Cluster headache is a type of headache that affects mostly men and is characterized by episodes of severe pain affecting one side of the head, especially around the eyes and above the ear. They can occur more than once a day for a period of time between three weeks and three months and, in some cases, can become chronic. Many factors are involved in its development, including genetics. In order to learn more about the causes of the disease, a genetic study has been carried out to identify regions of the genome associated with a higher risk. The international study, in which the Headache and Neurological Pain group of the Vall d'Hebron Research Institute (VHIR) has participated, has detected eight regions of the genome related to the risk of cluster headache, some of which show that tobacco plays a key role in these patients. This is an international study published in Annals of Neurology in collaboration with the Psychiatry, Mental Health and Addictions group of VHIR.

The research was based on genetic data from 4,777 cluster headache patients and 31,575 healthy individuals, mostly from Europe and also from East Asia. Thus, eight regions of the genome associated with an increased risk of suffering cluster headache were identified, including several genes related to the brain and arteries, which reinforces the role that blood vessels may play in the pathology.

Particularly noteworthy is the finding of a genetic link between headache and smoking. "These results are in line with the data we knew previously, since approximately 80% of people with cluster headache smoke and, among those who do not, most have been exposed to parental tobacco smoke during childhood", explains Dr. Patricia Pozo-Rosich, head of Section of the Neurology Service and Headache Unit at Vall d'Hebron University Hospital, head of the Headache and Neurological Pain group at VHIR and director of the Migraine Adaptive Brain Center at Vall d'Hebron.

By means of statistical analysis, the study has confirmed the cause-effect relationship between smoking and cluster headache, i.e., that smoking is a cause of this type of headache. Although the mechanisms are not known in depth, the researchers emphasize that smoking affects the expression of some genes related to the development of this pathology. For example, it has been seen that smoking increases the expression of the MERTK gene and decreases it in the CFTR gene, and these changes are also observed in patients with cluster headache.

The effect that smoking has on these genes can persist for decades. This is why Dr. Pozo-Rosich emphasizes that "the relationship we have found between smoking and cluster headache provides one more reason to avoid smoking". "In the case of patients suffering from cluster headache, it is especially advisable to stop smoking, since, in addition, smoking usually causes more severe symptoms and makes it more difficult to respond to treatment", she adds.

Cluster headache and migraine: shared genetics?

In addition to smoking, the genetic relationship of cluster headache with depression, challenging behavior, attention deficit hyperactivity disorder (ADHD), musculoskeletal pain or migraine was also analyzed.

The researchers especially explore the relationship between two different types of headache: cluster headache and migraine. Although some regions of the genome shared between the two diseases are identified, it is observed that there is a different genetic basis between the two diseases. This finding corresponds to the fact that they are two different clinical entities despite having some features in common, and therefore also require case-specific attention.

An international multicenter study with data from more than 35,000 individuals

Compared to previous studies, the one presented now has a much larger sample of patients: in total, data from more than 35,000 people have been analyzed. This has been possible thanks to the creation of the International Consortium for Cluster Headache Genetics, which involves 16 headache research groups from 13 countries and works to understand the genetic causes of this disease.

Future research will continue to investigate the development of cluster headache to also understand the differences that exist between ethnicities. The results of the current study indicate that, compared to the European population, there are some different genes involved in the predisposition to the pathology in the Asian population.