New clues about the causes of severe headaches
Inflammation, altered gene regulation, and exposure to substances in tobacco smoke may all contribute to the development of cluster headache. This is demonstrated by two new studies from Karolinska Institutet, which improve our understanding of the biological mechanisms behind this painful condition.
Cluster headache is a rare neurological disorder characterised by sudden, severe headache attacks. Due to the extreme pain, it is sometimes referred to as 'suicide headache', and the underlying causes remain largely unknown. In two new studies, researchers at Karolinska Institutet in Sweden have investigated both genetic and environmental factors that may contribute to cluster headache.
In one study, the researchers analysed genetic risk factors that had previously been identified in genome-wide association studies (GWAS), which compare the entire genome of people with and without the condition. This study involved genetic analyses of over 1,500 individuals, as well asmolecular analyses of blood samples, skin cells, and DNA from smaller groups of patients and control subjects. The results have been published in The Journal of Headache and Pain.
Genes point to inflammation
The researchers confirmed the relevance of seven genes previously associated with cluster headache and demonstrated that several of these genes are expressed differently in individuals with the condition. Six of the seven genes are active in immune cells or are linked to the body’s inflammatory signalling pathways.
“This strengthens the hypothesis that the immune system and inflammation may play a central role in cluster headache,” explains Caroline Ran, associate professor at the Centre for Cluster Headache in the Department of Neuroscience at Karolinska Institutet. “Several of the genes influence the same biological signalling pathways, which provides us with important clues about the mechanisms behind the condition.”
The second study, published in the journal Cephalalgia, investigated whether exposure to substances in tobacco smoke affects the regulation of genes in people with cluster headache. Previous studies have shown that people with this condition smoke more frequently than the general population. The researchers analysed blood, DNA, and cerebrospinal fluid samples from patients and healthy control subjects. The number of participants varied between 26 and 79, depending on the analysis.
Exposure to heavy metals
People with cluster headache had markers indicating increased exposure to heavy metals and other substances found in tobacco smoke. They also had changes in markers that regulate DNA methylation, a mechanism that influences how active different genes are.
“This study cannot prove cause and effect, but the results suggest that environmental factors, such as heavy metals in tobacco smoke, may interact with biological mechanisms in cluster headache,” says Andrea Carmine Belin, associate professor at the Centre for Cluster Headache in the Department of Neuroscience at Karolinska Institutet.
The researchers emphasise that both studies have limitations. The biological analyses were carried out on relatively small groups of participants, and several of the findings need to be confirmed in larger studies.
The studies were carried out in collaboration with Karolinska University Hospital and other researchers at Karolinska Institutet. Funding for the research came from the Mellby Gård Foundation, the Swedish Brain Foundation, Region Stockholm, the Swedish Research Council, the International Headache Society and the Swedish Headache Society, among others. The researchers state that they have no conflicts of interest.
Publications
“Genome-wide association susceptibility loci for cluster headache support a role for inflammation in the pathophysiology”, Caroline Ran, Clémence Deborgies Sanches, Julia Swedblom, Katrin Wellfelt, Alessandro Antoniazzi, Joseph Lloyd, Felicia Jennysdotter Olofsgård, Stefan Spulber, Elisabet Waldenlind, Maria Lantz, Anna Steinberg, Anna Sundholm, Christina Sjöstrand, Andrea Carmine Belin, The Journal of Headache and Pain, online 4 August 2026, doi: 10.1186/s10194-026-02485-x.
“Increased markers of heavy metal exposure and DNA methylation in cluster headache”, Joseph Lloyd, Katrin Wellfelt, Felicia Jennysdotter Olofsgård, Clémence Deborgies Sanches, Anna Steinberg, Anna Sundholm, Caroline Ran, Andrea Carmine Belin, Cephalalgia, online 25 August 2026, doi: 10.1177/03331024261480707.