Genetics of cluster headache

Abstract

Background Cluster headache is the most severe primary headache disorder. A genetic basis has long been suggested by family and twin studies; however, little is understood about the genetic variants that contribute to cluster headache susceptibility. Methods We conducted a literature search of the MEDLINE database using the PubMed search engine to identify all human genetic studies for cluster headache. In this article we provide a review of those genetic studies, along with an overview of the pathophysiology of cluster headache and a brief review of migraine genetics, which have both been significant drivers of cluster headache candidate gene selection. Results The investigation of cluster headache genetic etiology has been dominated by candidate gene studies. Candidate selection has largely been driven by the pathophysiology, such as the striking rhythmic nature of the attacks, which spurred close examination of the circadian rhythm genes CLOCK and HCRTR2. More recently, unbiased genetic approaches such as genome-wide association studies (GWAS) have yielded new genetic avenues of interest including ADCYAP1R1 and MME. Conclusions The majority of candidate genes studied for cluster headache suffer from poor reproducibility. Broader genetic interrogation through larger unbiased GWAS, exome, and whole genome studies may provide more robust candidates, and in turn provide a clearer understanding of the causes of cluster headache.

Other primary headaches—thunderclap-, cough-, exertional-, and sexual headache

“…Knowledge of the primary headaches comes largely from the work in the most prevalent disorders, namely tensiontype headache, migraine, and cluster headache. This supports the concept that these disorders occur in those genetically predisposed [2][3][4] and, where the inherent pathology is in the central nervous system. When individuals first experience a headache, the concern is often about a sinister precipitating pathology [5].…”

Anoctamin 3: A Possible Link between Cluster Headache and Ca2+ Signaling

“…The hypothalamus is also reported to be activated during a CH attack, a possible explanation for the rhythmic pattern with which the symptoms occur during active periods [8,9]. The cause of CH is currently unknown, but several studies suggest that genetic factors contribute to the risk of developing the disorder [10]. Genetic associations with CH have today been reported for several candidate genes [11,12,13,14,15,16].…”

Very young age of onset in trigemino-autonomic cephalalgias – case report and review of the literature

“…However, heritability of the TACs is not proven by this fact. Several studies showed no major genetic risk for TACs (8), although a higher familial risk has been shown in epidemiological studies (1). It seems unlikely that environmental factors or social/observational learning can induce TACs in these very young patients.…”