New genetic clues of the potential causes of migraine

Each year, the Lundbeck Brain Prize [read more here] is awarded to one or more researchers who have had a ground-breaking impact on brain research. In 2021, there were four winners who each contributed to our knowledge of the causes and treatment of migraine. One of the four, Professor Jes Olesen of the Danish Headache Center in Copenhagen, gave the Brain Prize Lecture at the hybrid ECNP 2021 meeting.

Migraine is a tricky disorder to make sense of, as there is not a single cause of an attack. Instead, there is the concept of the migraine nociceptive unit. This takes into account that there are multiple tissues that contribute to migraine pain, including in the endothelium, vascular smooth muscle, perivascular nerves, and mast cells.

A key question in migraine research is how signaling in these different cell types is integrated into what the patient experiences during a migraine attack.

 

Aura is not the only indicator of migraine

It is not a simple question to answer, as each patient’s experience can be very different. There are over 100 types of migraine in the ICHD-3 classification, which is chaired by Professor Olesen [read more here]. Whilst many doctors are aware of aura symptoms, most do not realize that migraine without aura is the most common form, and so it may often not be correctly diagnosed.

Many doctors are not aware that migraine usually occurs without aura

Migraine without aura can be studied using inducers such as nitric oxide producers1 or calcitonin gene-related peptide (CGRP)2, but the underlying causes are still not well known.

 

Migraine is a genetic disorder

It is already known that migraine has a strong genetic component, with an estimated heritability of 38% to 53%.3,4 Studies showed a higher concordance rate of migraine in monozygotic twins (34%) than in dizygotic twins (12%).5

Some rare conditions such as familial hemiplegic migraine have been shown to be caused by mutations in single genes. However, the affected genes in this condition do not appear to be involved in the more common forms of migraine and can therefore not be used to identify these.

The Brainstorm consortium found a significant association between genes involved in migraine and in some psychiatric disorders

Interestingly, the Brainstorm consortium found that genes involved in migraine correlate weakly but significantly with genes involved in major depressive disorder (MDD), attention deficit hyperactivity disorder (ADHD) and Tourette’s syndrome.6

 

New studies bring new possibilities

Investigations of the genetics of migraine need large genome-wide association studies. The most recent, which is in press, included 100000 cases of migraine and 400000 controls. It identified 123 genes of interest with a minor allele frequency of more than 1%. Professor Olesen shared his excitement about what could be found by repeating Brainstorm with these newly discovered variants.

A recent genome-wide association study found 123 gene variants associated with migraine

These genes show preferential expression in the vascular smooth muscle and the brain. However, the effect size is relatively low, and there is no obvious causality from these genes. An interesting result was that a few variants were associated specifically with migraine with aura or migraine without aura. The majority of variants were seen in both.

As migraine has a high prevalence to start with7, it is hard to find any gene variants with a high relative risk of migraine. A study of extended families failed to find any genes with a relative risk of even 2.8 This makes it challenging to focus research into what the causal effects of these variants might be.

Epigenetics is a potential player in some newly discovered gene variants

However, current research on some of the rare variants suggests that altered binding of polycomb elements may change gene expression through epigenetic mechanisms.8

Genetic analysis is therefore a promising approach in migraine, but our level of understanding of the complex interaction of genetics, epigenetics, and environment is still in its early phase, making predictive analyses a challenge.

 

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Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References
  1. Thomsen LL et al. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol. 1994;1(1):73-80
  2. Lassen LH et al. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(1):54-61
  3. Honkasalo ML et al. Migraine and concomitant symptoms among 8167 adult twin pairs. Headache. 1995;35(2):70-8
  4. Mulder EJ et al. Genetic and environmental influences on migraine: a twin study across six countries. Twin Res. 2003;6(5):422-31
  5. Ulrich V et al. Evidence of a genetic factor in migraine with aura: a population-based Danish twin study. Ann Neurol. 1999;45(2):242-6
  6. Brainstorm Consortium. Analysis of shared heritability in common disorders of the brain. Science. 2018;360(6395):eaap8757
  7. Jensen R, Stovner LJ. Epidemiology and comorbidity of headache. Lancet Neurol. 2008;7(4):354-61
  8. Techlo TR et al. Familial analysis reveals rare risk variants for migraine in regulatory regions. Neurogenetics. 2020;21(3):149-57
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