Are migraines genetic? What is a migraine, what are the symptoms and what are the causes?

If you are unlucky enough to suffer from migraines, you will know that a migraine is not just a bad headache. The headache and accompanying symptoms can be extremely debilitating and often leave sufferers with little choice but to lie in bed in the dark. The symptoms can last for several days, leading to absences from work and social isolation among family and friends. Have you ever wondered what a migraine is or what causes it? In this article, we will answer these questions and more.

What is the difference between a headache and a migraine?

Migraine is one type of headache. There are many types of headaches, including cluster headaches, ice-pick headaches, rebound headaches, and tension headaches. Migraine is a primary headache disorder, which means the diagnosis is the headache. A secondary headache is one caused by another health condition, such as hypertension or sinusitis [1, 2].

What is a migraine and what are the main symptoms?

A migraine is a neurological disorder. It is a type of headache associated with severe, throbbing pain that is often on one side of the head and gets worse with movement, as well as sensitivity to light, sound and smells. The location of pain, course, duration and symptoms are highly variable and symptoms vary during different stages of the attack.

Furthermore, the time interval between attacks varies, and migraines are categorized as chronic (occur on more than 15 days in a month) or episodic (occur on less than 15 days in a month). Having between two and four a month is typical [2, 3].

When do migraines begin and who can get them?

The first migraine attack often occurs in childhood, or during teenage years, but they can begin at any time in adulthood. Migraines usually decrease in intensity and frequency after around the age of 50 and especially after menopause [3, 4].

Anyone can have migraines, although they are three times more common in women [2, 3].

The stages of a migraine attack and symptoms at each stage

A typical migraine attack has four stages each with a range of symptoms [2, 3].

1. Prodome

This stage can occur hours or days before the onset of the headache but might not occur at all. Symptoms of this stage include

• Sensitivity to light, sound or smells
• Nausea
• Fatigue
• Problems sleeping
• Excessive yawning
• Food cravings
• Loos of appetite
• Mood changes, irritability, depression
• Speech difficulties
• Severe thirst
• Bloating
• Increased urination, constipation or diarrhea
• Muscle stiffness

2. Aura

At least 20% of migraine sufferers experience symptoms, collectively known as an aura, before the headache starts. An aura can be over quickly or last up to an hour. In some cases, people will have an aura but will not develop a headache. The symptoms of a migraine aura are variable but often include visual disturbances; there may also be other symptoms. The symptoms are reversible and include

• Flashing, flickering or shimmering dots, lights or sparkles
• Blind spots
• Blurred vision, tunnel vision or temporary loss of vision
• Seeing zigzag, wavy or jagged lines
• Numb or tingling skin, especially on one side of the body, one arm or one side of the face
• Changes in smell or taste
• Ringing in ears
• Difficulty speaking

3. Headache

A migraine headache typically lasts from 4 to 72 hours. Symptoms include

• Severe, throbbing pain on one side of the head
• Sensitivity to light, sound and smells
• Worsening pain with movement
• Nausea and vomiting
• Stomach pain
• Loss of appetite
• Irritability
• Sweating or shivering
• Fatigue

4. Postdrome

This stage is sometimes called a migraine hangover and can last 1-2 days. Symptoms include

• Difficulty concentrating
• Depression
• Fatigue and weakness
• Feeling very happy
• Food cravings or loss of appetite

There are many migraine subtypes

Although migraine is one type of headache, there are several types of migraines. These differ in the occurrence of an aura or the presentation of symptoms. Migraine without aura is the most common type (around 75% of cases) [5] followed by migraine with aura [2, 3].

Subtypes include

• Migraine with aura
• Migraine without aura
• Abdominal migraine: often seen in children, it causes severe stomach pain, nausea and vomiting
• Chronic migraine
• Hemiplegic migraine: temporary paralysis or weakness on one side of the body
• Menstrual migraine: migraine that starts up to 2 days before to 3 days after a menstrual period
• Migraine with brainstem aura: vertigo, slurred speech and dizziness occur before the headache, which starts at the back of the head
• Ocular (retinal) migraine: temporary partial or complete loss of vision in one eye and pain that starts behind the eye before spreading to the rest of the head
• Status migrainosus: a severe migraine that can last more than 72 hours and require hospitalization
• Silent (acephalgic) migraine: aura without headache
• Vestibular migraine: associated with balance problems

How common is migraine?

If you suffer from headaches and/or migraines, you are not alone, Headaches are very common and migraines account for a large proportion of headaches. In 2016, the WHO estimated that half to three quarters of all adults aged 18-65 years had suffered from a headache in the previous year, and of these, at least 30% reported migraines [6].

