The Finnish study also showed that higher polygenetic risk scores were associated with stronger family history of migraine, lower age-at-onset and the migraine with aura subtype [27▪]. This is in accordance with a large Dutch clinical study in which a stronger family history of migraine, defined as one or both parents being affected, was associated with lower age-at-onset, higher frequency and higher number of medication days and the migraine with aura subtype [28▪].
A recent study from UK Biobank that had 74 461 cases and 149 312 controls identified 28 genomic loci associated with a broadly defined ‘headache’ phenotype (Table 1) . Of note, ‘only’ 14 of the found loci were previously identified in a migraine GWAS (Table 1) . There are three possible explanations for this finding. Firstly, these loci are involved in a broader headache pathway, as part of the cases may in fact be patients with tension type headache. Epidemiological studies showed co-occurrence of migraine and tension type headache previously . Secondly, not all migraine patients in the migraine GWAS may be true migraine patients and may have been misdiagnosed patients with another headache phenotype. Given the robustness of the associated SNPs in the migraine GWAS and the fact that six of the loci identified in the headache GWAS were also identified in clinical-based migraine GWAS, this scenario seems unlikely [10,14]. Thirdly, part of the headache cases suffered from migraine.
Substantial epidemiological comorbidity is found between neuropsychiatric disorders, including migraine [31,32▪]. To quantify the degree of genetic overlap between different brain disorders, the Brainstorm Consortium was formed. This consortium used GWAS summary statistics of a staggering 265 218 cases and 784 643 controls to assess the genetic risk factor overlap of 25 common brain disorders [32▪].
The Brainstorm Consortium found no significant genetic risk overlap across neurological disorders. However, their results may indicate a possible genetic sharing between epilepsy and migraine, albeit not significant (Fig. 2) [32▪]. Not reaching significance may be explained by several factors including the relative small epilepsy cohort that was used, the heterogeneity of the epilepsy phenotype, and the fact that only summary statistics were used for the analyses [32▪]. The correlation between migraine and epilepsy is not surprising. For instance, in patients with hemiplegic migraine, there is often co-occurrence of epileptic and (hemiplegic) migraine attacks , and comorbidity between common migraine and epilepsy was also seen in epidemiological studies . The Brainstorm Consortium also failed to find a significant genetic risk between ischemic stroke and migraine, despite the fact that an earlier GWAS had revealed substantial genetic overlap between both disorders  and epidemiological studies demonstrated increased risk of ischemic stroke in migraine patients [5,36]. Future studies with larger cohorts and more detailed data may be able to show genetic correlation for migraine and comorbid neurological disorders, such as epilepsy and stroke.
Integration of genetic, phenotypic and epigenetic data will help to identify the biological mechanisms by which genetic factors contribute to migraine pathogenesis. It also shows the impact of genetics on clinical features and comorbidities in migraine and may guide clinicians to an adequate genetic advice for patients.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38:1–211.
2. Pelzer N, Stam AH, Haan J, et al. Familial and sporadic hemiplegic migraine
: diagnosis and treatment. Curr Treat Options Neurol 2013; 15:13–27.
3. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017; 390:1211–1259.
4. Louter MA, Wardenaar KJ, Veen G, et al. Allodynia is associated with a higher prevalence of depression
patients. Cephalalgia 2014; 34:1187–1192.
5. Schurks M, Rist PM, Bigal ME, et al. Migraine
and cardiovascular disease: systematic review and meta-analysis. BMJ 2009; 339:b3914.
6. Ottman R, Lipton RB. Comorbidity of migraine
and epilepsy. Neurology 1994; 44:2105–2110.
7. Stam AH, de Vries B, Janssens AC, et al. Shared genetic factors in migraine
: evidence from a genetic isolate. Neurology 2010; 74:288–294.
8. Stewart WF, Bigal ME, Kolodner K, et al. Familial risk of migraine
: variation by proband age at onset and headache severity. Neurology 2006; 66:344–348.
9. Russell MB, Iselius L, Olesen J. Migraine
without aura and migraine
with aura are inherited disorders. Cephalalgia 1996; 16:305–309.
10. Anttila V, Winsvold BS, Gormley P, et al. Genome-wide meta-analysis identifies new susceptibility loci for migraine
. Nat Genet 2013; 45:912–917.
11. Ferrari MD, Klever RR, Terwindt GM, et al. Migraine
pathophysiology: lessons from mouse models and human genetics
. Lancet Neurol 2015; 14:65–80.
12. Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C. The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain 2015; 138:3476–3495.
13. Pelzer N, de Vries B, Kamphorst JT, et al. PRRT2 and hemiplegic migraine
: a complex association. Neurology 2014; 83:288–290.
14. Gormley P, Anttila V, Winsvold BS, et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine
. Nat Genet 2016; 48:856–866.
