Observed genes

Polygenic score

Influential genes: CACNA1A, HMOX2, NPFF

In a genome-wide association study of migraines, a risk variant in the HMOX2 gene was found to be specifically associated with migraine with aura.

Mutations in the CACNA1A gene have been associated with familial hemiplegic migraine (FHM)

Although the precise function of NPFF in migraines remains incompletely understood, it is believed to play a role in various mechanisms associated with inflammation and the modulation of pain.

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Overview

Migraine is a primary headache, meaning it is unrelated to other conditions, characterized by recurrent episodes of unilateral, localized pain frequently accompanied by nausea, vomiting, and sensitivity to light and sound.

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The exact cause of migraine is unknown, although various factors are thought to contribute to its development and severity. These factors can either be genetic or a result of temporary changes in the chemicals, nerves, and blood vessels in the brain.

Migraine is associated with cardiovascular, psychiatric, and sleep disorders. It is the second most disabling condition worldwide. The affected patients report missing work or school, cannot perform daily activities, or reduced participation in social and family activities. 

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Chronic migraine is associated with higher headache-related disability/impact, medical and psychiatric comorbidities, health care resource use, direct and indirect costs, lower socioeconomic status, and health-related quality of life.[1]

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Prevalence & Risk factors

Migraine is a common health condition affecting around one in every five women and around one in every 15 men. It usually appears early in adulthood, peaking at 30-39 years.[2] Well-known triggers contribute to migraine attacks: 

• Poor sleeping habits
• Emotional stress
• Weather changes
• Hormonal changes in women related to menstruation or oral contraception
• Use certain substances such as alcohol or nicotine
• Consumption of chocolate, dairy, and others

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Even though its cause is unclear, there is a high correlation with a genetic predisposition, being present in up to 60% of first-degree relatives.[3]

Genetics

Migraine is a complex disorder composed of several subtypes. The most common forms are migraines without aura (MO) and migraines with aura (MA). Most of them have a polygenic nature (cooperation of multiple variants with small effects) with heredity between 34-64%. In addition to genetics, lifestyle and the environment (stress or sleep) also contribute to the development of migraine.

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Identification of genes and variants associated with monogenic disorders has been enabled by progress in the field of new generation sequencing (NGS) and genome-wide association studies (GWAS) conducted on large case-control cohorts have given us information about common polygenic forms of migraine. Common variants include single nucleotide polymorphisms (SNPs), insertions and deletions, short tandem repeats, or copy number variants.[4] Large GWAS meta-analysis of migraine identified 123 potential risk loci connected to migraine.[5]

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There are several rare monogenic subtypes, caused by autosomal dominant mutations in genes encoding ion channels. Research studies focused on the rare subtypes have uncovered mutations in CACNA1A, ATP1A2, and SCN1A genes. These genes are eminent for the transport of ions in synapses (space between nerve cells) and the transmission of signals. Furthermore, a study focused on MA has pointed out a frameshift mutation on the KCNK18/TRESK gene, which is considered causative.

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The assumptions of the effect of X-chromosome hormones are also a current research topic, given the fact that the majority of migraineurs are females (3:1). Moreover, mitochondrial DNA and epigenetics might play a certain role as well, however, these hypotheses need further investigation.[6] 

Genetic testing allows us to detect whether you have the predisposition to develop this disease. In Macromo, we use polygenic risk scores and causative evidence-based genetic variants for evaluation. The polygenic risk score (PRS) represents the total number of genetic variants that increase an individual's risk of developing a particular disease. All variants across their genome are summed and ranked according to their effect on disease development.

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Signs & Symptoms

This condition is characterized by recurrent attacks passing through several stages. 

1. The prodromal phase is not always present, but it can appear one to two days before the beginning of the headache when the person starts to yawn excessively, experience sudden hunger or a lack of appetite, and mood changes.
2. Typically preceding the headache, one can suffer neurological symptoms such as visual, sensory, and speech disturbances, or even, in rarer cases, paresis and dizziness. This pre-headache stage is the so-called “aura”.
3. The headache itself has its characteristic signs and symptoms. They are unilateral, lasting up to 24 hours, and progress to pulsating throbbing and pounding pain. Exercise can worsen the pain intensity. Light and sound sensitivity, nausea, and vomiting are commonly associated with migraines.
4. The postdrome stage, the last one, can be present when muscle weakness or feeling of exhaustion/euphoria settles in.

These patterns may differ and not always follow the four stages.

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Diagnosis

The diagnosis is clinical and based on the history of attacks. The most important step is to rule out any causes that suggest more complicated diagnoses.

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Therapy

Unfortunately, there is currently no cure for migraine. Treatment is aimed at easing the symptoms and reducing their incidence. 

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Patients suffering from recurrent migraines should be aware of the specific triggers and avoid them. General steps to manage migraine include staying hydrated, taking paracetamol, NSAIDs or aspirin, and combinations including caffeine. In severe cases, migraine-specific agents such as triptans or ergotamine can be prescribed (never in the combination of these two).

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Prevention

General prevention starts with identifying and subsequently avoiding triggers. 

• Lifestyle modification, a healthy diet, moderate exercise, and a regular sleep schedule are essential to help patients suffering from recurrent migraines. 
• Acupuncture is rising in popularity as a way to treat medication-resistant migraines.
• A migraine diary can help identify triggers and medication which led to an attack by logging and describing each episode.

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Prognosis

Migraine itself is a chronic disorder with a highly variable long-term prognosis. In many, it may have a very benign prognosis. In some, it persists and may be associated with a small increased risk of ischemic stroke and mental health problems.

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Recommendations

• If you experience an intense, unilateral, and pounding headache lasting less than 24h, consider visiting a doctor.
• Improve your health by avoiding triggers and managing stressful situations if you are predisposed to migraines.

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