In 2016, just over 1 billion people were estimated to suffer from migraine, with the global age standardized prevalence being 14.4% overall (18.9% in women and 9.8% in men) [7].

This is similar to prevalence data from a recent review of 357 prevalence studies for headache disorders, which reported that 52.0% of the populations in these studies had a headache disorder and 14.0% had migraine. In both cases, the values were slightly higher for females compared to males when the results were analyzed by gender [8].

Worldwide, around 1 in 50 people are thought to suffer from chronic migraines [5]. With so many sufferers, it is clearly a leading cause of workplace absence and years lived with disability (YLDs). In fact, according to the 2019 Global Burden of Disease study, headache disorders (including migraine) reportedly caused 46.6 million YLDs worldwide in 2019, which was 5.4% of the total YLDs. Overall 88.2% of the headache disorder YLDs in 2019 were due to migraines. Headache disorders ranked third in the causes of YLDs for all age groups and both genders behind lower back pain and depressive disorders, making it one of the most disabling conditions. It is interesting to note that headache disorders ranked in first place in the 15-49 year group of combined gender. Analysis of more detailed categories ranked migraine second in causes of YLDs for both genders and all ages combined, but first in females aged 15-49 years [9, 10].

There are some known risk factors

The following are risk factors for migraines [3]:

• Being female
• Having a close relative with migraines
• High stress levels
• Other medical conditions, including depression, anxiety, bipolar disorder, and epilepsy
• Smoking

What causes migraines?

Migraine is a complex disorder, meaning there is no single, identifiable cause and the cause is a combination of genetic, environmental and lifestyle factors. The exact changes that take place in the brain and lead to a migraine attack, why they happen, and how environmental factors are involved, are not fully understood.

Activation of a region of the brain called the hypothalamus may be the cause of some of the prodromal symptoms, such as yawning, mood changes and tiredness [11].

Spreading depolarization (change in electrical charge distribution within a cell) across the cortex (called cortical spreading depression) is responsible for the aura [12], and it has been suggested that the absence of an aura is related to the area of the brain that is affected [5].

The headache phase is probably due to overactive nerve cells sending abnormal pain signals to the brain that in turn, triggers the release of chemicals (neurotransmitters or neuropeptides) that cause the lining of the blood vessels in the brain and the membranes covering the brain to swell, causing pain. This alters the flow of blood to the brain, which also contributes to the pain [2, 3, 4]. Activation of the trigeminovascular system (part of the nervous system in the face and head) has a role in migraines, and several neuropeptides that affect blood vessels and are thought to be involved in causing migraine pain, are associated with the trigeminovascular system. They include calcitonin gene-related peptide (CGRP), substance P and neurokinin A [11, 12]. Migraine pain is typically made worse by movement, which may be due to nerve cells becoming overly sensitive (called sensitization) [12].

Genetic causes of migraine

It is well known that migraines run in families, and it is estimated that up to 80% of people with migraines have a close relative who is also a migraine sufferer. Furthermore, the child of a parent with migraines has a 50% chance of also having them, and if both parents have migraines, the child has a 75% risk. [2]. Despite this, there is no clear pattern of genetic inheritance [4]. It has also been suggested that migraine triggers are hereditary [3].

The exact genetic cause of migraines is unknown. It is likely that for most cases of migraine, there is no single genetic cause; rather migraine is polygenic and is caused by the interaction between several genes. The exceptions are familial hemiplegic migraine (FHM) and possibly some cases of familial migraine with aura, which are monogenic (have a single genetic cause).

Genome-wide association studies (GWAS) are used to identify genetic variants with a significant association with a particular disease. For migraines, GWAS have found variants in genes associated with the controlling the diameter of blood vessels and vascular pathways, as well as in genes that are associated with levels of glutamate (a neurotransmitter) or neuron activity [4, 13]. One large GWAS of 59,674 migraine sufferers and 316,078 healthy controls identified 44 single-nucleotide polymorphisms in 38 genes associated with polygenic forms of migraine. Some of these genes were found in previous association studies [13]. However, more research is required to identify clear causal associations.

The fact that migraine is more common among females has led researchers to investigate whether there is a possible X-chromosomal component to the disease; in other words, whether a genetic variant that causes migraines is located on the X chromosome. Linkage analysis studies, which trace disease in families, have in fact found migraine susceptibility loci (regions) on the X chromosome, but have not yet identified any genes or genetic variants associated with migraine within them [13].