15. Freilinger T, Anttila V, de Vries B, et al. Genome-wide association analysis identifies susceptibility loci for migraine
without aura. Nat Genet 2012; 44:777–782.
16. Chasman DI, Schurks M, Anttila V, et al. Genome-wide association study
reveals three susceptibility loci for common migraine
in the general population. Nat Genet 2011; 43:695–698.
17. Anttila V, Stefansson H, Kallela M, et al. International Headache Genetics
Consortium. Genome-wide association study
implicates a common susceptibility variant on 8q22.1. Nat Genet 2010; 42:869–873.
18. Ligthart L, de Vries B, Smith AV, et al. Meta-analysis of genome-wide association for migraine
in six population-based European cohorts. Eur J Hum Genet 2011; 19:901–907.
19▪. Nyholt DR, Borsook D, Griffiths LR. Migrainomics - identifying brain and genetic markers of migraine
. Nat Rev Neurol 2017; 13:725–741.
Comprehensive review on results regarding current and potential neuroimaging and genetic markers of migraine.
20. Gupta RM, Hadaya J, Trehan A, et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 2017; 170:522.e515–533.e515.
21. Iljazi A, Ayata C, Ashina M, Hougaard A. The role of endothelin in the pathophysiology of migraine
—a systematic review. Curr Pain Headache Rep 2018; 22:27.
22. Nyholt DR, Gillespie NG, Heath AC, et al. Latent class and genetic analysis does not support migraine
with aura and migraine
without aura as separate entities. Genet Epidemiol 2004; 26:231–244.
23. Ligthart L, Boomsma DI, Martin NG, et al. Migraine
with aura and migraine
without aura are not distinct entities: further evidence from a large Dutch population study. Twin Res Hum Genet 2006; 9:54–63.
24. Launer LJ, Terwindt GM, Ferrari MD. The prevalence and characteristics of migraine
in a population-based cohort: the GEM study. Neurology 1999; 53:537–542.
25. Zhao H, Eising E, de Vries B, et al. Gene-based pleiotropy across migraine
with aura and migraine
without aura patient groups. Cephalalgia 2016; 36:648–657.
26. Polderman TJ, Benyamin B, de Leeuw CA, et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet 2015; 47:702–709.
27▪. Gormley P, Kurki MI, Hiekkala ME, et al. Common variant burden contributes to the familial aggregation of migraine
in 1,589 families. Neuron 2018; 98:743.e744–753.e744.
With the use of a polygenetic risk score, the authors demonstrated that genetic load is higher in familial migraine cases than in nonfamilial cases, and higher for migraine with aura and hemiplegic migraine.
28▪. Pelzer N, Louter MA, van Zwet EW, et al. Linking migraine
frequency with family history of migraine
. Cephalalgia 2018; 39:229–236.
A stronger family history of migraine is associated with lower age-at-onset, higher frequency and number of medication days, and the migraine with aura subtype.
29. Meng W, Adams MJ, Hebert HL, et al. A genome-wide association study
finds genetic associations with broadly-defined headache in UK biobank (N = 223,773). EBioMedicine 2018; 28:180–186.
30. Hagen K, Asberg AN, Uhlig BL, et al. The epidemiology of headache disorders: a face-to-face interview of participants in HUNT4. J Headache Pain 2018; 19:25.
31. Lipton RB, Fanning KM, Buse DC, et al. Identifying natural subgroups of migraine
based on comorbidity and concomitant condition profiles: results of the Chronic Migraine
Epidemiology and Outcomes (CaMEO) Study. Headache 2018; 58:933–947.
32▪. Anttila V, Bulik-Sullivan B, Finucane HK, et al. Analysis of shared heritability in common disorders of the brain. Science 2018; 360.
Migraine shares common genetic variant risks with psychiatric diseases among which depression. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability based methods in understanding their cause.
33. Yang Y, Zhao H, Boomsma DI, et al. Molecular genetic overlap between migraine
and major depressive disorder. Eur J Hum Genet 2018; 26:1202–1216.
34. Prontera P, Sarchielli P, Caproni S, et al. Epilepsy in hemiplegic migraine
: genetic mutations and clinical implications. Cephalalgia 2018; 38:361–373.
35. Malik R, Freilinger T, Winsvold BS, et al. Shared genetic basis for migraine
and ischemic stroke: a genome-wide analysis of common variants. Neurology 2015; 84:2132–2145.
36. Kurth T, Chabriat H, Bousser MG. Migraine
and stroke: a complex association with clinical implications. Lancet Neurol 2012; 11:92–100.
37▪. Pelzer N, Haan J, Stam AH, et al. Clinical spectrum of hemiplegic migraine
and chances of finding a pathogenic mutation. Neurology 2018; 90:e575–e582.
This article will help guide physicians in selecting hemiplegic migraine patients for mutation screening and will also help with providing adequate genetic counseling.
* Arn M.J.M. van den Maagdenberg and Gisela M. Terwindt contributed equally to this manuscript.