GENERAL INTRODUCTION 17 1 (undisputed) HM genes. 91-93, 111, 112 This may indicate that HM in mutation-negative patients may be oligogenic or polygenic, in line with the excess presence of common variants in such patients.94 For cluster headache no gene sequencing studies have ever been performed which is logical as the gene array studies for this disease only just started. An alternative approach to understanding molecular mechanisms involved in the pathophysiology of headache disorders is to study gene expression profiles. Contrary to genetic variation, gene expression is not fixed through life and expression is driven by both genetic and environmental factors.113 Typically, an RNA-seq approach (i.e. simultaneous sequencing of coding (messenger) and non-coding RNAs in a sample) is for instance used to identify differences in expression between individuals with and without disease or over the course of an attack. Various RNA-seq studies have been performed in migraine, but the results are not unambiguous not in the least because of potential caveats of using peripheral blood, the main source of biomaterial for such studies in the case of migraine.114 Gene expression studies in cluster headache are scarce. One study suggested the involvement of several brain-related mechanisms (voltage-gated channels and GABA receptor function), mitochondria, inflammation and intracellular signalling cascades.115 Another study found an indication for inflammatory activity in the active phase of the disease.116 Further genetic studies GWASs have proven successful in identifying many dozens of low-effect risk DNA variants for the more common forms of migraine with the number of associated DNA variants increasing steadily with larger sample sizes. Currently, next-generation sequencing, utilising whole-exome and ‑genome sequencing data, and other -omics data are being used to facilitate their functional interpretation and the discovery of additional risk factors. Various methods and analysis tools, such as genetic correlation, polygenic risk scores (PRSs) and causality analysis, are used to further characterise genetic risk factors. Downstream bioinformatics methods One way of making better use of the large number of small effect variants identified in migraine GWAS to have clinical benefit is the calculation of PRSs. A PRS is the combined effect of many common risk variants of genetic load for the discovery trait that can be used to estimate risk for a certain trait/phenotype in individuals in a target sample.117 This is done by testing whether a higher PRS based on the discovery sample is associated with case status or a specific trait in the target sample via regression models. A PRS provides a promising possibility to investigate the shared genetic architecture between migraine with known and hitherto unknown co-morbidities or traits. The aggregation of migraine in families and the earlier age of onset of migraine can to some extent be contributed to common polygenic variations, where the PRS explained a larger part of the phenotype variance in familial cases, especially those with migraine with aura and hemiplegic migraine compared to population cases.94
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