraines?
One really common migraine trigger for many women is the change in estrogen levels around the time of their period or during ovulation. Migraines often go away for these women during pregnancy and after menopause.
Why would a change in estrogen levels trigger migraines? One reason is that mast cells have estrogen and progesterone receptors. The fluctuation of estrogen can cause mast cell degeneration and subsequent migraine pain.
Migraine Genotype Report:
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Membership lets you see your data right in each article and also gives you access to the members’ only information in the Lifehacks sections.
Researchers estimate that migraines are ~50% due to heredity factors (such as genetic variants), which combine with environmental factors (hormones, high histamine foods) to cause migraines.[ref][ref]
How can you use this info? Identifying the genetic variants you carry that influence migraine susceptibility may help you figure out why YOU get migraines, and, hopefully, which migraine ‘lifehacks’ will be most effective for you. Keep in mind that your 23andMe or AncestryDNA only covers part of your genes, so this section doesn’t cover every variant linked to migraines.
Pain Receptors Genes Associated with Migraines:
TRPM8 gene: encodes the cold and menthol receptors. When skin temperatures decrease by 15 degrees C, it hurts due to the activation of this pain receptor.[ref]
Check your genetic data for rs10166942 (23andMe v4, v5; AncestryDNA):
- C/C: decreased risk of migraines[ref][ref]
- C/T: slightly decreased risk of migraines
- T/T: higher risk of migraines, less sensitive to cold[ref]
Members: Your genotype for rs10166942 is —.
CGRP Pathway Genes Associated with Migraines:
CGRP and brain-derived neurotrophic factor (BDNF) coexpress on the trigeminal nerve terminals.[ref]
BDNF Gene: codes for brain-derived neurotrophic factor
Check your genetic data for rs6265 (23andMe v4, v5; AncestryDNA):
- T/T: increased risk of migraines[ref]
- C/T: slightly increased risk of migraines
- C/C: typical risk of migraines
Members: Your genotype for rs6265 is —.
MMP16 gene: Large genome-wide association studies found a genetic variant on chromosome 8 near the MMP16 gene that is consistently associated with a reduced risk of migraines (without aura). The MMP16 gene codes for an enzyme involved in the breakdown of the extracellular matrix and tissue remodeling.
Check your genetic data for rs10504861 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs10504861 is —.
Methylation Pathway Genes Associated with Migraines:
Methylation is important in converting serotonin into melatonin.
NNMT gene: The nicotinamide-N-methyltransferase (NNMT) gene codes for an enzyme that transfers a methyl group from SAMe to nicotinamide. There are links between the variants of this gene and increases in homocysteine levels.
Check your genetic data for rs694539 (23andMe v4, v5; AncestryDNA):
- TT: a 4-fold increase in the risk of migraines in women[ref]
- CT: typical migraine risk
- CC: decreased migraine risk
Members: Your genotype for rs694539 is —.
MTHFR gene: Several studies have linked the MTHFR C677T variant to an increased risk of migraines, but not all of the studies agree. This one may be a mild increase in risk or perhaps for just certain population groups.[ref]
Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):
- G/G: typical risk of migraine
- A/G: slightly increased risk of migraines
- A/A: slightly increased risk of migraine[ref][ref][ref]
Members: Your genotype for rs1801133 is —.
Serotonin Pathway Genes Associated with Migraines:
C7orf10 gene: codes for an enzyme involved in the production of glutarate from tryptophan (precursor for serotonin) and lysine.
Check your genetic data for rs4379368 (23andMe v4, v5; AncestryDNA):
- C/C: typical risk of migraines
- C/T: decreased risk of migraines
- T/T: decreased risk of migraines (Caucasian ancestry)[ref] (opposite found in a Chinese population)[ref]
Members: Your genotype for rs4379368 is —.
SLC6A4 gene: codes for a serotonin transporter.
Check your genetic data for rs2066713 (23andMe v4,v5; AncestryDNA):
- G/G: typical risk of migraines
- A/G: decreased risk of migraines
- A/A: decreased risk of migraines[ref]
Members: Your genotype for rs2066713 is —.
Note: a lot of other genetic variants in the serotonin transport and receptor genes have been studied and found not to be involved in migraine risk.
Histamine / Mast Cell Activation Pathway Genes Associated with Migraines:
AOC1 gene: codes for diamine oxidase, which breaks down histamine in the gut.
