**1. Molecular basis of headache subtypes**

Recently, researchers have identified the gene variations that increase the susceptibility to develop headaches. To analyze the cause, clinical history of headaches is very important. While headaches can be caused by medical conditions, injuries, or infections, sometimes they are not due to any specific disease or other identified medical conditions. The three most common of those types of primary headaches are tension, cluster and migraine headaches (**Figure 1**). Tension‐type headache (TTH) brought on by stress or depression, so everyone has

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**Figure 1.** Diagram of primary headaches subtypes.

experienced TTH. TTH can be brief, episodic or continuous. According to some researchers, TTH could be secondary to the vasoconstriction, rather than dilatation [1–3].

The neurobiological mechanisms of tension‐type headache are concerning. Central sensitiza‐ tion plays a major role in chronic TTH. Whether peripheral mechanisms or central mechanisms are primarily responsible for TTH is an important issue to differentiate it pathophysiologi‐ cally from migraine. The literature suggests that migraine and tension‐type headache may have the similar pathophysiology. Moreover, exact mechanism for both the disorders is still to be elucidated [4–6].

The prevalence of migraine has been shown to be increasing. The researchers have suggested that the central nervous system (CNS) susceptible to headache has been linked to an impor‐ tant survival or reproductive advantage. Some possible reasons are determined; one of these says that migraine is a defense mechanism; the other one consider it as a result of novel envi‐ ronmental factors; the next one regards migraine as a compromise between genetic harms and benefits. Genetic epidemiological studies are necessary to prove the involvement of genetic factors. Twin studies have been used to assess the respective roles of genetic and environmen‐ tal factors in migraine [7, 8].

We briefly mention here the headache types and characteristics. The first title is TTH. Biological mechanisms of TTH are yet to be explained. This disease usually is associated with depression and anxiety. In addition, the genetic factors are most important for TTH patho‐ genesis. The neurological mechanisms of TTH are not known clearly. Genetic and neurobio‐ logical research studies have increased our understanding of the complex mechanisms that may lead to TTH. There is strong evidence for a genetic predisposition for TTH. Moreover pain pathways in the central nervous system are positively associated with TTH. Research has enhanced our current understanding regarding the means through which psychological factors lead to TTH, suggesting sympathetic hyperactivity as a possible mechanism [9, 10].

The etiology of cluster‐type headache (CH) is still unknown. Until recently, researchers thought that CH was not an inherited disorder; however, several new studies have suggested that genetic factors play an important role in the CH. Some studies show that CH phenotype is inherited such as in autosomal dominant disease [11, 12]

To identify genetic factors that confer susceptibility to migraine, many studies have been con‐ ducted on the genetic basis of migraine types. First approach on this is classical linkage analysis. This approach aims to identify affected segments of chromosomes in individuals using a family‐ based approach. For monogenic migraine types, this approach has been particularly successful. A second commonly used strategy to identify gene variants involves candidate‐gene association studies. These studies are determinate with alleles and genotype frequencies in control and case groups. Recently, DNA variants have advanced spectacularly, allowing the cost‐effective analy‐ sis of DNA variants in patients in so‐called genome‐wide association studies (GWAS). Also, GWAS included hundreds of genes for many complex diseases. To determine the size of rarer gene variants is too expensive and takes more time. Instead, methods such as next‐generation sequencing of exons (exome sequencing) and whole‐genome sequencing can be used [13].
