Researchers have identified a genetic variant that is often present among people who never experience headache. A researcher says that this provides a different way to interpret headache as a continuum of phenotypes and the biological mechanisms behind headache.
Researchers are usually interested in identifying genetic variants that predispose to developing various diseases such as cardiovascular diseases, diabetes, multiple sclerosis or migraine.
Researchers approached this from a different perspective in a new genome-wide association study. Instead of trying to identify genetic variants that increase the risk of developing headache, they identified a genetic variant that is frequently present among people with complete freedom from headache.
“Many people say that they have never had headache. In investigating a disorder, examining the opposite case can sometimes be interesting, and we did this by identifying the genetic characteristics of the people who say they have never had headache,” explains a researcher behind the study, Thomas Folkmann Hansen, Associate Professor, Danish Headache Center, Department of Neurology, Rigshopitalet, Glostrup, Denmark.
The research has been published in Communications Biology.
No headache
The researchers had carried out other studies to describe the characteristics of people who never experience headache. One thing these studies showed is that these people do not have a higher pain threshold.
They are also not completely resistant to headache induced with nitroglycerin. Unlike most people, they just do not experience headache.
The researchers therefore embarked on a genome-wide association study, investigating the genetic differences between people in general and people who say they never experience headache.
“We know that some people do not develop headache and that this is stable over many years. They do not experience headache from influenza, from mild trauma or when they forget to drink or eat, or even drinking too much. Some people do not know what a headache is,” says Thomas Folkmann Hansen, who adds that the vast majority are men.
More than 60,000 participants
The researchers asked 63,992 people whether they had ever had headache, and they then linked the answers with genetic data from the Danish Blood Donor Study Genomic Cohort.
Five percent (2,998 people) responded that they had never had headache, and the researchers investigated whether some specific but common genetic variants are more frequent in this group compared with the rest.
Thomas Folkmann Hansen says genetics has a major role in various types of headache.
“Genetics can explain more than 50% of migraine,” notes Thomas Folkmann Hansen.
Genetic variant protects
The study discovered a statistically significant genome-wide association between the lead variant rs7904615[G] in ADARB2 and never experiencing a headache. This means that the people who said that they have never had headache had this genetic variant more frequently than everyone else.
Thomas Folkmann Hansen says that ADARB2 is not particularly well studied but that it helps to regulate the expression of genes in the brain.
Some experiments with mice in which researchers destroyed parts of ADARB2 found that this changes their behaviour slightly, suggesting that ADARB2 is involved in regulating behaviour. The link to headache is therefore plausible.
“ADARB2 is not really associated with the development of disease, and there is therefore little interest in it. This is one reason why publishing our study took so long. We would like others to rediscover what we have found in this study, but no one has performed a similar study,” explains Isa Amalie Olofsson, a Postdoctoral Fellow in the BRIDGE Translational Excellence Programme at the University of Copenhagen, who carried out the research in connection with her PhD studies.
New understanding of the biology behind headache
According to Thomas Folkmann Hansen, the new discovery makes researchers more aware of headache as a continuum of conditions.
Some people have severe headache and are at one end of the continuum, including people with debilitating migraine.
The other end of the continuum has people who not only rarely have headache but instead seem to be protected from headache by their genetics.
There are many possibilities in between, such as tension-type headache, cluster headache or just plain headache.
“Viewing headache as a continuum with different phenotypes and different genes involved makes us more aware of the biology behind headaches. The dream scenario in our study was to find a gene for a receptor or something else that we could influence with drugs and thereby prevent people from developing headache. Our findings do not immediately point in this direction, but we will continue our research to determine whether improved understanding of ADARB2 can lead to the development of new types of drugs for alleviating headache,” concludes Thomas Folkmann Hansen.
