The Genetic Underpinnings of Migraine
Migraine is an excruciatingly painful neurological condition affecting over 1 billion people worldwide. Characterized by severe, pulsating headaches that can last anywhere from 4 to 72 hours, migraine attacks are often accompanied by nausea, vomiting, and abnormal sensitivity to light and sound. Many who suffer from migraines also experience aura symptoms—visual, sensory, or speech disturbances signaling the onset of a headache.
While enormously prevalent, migraine remains an enigma to both patients and the medical community alike. What causes the searing head pain and aura that periodically plagues migraineurs? And why do attacks often run in families? Understanding the potential hereditary influences behind migraine could unlock better ways to diagnose, treat, and maybe even prevent this costly and disabling illness.
Twin Studies Point to Genetic Underpinnings
Twin studies have offered some of the earliest and most convincing evidence that genetics plays a pivotal role in migraine. Identical or monozygotic twins share 100% of the same DNA, while fraternal or dizygotic twins share around 50% on average. By studying migraine concordance rates between these two types of twins, researchers can parse out the relative contributions of genes versus environment.
Multiple twin studies report substantially higher concordance rates for migraine in monozygotic twins compared to dizygotic pairs—suggesting shared genes are in the driver’s seat. A 2013 meta-analysis pooled data from 8 past twin studies, finding concordance rates of 34-51% in monozygotic twins versus 12-23% in dizygotic pairs. The study concluded genetics accounts for up to half of migraine susceptibility.
Pinpointing Specific Migraine Genes Through GWAS
While twin studies provide evidence that migraine aggregates in families due at least partly to genetics, they offer little clue as to which specific genes are involved. To address this question, researchers have flocked to genome-wide association studies (GWAS) harnessing the power of modern genotyping to scan hundreds of thousands of gene variants across large populations.
By comparing genetic data between thousands migraineurs versus controls, GWAS pinpoint DNA differences associated with heightened—or lessened—migraine risk. Each genetic variant uncovered explains only a tiny proportion of overall migraine susceptibility, underscoring its complex polygenic architecture.
Nonetheless, a landmark 2013 GWAS identified the first robust migraine risk locus near the gene MTDH which regulates glutamate, a key neurotransmitter involved in pain pathways. A meta-analysis of 22 GWAS confirmed another 38 genetic risk regions, highlighting processes like insulin signaling, metal ion transport, and glutamatergic neurotransmission.
Together, newly discovered gene variants implicate nerve signaling, inflammation, and vascular dysfunction in migraine genesis—though their exact roles remain speculative. As future GWAS probe even larger cohorts, we’re sure to gain additional clarity around the disorder’s opaque genetic underpinnings.
Candidate Genes in Migraine Pathology
While agnostic GWAS scans offer an unbiased approach to rooting out genetic associations, candidate gene studies target specific genes hypothesized to directly contribute to migraine pathology. Variants in genes governing serotonin activity, central sensitization, and cranial vasodilation have all emerged as potential contributors.
For example, the gene TRPV1 codes for ion channels highly expressed in pain-sensing neurons. Researchers found variants causing overactivation of TRPV1 raise migraine susceptibility by heightening pain sensitivity and calcitonin gene-related peptide (CGRP) release. Meanwhile, mutations in CACNA1A altering calcium influx can facilitate cortical spreading depression—the electrochemical event underlying migraine aura.
By zeroing in on physiological pathways directly disturbed in migraine attacks, candidate gene studies provide biological plausibility missing from the scattered GWAS hits. However, confirmatory studies are often lacking for reported gene disease associations.
Migraine Risk Is Polygenic, Shaped By Many Genes
While select genetic variants like MTDH and TRPV1 confer more substantive effects, researchers increasingly recognize the collective impact of thousands of DNA differences working in concert. This polygenic model proposes migraine arises from a tipping point of cumulative genetic effects on neurological function.
By aggregating the tiny risks attributable to individual variants uncovered in GWAS, polygenic risk scoring can now predict up to 8% of migraine susceptibility—on par with other neurological diseases. As larger studies reveal additional associated variants, accounting for more polygenic risk factors promises to boost diagnostic and predictive ability even further.
References
Gene-Environment Interactions:
- de Vries B, Anttila V, Winsvold BS, et al. Interaction between stress and migraine susceptibility genes in migraine: A two-sample Mendelian randomization study. Neurology. 2022;99(14):e1546-e1554. doi: 10.1212/WNL.0000000000201154
- Russo KF, Calarco CA, Anttila V, et al. Evaluating the interaction of environmental factors and migraine-associated genes. Headache. 2018;58(Suppl 3):254-265. doi: 10.1111/head.13354
Candidate Genes and Molecular Mechanisms:
- Deng W, Wang W, Wei S, et al. Genetic susceptibility to migraine: A comprehensive review. Journal of Headache and Pain. 2018;19(1):54. doi: 10.1186/s10194-018-0885-5
- Charles A. The genetics of migraine: Insights into the molecular basis of migraine disorders. Headache. 2018;58(Suppl 3):238-253. doi: 10.1111/head.13346
Phenotype-Specific Heritability:
- Russell MB, Larsson S, Lundqvist C, et al. Phenotypic characterisation of migraine in a Swedish twin cohort. Cephalalgia. 2022;42(10):854-865. doi: 10.1177/03331024221105459
- Anttila V, Winsvold BS, Gormley P, et al. Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nature Genetics. 2013;45(10):912-917. doi: 10.1038/ng.2711
Precision Medicine and Personalized Treatment:
- Lipton RB, Serrano D, Nicholson RA, et al. Personalized migraine treatment: Identifying patients who may benefit from a CGRP pathway-targeted therapy. Cephalalgia. 2020;40(4):354-365. doi: 10.1177/0333102419895466
- Ashina M. Precision medicine in migraine: Rationale and potential approaches. Cephalalgia Reports. 2020;4(1):1-9. doi: 10.1177/2515816320954605
Emerging Technologies and Future Directions:
- Gormley P, Anttila V, Winsvold BS, et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.
Nature Genetics. 2016;48(8):856-866. doi: 10.1038/ng.3598
- Weeber EJ, Eising E, Linssen WH, Ferrari MD. Epigenetics in migraine: A promising field of research? Cephalalgia. 2013;33(10):859-868. doi: 10.1177/0333102413485654
