When asking a family about headaches, many times they can identify multiple family members that intermittently have headaches. Oftentimes, the families view this as normal and have the perception that everybody has headaches. It is only when it becomes a problem that the families think that there may be a problem. This recognition that headaches “run in the family” is an early observation by families that headaches may have an inheritable or genetic pattern which can begin the discussion that headaches are a symptom of a disease. The understanding and discussion with a family that, what they are having is a disease with headaches being one of the symptoms, can be one of the first steps to improved treatment and outcome. Although several headache types, including the risk of developing a secondary headache, may have a genetic basis, this chapter will focus on migraine and its genetic component.
For migraine there is a balance between genetic components that are not changeable (i.e., genetic defects or polymorphisms) and genetic modifications (i.e., epigenetics and expression alterations). The modifiable genetic factors can be influenced by both external and internal environmental factors, thus serving as a point of intervention. The impact on fixed and modifiable genetic factors is likely explanation for the variation within families. For recurrent headaches in children and adolescents, the presence of a strong family history of headaches is often observed and has been suggested as a part of the criteria for the diagnosis of migraine.
Understanding the genetic basis of headaches whether primary such as migraine or secondary with genetic risk factors, not only may be useful for the diagnosis but also advances the understanding of the pathophysiology of headaches. This is clearest for migraine where there have been up to 38 different polymorphisms related to migraine identified on large population studies, as well as specific genes identified for the rare migraine sub-types of hemiplegic migraine. The recognition of all these different genetic pathways involved with migraine suggests that migraine is really a polygenic disorder where the phenotypic features seen during the headache are a common end representation of these pathways.
A thorough review of the genetic basis of migraine is beyond the scope of this chapter but having a basic understanding of the foundation of these studies will help in guiding the approaches taken for diagnosis, treatment, and patient education. This extends from the observation of familial basis as observed in population studies to the molecular biology of the identified genes and the pathways involved.
Population studies. One of the central tenets of populations studies is to address whether a given disease occurs more often within a family than odds of it occurring independently. For common diseases like migraine, this high prevalence rate increases the chance occurrence within a family and thus increases the familial associations.
In order to address some of these issues, a study of 4000 individuals from the Danish Central Persons Registry with migraine with aura were compared to an equal number with migraine without aura as the probands. When the results were analyzed, it was found that for migraines without aura, there was a 1.9-fold increased familial risk of having migraine without aura whereas unrelated spouses had a 1.5-fold increased risk, suggesting both genetic and environmental contributions for migraine without aura. The genetic influence was even greater for migraine with aura, with first-degree relatives having a fourfold increased risk of migraine with aura in contrast to no increase in spouses. Additionally, there appeared to be a generational effect seen where the greatest risk for having migraine without aura was seen in the children of probands—3.43-fold increase.
Population Twin Studies. Twin studies are one way to address the question of genetic vs environmental contribution. Twins that are monozygotic (i.e., identical genetic make-up) can be compared to dizygotic twins (i.e., share approximately half their genes), while also adding in the contribution of shared vs independent environmental factors. One such study was based on the New Danish Twin Register of 2026 monozygotic twins and 3334 same-sex dizygotic. When proband comparison was performed, than the pairwise concordance rate was much higher for monozygotic twins (28%) compared with same-sex dizygotic twins (18%). While this study clearly identified a genetic factor in migraine, the lack of complete agreement (i.e., 100% comparison) identified the gap in this approach.
To address this, a population-based twin study of children, aged 8 to 9 years old, found that, of those children reporting a history of headaches, 79% of them were classified as migraine or tension type headaches. Looking at the proband wise concordance, it was highest for monozygotic girls and boys at 0.52 and 0.51, followed by same-sex dizygotic boys and girls at 0.22 and 0.27, while for opposite-sex dizygotic children it was 0.15. This clearly demonstrated the genetic contribution for headaches and in particular, migraine.
Environmental influences. As none of these analyses revealed a 100% concordance, this suggested that there are additional non-genetic factors. To answer this question, researcher tested models of genetic and environmental contributions to explain concordance rates in monozygotic and dizygotic. The best fit was found for a genetics contribution of 61%, while the environment contributed 39%—independent if shared or nonshared.
What do these population and twin studies mean for people affected by headache disorders? The most straight-forward explanation is that migraine is a genetic disease, but there are factors that can be modified to affect the impact of the disease and thus change the expression and outcome. What we can tell the patient is that we can’t change your genes, but we can change how the genes are impacting your life.
Molecular Genetics. With the understanding of migraine as a genetic disease, the search for the actual genes continues to advance as we understand more about this polygenic disease.
Familial Hemiplegic Migraine . One of the first migraine disorders to begin to answer this question was familial hemiplegic migraine (FHM). This is a very rare, unique disorder where the patient develops clear one-sided weakness before or during the attack. Currently, the International Classification of Headaches (ICHD-3) classifies this as a type of migraine with aura. In this regard, one must be clear to differentiate a sensory aura in which the patient is numb, thus not getting feedback for movement, from those that are truly weak. In this regard, the identification of the particular genetic mutation may be helpful in confirming the diagnosis, although when the familial nature has been identified, this is rarely needed.
