Primary headache disorders are among the most common disabling diseases in the world. Migraine is a highly prevalent primary headache disorder (11% in the general population and up to 25% in young women). Migraine is a complex disorder, frequently associated with a wide variety of internal and external (environmental) triggers, but not limited to its multifactorial origin. Cluster headache (CH) is one of the most frequent trigeminal autonomic cephalalgias (TACs), with a prevalence of 0.1-0.4% among general population and a clear male predominance.

Complex genetic and environmental factors might play a role in CH etiology. Concomitantly with headache disorders, several comorbidities associated with pain have been described, such as temporomandibular disorders (TMDs)  whose pathophysiology seems to indicate the existence of common mechanisms, namely genetic pathways.

During the last 17 years, IBMC/i3s group has been deeply involved in the genetic and epidemiological study of primary headaches (. We have been able to clinically characterize patients, relatives and controls (?1,500 individuals). Importantly, during the last years we performed several candidate-gene association studies focusing in different pathways. Our group found several variants involved in the vascular component, trigeminal nociceptive plasticity, neurogenic inflammation and in the release of neurotransmitters. Despite all advances in the study of primary headaches in the last years a significant amount of questions remains unanswered. Given the largely unknown pathophysiology of migraine and CH (and associated comorbidities, as TMDs), genome-wide approaches are unbiased with respect to prior knowledge and genome location; and powered to detect association with causal variants that are relatively common in the population.

With this project, we aim to ascertain at a National level a larger sample of migraineurs and cluster headache (CH) Portuguese patients, and consequently to increase our control group to obtain a proportion of one case per 2 controls. Also, we aim to deepen the link between primary headaches and associated comorbidities as TDM regarding the shared common mechanisms between the two pathologies. After a careful selection of patients, relatives and controls we will perform for the first time, a Genome-Wide Association study (GWAS) in this clinically well-defined cohorts of Portuguese patients with migraine and/or CH, TMD and with both headache disorders and TMD. This Project could represent the first GWAS in different geographical regions of Portugal to identify common rare exonic variants associated with migraine and CH susceptibility. In addition, we also expect to provide new insights regarding shared genetic risk for migraine and TDM. Understanding the mechanisms underlying migraine, cluster headache and TMD pathophysiology could lead to the development of more effective and better-tolerated therapeutic approaches to avoid the overlay of painful events.