Check your genetic data for rs1049793 (23andme v4; AncestryDNA):
- C/C: typical
- C/G: increased risk of migraines
- G/G: increased risk of migraines[ref] (reduced DAO enzyme, which breaks down histamine from foods)
Members: Your genotype for rs1049793 is —.
Check your genetic data for rs10156191 (23andMe v4; AncestryDNA):
- C/C: typical
- C/T: increased risk of migraines, especially in women
- T/T: increased risk of migraines, especially in women[ref] (reduced DAO enzyme, which breaks down histamine from foods)
Members: Your genotype for rs10156191 is —.
Inflammatory Pathway Genes Associated with Migraines:
TNF gene: tumor necrosis factor-alpha is one of the body’s main pro-inflammatory cytokines.
Check your genetic data for rs3093664 (23andMe v5; AncestryDNA):
- G/G: increased risk of menstrual migraines[ref] (increased inflammatory response)
- A/G: increased risk of menstrual migraines
- A/A: typical
Members: Your genotype for rs3093664 is —.
Check your genetic data for rs1800750 (23andMe v4, v5; AncestryDNA):
- G/G: typical risk of migraines
- A/G: increased risk of migraines
- A/A: increased risk of migraines[ref] (increased inflammatory response)
Members: Your genotype for rs1800750 is —.
Check your genetic data for rs1800629 (23andMe v4, v5; AncestryDNA):
- A/A: increased risk of migraines[ref] (increased inflammatory response)
- A/G: increased risk of migraines
- G/G: typical
Members: Your genotype for rs1800629 is —.
IL1A gene: codes for interleukin-1A, which is part of the body’s inflammatory response
Check your genetic data for rs17561 (23andMe v4; AncestryDNA):
- C/C: typical
- A/C: increased risk of migraines
- A/A: increased risk of migraines[ref] (increased inflammatory response)
Members: Your genotype for rs17561 is —.
Ion and neurotransmitter pathways associated with migraines:
KCNK18 gene: encodes a potassium receptor that regulates the excitability of neurons in pain, including the trigeminal nerve
Check your genetic data for rs869025175 (23andMe v5):
- I/D: rare mutation, strongly linked to migraines due to potassium receptor loss of function mutation[ref]
- I/I: typical
Members: Your genotype for rs869025175 is —.
MTDH gene: “MTDH is known to downregulate EAAT2 (excitatory amino acid transporter 2), a major glutamate transporter, and could thus affect glutamate regulation at a synaptic level”[ref]
Check your genetic data for rs1835740 (23andMe v4, v5; AncestryDNA):
Members: Your genotype for rs1835740 is —.
Cholesterol Pathway Genes Associated with Migraines:
LRP1 gene: codes for an LDL cholesterol receptor. Migraine intensity and frequency link (in a small study) to cholesterol levels.[ref]
Check your genetic data for rs11172113 (23andMe v4, v5; AncestryDNA):
- C/C: slightly decreased risk for migraines[ref]
- C/T: slightly decreased risk for migraines
- T/T: typical risk for migraines
Members: Your genotype for rs11172113 is —.
Menstrual Migraine Specific Variants:
NRP1 gene: encode neurolipin 1
Check your genetic data for rs2506142 (AncestryDNA):
- G/G: 2-fold increased risk of menstrual migraines[ref]
- A/G: increased risk for menstrual migraines
- A/A: typical
Members: Your genotype for rs2506142 is —.
Lifehacks: Preventing Migraines
Below are some research-based options for either reducing the frequency or taking away the pain of migraines. This members-only section includes lifehacks, including supplement research and topical migraine relief details. Additionally, you will see your genetic data matched to specific recommendations. Consider joining today to see the rest of this article.
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Related Articles and Topics:
MTHFR and Migraines
The MTHFR C677T variant increases the risk of migraines. Learn how to check your genetic data and how to mitigate the risk.
PMS, Genetics, and Solutions
A lot of women know the moodiness and brain fog that comes with premenstrual syndrome (PMS). Studies estimate that PMS is up to 95% heritable – which means that it has a huge genetic component. Learn about the genes and find out which solutions may actually work for you.
Serotonin Genes
Serotonin is a neurotransmitter that is important in depression, sleep, and many other aspects of health. Learn how your genetic variants in the serotonin receptor genes impact their function.
Histamine Intolerance
High histamine levels can cause a variety of symptoms, including migraines, hives, sinus drainage, and stomach problems.
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