Currently, there are 4 gene mutations identified for FHM – the calcium voltage-gated channel subunit alpha1 A (CACNA1A), the ATPase NA +/K + transporting subunit alpha 2 (ATP1A2), the sodium voltage-gated channel alpha subunit 1 (SCN1A), and the proline rich transmembrane protein 2 (PRRT2). The first 3 of these are now classified with the corresponding 5th digit in the ICHD-3 as FHM type 1 (ICHD-3 1.2.3.1.1), FHM type 2 (ICHD-3 1.2.3.1.2) and FHM type 3 (ICHD-3 1.2.3.1.4), while the 4th falls into the FHM, other loci (ICHD-3 1.2.3.1.4). It is notable that the first 3 are all ion channels, thus suggesting the neurophysiologic disturbance as the etiology of the FHM. There are now several laboratories that can test for these mutations to provide identification and genetic counseling to the family. An updated review of this information can be found at the dedicated NIH website ( https://ghr.nlm.nih.gov/condition/familial-hemiplegic-migraine ).
Migraine. The identification of gene association with migraine has grown significantly, and although most of these are associations and still need to prove direct cause and effect, they are enlightening as to possible etiologies. One of the largest approaches was an international consortium that complied the results of 375,000 individuals and identified 38 unique loci that increased the susceptibility of migraine. This was a large collaborative undertaking and one of the largest advances in understanding the genetics of migraine. These genes can be roughly grouped into four categories: neurological genes, vascular genes, hormonal genes, and inflammatory genes. This observation aligns well with previous hypothesized pathophysiology of migraine, while also demonstrating the widely different pathways that may be involved.
When multiple genes contribute to a single, identified disease we use the term polygenic, and can determine a polygenic risk score. Applying this approach, an analysis can be performed that shows the impact of this risk. Applying such an analysis clearly demonstrated that FHM had the greatest risk score with an odds ratio of 1.96 (1.86–2.07), followed by migraine with typical aura-odds ratio 1.85 (1.79–1.91) and migraine without aura-odds ratio of 1.57 (1.51–1.63). The risk score was highest in children and younger adolescents compared to late adolescents and adults, implying that the genetic contribution is clear for children and adolescents, while diminishing as people get older.
What does this identification of genes mean for patients? It confirms that migraine is a genetic disorder, and that multiple genes are likely to contribute to the headache characteristics and risk factors for progression as well as treatment. Thus, although migraine is a disease, it is a disease that is influenced by multiple different genes whose individual contributions and phenotype, make each persons’ headache a little different.
Beyond genetics. As we begin to understand the wide variety of genes involved in migraine, the next step is to determine the impact of these genes and their expression. These areas of research continue to advance our understanding of the biological markers or fingerprints of an individual patient. This approach is exclusively in the research arena and includes genomic expression of mRNA, metabolomics, proteomics, and epigenetics. Through these areas of research, a further understanding of the pathophysiology should help with improved treatment and outcomes.
General practitioners
How can a general practitioner use this information? Having a basic understanding that recurrent headaches, especially migraine, runs in families, efforts to pursue this history can help solidify the diagnosis as well as comfort the patient by relating to other family members. Oftentimes, this is made difficult by several misperceptions that the family may have. This includes anchoring of the onset to a specific life event (i.e., a life stressor or mild head injury), a perception that the headaches of migraine are always severe and disabling when in fact moderate headaches also count, the perception that “doesn’t everyone get headaches,” or blaming the recurrent headaches on an external factor (i.e., sinus headaches). Beginning to recognize the pattern of recurrent headaches in families helps remove some of these barriers and help progress the concept of migraine as a genetic disease expressed as intermittent headaches of variable frequency.
Specialists
How can this information help a Headache Medicine specialist? Understanding the complexity of migraine as a polygenic disease with multiple genetic pathways involved can support the need for a broad number of treatment approaches needed to improve the outcomes of patients with migraine. This, not only, may include variable acute and preventive medication, but also use of biobehavioral and health habits to influence the pathways as well as potentially alter genomic expression and epigenetic changes. This understanding allows us to work with patients to explain that we may need to continually monitor and modify treatments to find their own unique combination of treatments to improve their headaches. Future treatments based upon genetic profiles are in their infancy, but may play a strong role as our testing gets more specific.
Families
What does this mean for patients and families? Knowing that the most significant risk factor of having headaches in a patient with migraine is genetic helps explain that migraine is a disease and not something that is a fault of the patient. The fact that the impact of these genes can be modified opens up possibilities for improvement, both on the individual and societal level. Having this understanding of migraine as a disease should also help remove some of the stigma that may exist for migraine.
Conclusions
Primary headaches, especially migraine, clearly have a genetic contribution that may be modifiable. The variety of genes identified can be clustered in groups of pathways. This understanding should serve as a strong foundation for the discovery of new treatments of all types and improve outcome. ICHD-3 has begun to recognize this future contribution, holding the 5th digit of the diagnostic coding for this genetic identification. It can be expected that this will continue to grow, as new unique genetic factors are identified. Additionally, as identification of these genes and screening methods and markers are identified, a broad spectrum screening of the genotype in co-association with phenotypic differences may help further identify the pathophysiological processes underlying migraine and chronic migraine. This identification of additional biomarkers should also assist with a more detailed diagnostic analysis of migraine with the variety of the genetic contribution of migraines elucidated.
References
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