Epigenetics may also be important in the migraine. Epigenetic changes affect whether a gene is expressed. A gene that is expressed is “switched on” and able to provide the instructions for protein production. Some epigenetic changes are a normal part of development, while others are caused by diet, lifestyle and behaviors [14]. Some environmental factors (known as triggers) associated with migraine, such as stress and eating certain foods, as well as hormonal changes during the menstrual cycle, could influence epigenetic changes and gene expression [13].

Familial hemiplegic migraine: an inherited form of migraine with aura

One type of migraine, familial hemiplegic migraine (FHM), has a known monogenic cause. This rare, inherited form of migraine with aura has four subtypes each based on a distinct genetic cause. The aura is always accompanied by weakness on one side of the body, and there may be drowsiness, confusion and speech difficulties. In some cases, the headache may be particularly severe and require hospitalization. There may also be fever, seizures, prolonged weakness, or even coma, and in some cases, there will be permanent movement difficulties (ataxia) and involuntary eye movements (nystagmus) [15].

The four subtypes are [16, 17]

• FHM type 1, which is caused by genetic variants in the CACNA1A gene on chromosome 19 and is the most common type. It is associated with ataxia and nystagmus in 40-50% of cases.
• FHM type 2, which is caused by genetic variants in the ATP1A2 gene on chromosome 1. It is associated with seizures.
• FHM type 3, which is caused by genetic variants in the SCN1A gene on chromosome 2.
• FHM type 4, which is diagnosed in the absence of a genetic variant known to cause FHM.

The genes CACNA1A, ATP1A2 and SCN1A are important for the transport of ions across cell membranes that is essential for communication between nerve cells in the brain and other parts of the nervous system. Changes in the ion balance affects the release and uptake of neurotransmitters in the brain, which ultimately leads to headaches and other symptoms of FHM [15].

The causal genetic variants are inherited in an autosomal dominant manner. This means that a person with FHM has a 50% chance of passing it on to a child. FHM can also occur sporadically (called sporadic FHM), and may be due to a spontaneous genetic change in CACNA1A or ATP1A2, although some people with FHM do not have either of these genetic variants. The onset of FHM can also appear to be sporadic, when in reality the person has inherited a genetic variant from an asymptomatic parent [18].

Gene variants in the genes PRRT2 and SLC4A4 have also been identified in familial migraine [15].

Genetic testing is useful to determine the genetic cause and subtype where there is a family history of FHM.

Certain triggers can lead to a migraine attack

Although it is not clear exactly what brings on a migraine, certain environmental or lifestyle factors can trigger a migraine attack. Triggers are variable and personal; they include [1–3]

• Certain foods or drinks, e.g., aged cheese, chocolate, alcohol, foods containing certain chemicals or preservatives
• Missing meals
• Too much caffeine or caffeine withdrawal
• Dehydration
• Disrupted sleep, irregular sleeping patterns or extreme tiredness
• Flashing or bright lights
• Hormone fluctuations, e.g., caused by menstrual periods
• Smells, e.g., strong perfume, smoke
• Stress, anxiety, or other extreme emotions
• Weather changes

Triggers may not always result in a migraine attack; however, knowing personal triggers means some sufferers can predict the occurrence of their migraine, for example, when they always occur at a certain time in the menstrual cycle or after a period of extreme stress [19] and may help them manage their condition. Keeping a headache diary is a good way to determine personal triggers.

A migraine will often start in the early morning, and this may be due to sleep disturbances, dehydration or caffeine withdrawal, as well as natural pain relieving hormones being at their lowest levels [19, 20].

Treatment and management of migraines

Migraines are treated with pain medication early in an attack (over-the-counter medications or prescription medications, e.g., triptans).  Taking pain relief as early as possible is especially important for patients who suffer from vomiting, which will reduce the effectiveness of the medication [20].

During an attack, some people may also find it helpful to lie in the dark, keep calm and still, apply a cold cloth to the forehead or neck or apply pressure to the temples or scalp. Sleep is usually helpful.

The management of migraines includes preventative prescription medication for chronic migraine sufferers that aims to reduce the frequency or severity of migraine attacks. Non-pharmaceutical approaches include mindfulness and stress management (meditation, yoga, breathing exercises), cognitive behavior therapy, and biofeedback, as well as lifestyle modifications (maintaining a regular sleep and meal schedule, drinking enough water, and exercise) to remove or minimize potential triggers [2, 3].

Outlook for migraine sufferers

Migraines may change in frequency or intensity over time and may become chronic; however, they generally decrease later in life, especially after menopause. Migraines cannot be cured but can be managed with pain medication. Having knowledge of personal triggers means migraine sufferers can avoid them and this might help manage their conditions.

