Machine generated keywords: gene, genetic, migraineur, hormone, interictal, aura, snps, trigger, sleep, vestibular, score, stress, expression, male, episodic migraine

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Genetics

Machine generated keywords: gene, genetic, snps, polymorphism, variant, gwas, genotype, expression, loci, susceptibility, metaanalysis, migraine susceptibility, aura, subtype, tagentityend

Advances in genetics of migraine

DOI: https://doi.org/10.1186/s10194- 019- 1017- 9

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 P. Martelletti (ed.), Migraine in Medicine, https://doi.org/10.1007/978-3-030-97359-9_2

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Abstract-Summary There are rare monogenic forms of migraine, as well as more common polygenic forms; research into the genes involved in both types has provided insights into the many contributing genetic factors.

This review summarises advances that have been made in the knowledge and

understanding of the genes and genetic variations implicated in migraine etiology.

Hemiplegic migraine is a rare monogenic MA subtype caused by mutations in three main genes—CACNA1A, ATP1A2 and SCN1A—which encode ion channel and transport proteins.

Variants in other genes encoding ion channels and solute carriers, or with roles in regulating neurotransmitters at neuronal synapses, or in vascular function, can also cause monogenic migraine, hemiplegic migraine and related disorders with overlapping symptoms.

Dissecting the genetic architecture of migraine leads to greater understanding of what underpins relationships between subtypes and comorbid disorders, and may have utility in diagnosis or tailoring treatments.

Further work is required to identify causal polymorphisms and the mechanism of their effect, and studies of gene expression and epigenetic factors will help bridge the genetics with migraine pathophysiology.

A comprehensive knowledge of the genetic factors underpinning migraine will lead to improved understanding of molecular mechanisms and pathogenesis, to enable better diagnosis and treatments for migraine sufferers.

Background Investigating the genetic basis of FHM, as well as the common types of MO and MA, has greatly helped in our understanding of migraine pathophysiology through the discovery of the genes that contribute to the disorder.

During migraine, distinct areas of the brain are activated, each contributing to aspects of migraine pathophysiology, whether this is triggering the attack, generat- ing the pain, or playing roles in some of the associated neurological symptoms that occur during an attack [1].

Common migraine forms, including MO and MA, are most likely due to the contribution of variants with small effect at many genetic loci, i.e. these are consid- ered to be polygenic disorders.

With regards to polygenic forms, genome-wide association studies (GWAS) in large migraine case-control cohorts has greatly helped our understanding of the many genetic factors and pathways that contribute to common migraine, with sub- sequent transcriptomics and functional experiments required for further understand- ing of the causal mechanisms.

Main Text Discovering loci and genes that contribute to common migraine requires different approaches to the Mendelian disorders, mainly based on finding differences in allele

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frequencies of genetic variants linked to genes, between cohorts of migraine cases and non-migraine controls, composed of unrelated individuals.

In common with the monogenic FHM and MA forms caused by ion channel gene

mutations, some ion channel gene loci are implicated in polygenic migraine.

Genes of the Notch signalling pathway are involved in both the monogenic migraine-related cerebrovascular disorder CADASIL (caused by pathogenic NOTCH3 variants) and common migraine, with GWAS loci identified near both the NOTCH4 receptor gene, and JAG1, which encodes Jagged1, a ligand of multiple Notch receptors.

It is likely that more migraine-related loci will be discovered as sample numbers increase in migraine GWAS using SNP-chips (including from various ethnicities), and the effect of rare variants identified from exonic and genomic sequencing becomes clearer.

Conclusions Migraine is a multifactorial disorder with genetics playing an important role in the susceptibility, and symptomology, as well as comorbidity with other traits and conditions.

For monogenic migraine, mapping of loci in family pedigrees, coupled with genomic sequencing to find variants, led to the discovery of the main FHM genes, CACNA1A, ATP1A2 and SCN1A. Knowledge of their roles as ion channels and in ion transport, along with functional experiments in cellular and animal models, has contributed to uncovering how their dysfunction may lead to cortical hyperexcit- ability and migraine.

With respect to the common polygenic forms of migraine, GWAS analyses using high-throughput SNP genotyping arrays has revealed many variants around genes with roles in neurological and vascular pathways in migraine.

With increasing sample sizes more susceptibility loci are likely to be found,

some of which may contribute to specific migraine subtypes or symptoms.

Acknowledgement A machine generated summary based on the work of Sutherland, Heidi G.; Albury, Cassie L.; Griffiths, Lyn R. 2019 in The Journal of Headache and Pain.

Polygenic risk score: use in migraine research