Migraine is a complex multifactorial disorder characterized by headache attacks associated with a constellation of neurological symptoms. In approximately one-third of patients, headaches are preceded by transient focal sensorial symptoms, so-called auras, involving visual and hearing systems. Genetic factors contribute to the clinical spectrum of migraine and multiple common variants have been associated with migraine with and without aura (Sutherland and Griffiths, 2017; de Boer et al., 2019). The diagnostic criteria of migraine were standardized according to the International Headache Society (Headache Classification Committee of the International Headache Society, 2018). Epidemiological evidence supports that familial aggregation with an early disease onset, particularly for the aura subtype, indicating a higher genetic susceptibility in migraine with aura (Russell et al., 1996; Ulrich et al., 1999; Mulder et al., 2003; Stewart et al., 2006).

Vestibular migraine (VM) consist of a subgroup of patients with migraine where the sensorial symptoms involve the vestibular system. VM is characterized by recurrent episodes of vertigo, a current or past history of migraine and simultaneous occurrence of both symptoms during crisis (Li et al., 2019). VM is one of the most common causes of recurrent vertigo. Prevalence studies have described MV as a frequent disease (0.9–2.7%), with variations in the frequency according to the population of study (Neuhauser et al., 2006; von Brevern et al., 2007; Formeister et al., 2018). However, VM is underdiagnosed, due to variability and overlap of symptoms with other causes of vertigo and to normal neurological examination and neuroimaging (Li et al., 2019).

The diagnostic criteria for VM were jointly developed by the Barany Society and the International Headache Society in 2012 (Lempert et al., 2012), and they differentiate probable and definite VM. Criteria for definite VM were included in the appendix of the 3rd edition of the International Classification of Headache Disorders (ICHD-III), one step forward to consider VM as an independent entity (Headache Classification Committee of the International Headache Society, 2018).

Migraine is a complex and multifactorial disorder with a large genetic component (Sutherland and Griffiths, 2017). Therefore, VM could also present a genetic predisposition (Knezevic et al., 2018; Rainero et al., 2019).

Familial clustering in VM has been occasionally observed, supporting the hypothesis of a genetic contribution to VM (Espinosa-Sanchez and Lopez-Escamez, 2015). Some studies reported families with an autosomal dominant inheritance with a moderate to high penetrance; however, no causative mutations have been found (Kim et al., 1998; von Brevern et al., 2006). Moreover, some loci segregating VM have been identified by linkage analysis in some few families with affected individuals in 22q12 (Lee et al., 2006) and 5q35 (Bahmad et al., 2009). These results suggest polygenic inheritance for VM; however, evidence to support a genetic contribution has not been critically appraised, and more research in this area is needed.

The aim of this systematic review is to assess available evidence in scientific publications to determine the role of inheritance in VM. So, we gathered information about the prevalence of VM in different populations, including family studies and twin studies, and we analyzed the quality of reported findings in genetic studies.

Thirty-one studies with a total sample size of 41,127 individuals were finally included in this revision, according to the eligibility criteria. A flowchart detailing the selection of studies is included in Figure 1.

The association between migraine and vertigo has been known for a long time; however, it has not been considered as an independent entity until the last decade (56). The current diagnostic criteria were published in 2012 (Lempert et al., 2012), therefore, only 8 of the studies included in this revision applied these criteria for the diagnosis of VM. The criteria proposed by Neuhauser et al. (2001) were reported in 8 of the studies, and in the rest of the publications, the authors used ICHD criteria for migraine and ad-hoc clinical criteria for vertigo. One of the family studies did not report any diagnostic criteria, but later this family was reported as familial VM.

There are several evidence to support heritability in complex traits such as vestibular disorders: (a) differences in the prevalence of the condition according to the ethnic background; (b) familial aggregation with early onset and anticipation; and (c) high concordance of the phenotype in monozygotic twins and adoptees with biological parents when they are compared with dizygotic twins or adoptive parents, respectively (Gallego-Martinez et al., 2018).

The population-based study from Formeister et al. (2018) showed a higher prevalence of VM in African American or Europeans than in Asian descendent population, suggesting a possible genetic contribution. It should be interesting to compare the prevalence of VM in East Asia in a large cohort with the Asian American descendent to assess the environmental effect on VM.

Moreover, the prevalence of VM in migraine patients seems to be higher in European countries (23% in Croatia, 21% in Turkey) (Vuković et al., 2007; Yollu et al., 2017) than in Asian countries (10% in South Korea) (Cho et al., 2016). However, the diagnosis of VM in neurotology clinics shows a great variation ranging from a 7% reported in Germany (Neuhauser et al., 2001), 22% in Egypt (Hazzaa and El Mowafy, 2016) to 41% in Australia (Power et al., 2018). These data suggest differences in the diagnostic criteria used rather than ethnic differences in VM and evidence that population-based studies are needed to estimate the prevalence of VM.

Familial aggregation is usually reported in rare diseases, and suggests a combined effect of genetic and environmental factors (Requena et al., 2014a). This type of studies compares the prevalence of a disease in individuals of the same generation within a family with the prevalence of that disease in general population. In order to do this, the sibling recurrence risk ratio (λ_s) is calculated. That proportion allows us to know how many times the disease is more frequent between the siblings of the affected individual, as compared with the general population. Our systematic review show that familial studies (Oliveira et al., 1997; Oh et al., 2001; Lee et al., 2006, 2008; Cha et al., 2008; Bahmad et al., 2009; Peddareddygari et al., 2019) showed a higher prevalence of the migraine-vertigo association than the observed prevalence of that association in the general population (3.2%) (Neuhauser et al., 2001), and also higher than the 2.7% prevalence of VM in general population (Formeister et al., 2018). We calculated λ_s for the migraine-vertigo association, which resulted in a risk ranging between 4–10 times higher than in general population.

Most of the studies included in this review reported information about age of onset of migraine and vertigo. Some of them described a significantly lower age of onset in patients with VM, as compared with controls affected either by migraine or vertigo (Vuković et al., 2007; Akdal et al., 2013). By comparing the age of VM onset in several studies, we found that there was an earlier onset of symptoms in those patients with simultaneous presentation of migraine and vertigo, as compared with those with metachronic onset of symptoms.

Early and simultaneous onset of symptoms observed in familial VM suggests genetic anticipation, a phenomenon of progression of severity of an inherited disorder in successive generations frequently found in neurological disorders and associated with expansion of nucleotide repeats (Carpenter, 1994). Teggi et al. (2018) reported a significantly lower age of migraine onset in patients with a familial history of migraine or VM, as compared with those without it. These results were also reported in some of the included familial studies (Lee et al., 2008; Bahmad et al., 2009; Peddareddygari et al., 2019), in which age of migraine onset seems to be lower than in non-familial cases.

The genetic association studies retrieved have reported allelic variants in the HTR6 and PRG genes associated with VM (Lee et al., 2007; Wu et al., 2020). Replication studies are needed to validate these results.

The genetic contribution to vestibular diseases, including VM is largely unknown (Requena et al., 2014b; Gallego-Martinez et al., 2018). The application of high throughput sequencing technologies in multiplex families with deep phenotyping will target candidate genes and clarify disease mechanisms and facilitate the genetic diagnosis of VM in clinical practice (Di Resta and Ferrari, 2018; Prodan Žitnik et al., 2018).

JL-E conceived the study design and develop the scientific arguments. AP-T and PP-C performed literature search, quality assessment of the studies, and interpretation of data. All authors drafted the manuscript and revised the final version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.