Conclusion

Migraine is a complex neurological disorder that presents as a headache associated with severe, throbbing pain on one side of the head, often with sensitivity to light, sound and smells, as well as nausea and vomiting. Migraine affects women more often than men and often runs in families. Most forms of migraine do not have a single genetic cause. They are caused by a combination of genetic, environmental and lifestyle factors that lead to altered pain signals in the brain and inflammation of blood vessels and membranes surrounding the brain, and ultimately to the symptoms of a migraine attack.

It is a common cause of illness and missed work, especially for young adults and middle-aged women, and although some people have success with lifestyle modifications to remove or minimize potential triggers, it remains a debilitating condition that negatively affects the quality of life. Preventative treatments are suitable for some people. Further research to determine the exact genetic cause could enable the development of targeted prophylactic treatment or predict the response to treatment. This would not only improve life for millions of migraine sufferers but would potentially ease the burden on public health systems and society caused by missed workdays.

References

[1] 14 Types of Headaches and How to Treat Them. Healthline. Retrieved 27 February 2023 from https://www.healthline.com/health/headache/types-of-headaches#primary-headaches

[2] Migraine Headaches. Cleveland Clinic. Retrieved 27 February 2023 from https://my.clevelandclinic.org/health/diseases/5005-migraine-headaches

[3] What is Migraine? WebMD. Retrieved 27 February 2023 from https://www.webmd.com/migraines-headaches/migraines-headaches-migraines#091e9c5e80008e62-4-9

[4] Migraine. National Library of Medicine. MedlinePlus. Retrieved 22 March 2023 from https://medlineplus.gov/genetics/condition/migraine/

[5] Pescador Ruschel MA, De Jesus O. Migraine Headache. [Updated 2023 Feb 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560787/

[6] Headache disorders. 8 April 2016. World Health Organization. Retrieved 27 February 2023 from https://www.who.int/news-room/fact-sheets/detail/headache-disorders

[7] GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018 Nov;17(11):954-976. doi: 10.1016/S1474-4422(18)30322-3. Erratum in: Lancet Neurol. 2021 Dec;20(12):e7. PMID: 30353868; PMCID: PMC6191530. https://www.thelancet.com/action/showPdf?pii=S1474-4422%2818%2930322-3

[8] Stovner, LJ et al. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain 23, 34 (2022). https://doi.org/10.1186/s10194-022-01402-2

[9] Steiner, TJ et al. Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J Headache Pain 21, 137 (2020). https://doi.org/10.1186/s10194-020-01208-0 https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-020-01208-0

[10] Headache disorders — Level 3 cause. Institute for Health Metrics and Evaluation. Retrieved 24 March 2023 from http://www.healthdata.org/results/gbd_summaries/2019/headache-disorders-level-3-cause

[11] Goadsby PJ et al. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017 Apr;97(2):553-622. doi: 10.1152/physrev.00034.2015. PMID: 28179394; PMCID: PMC5539409. https://journals.physiology.org/doi/epdf/10.1152/physrev.00034.2015

[12] Shankar Kikkeri N, Nagalli S. Migraine with Aura. [Updated 2022 Dec 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554611/

[13] Bron C et al. Exploring the Hereditary Nature of Migraine. Neuropsychiatr Dis Treat. 2021 Apr 22;17:1183-1194. doi: 10.2147/NDT.S282562. PMID: 33911866; PMCID: PMC8075356. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075356/pdf/ndt-17-1183.pdf

[14] What is Epigenetics? CDC Centers for Disease Control and Prevention. Retrieved 23 March 2023 from https://www.cdc.gov/genomics/disease/epigenetics.htm

[15] Familial hemiplegic migraine. National Library of Medicine. MedlinePlus. Retrieved 22 March 2023 from https://medlineplus.gov/genetics/condition/familial-hemiplegic-migraine/

[16] Familial hemiplegic migraine. Genetic and Rare Diseases Information Center of the National Institutes of Health. Retrieved 22 March 2023 from https://rarediseases.info.nih.gov/diseases/10975/familial-hemiplegic-migraine

[17] Jen JC. Familial Hemiplegic Migraine. 2001 Jul 17 [Updated 2021 Apr 29]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1388/

[18] Sporadic hemiplegic migraine. National Library of Medicine. MedlinePlus. Retrieved 22 March 2023 from https://medlineplus.gov/genetics/condition/sporadic-hemiplegic-migraine/

[19] Migraine. National Institute of Neurological Disorders and Stroke. Retrieved 22 March 2023 from https://www.ninds.nih.gov/health-information/disorders/migraine

[20] Understanding Why You Are Waking Up with a Migraine. Healthline. Retrieved 22 March 2023 from https://www.healthline.com/health/migraine/waking-up-with-a-migraine#causes