This may be the author’s version of a work that was submitted/accepted for publication in the following source: Sutherland, Heidi& Griffiths, Lyn (2017) Genetics of migraine: Insights into the molecular basis of migraine disor- ders. Headache, 57(4), pp. 537-569. This file was downloaded from: https://eprints.qut.edu.au/105633/ c Consult author(s) regarding copyright matters This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the docu- ment is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recog- nise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to [email protected] Notice: Please note that this document may not be the Version of Record (i.e. published version) of the work. Author manuscript versions (as Sub- mitted for peer review or as Accepted for publication after peer review) can be identified by an absence of publisher branding and/or typeset appear- ance. If there is any doubt, please refer to the published source. https://doi.org/10.1111/head.13053 Genetics of Migraine: insights into the molecular basis of migraine disorders Heidi G. Sutherland, PhD and Lyn R. Griffiths, PhD Genomics Research Centre, Institute of Health and Biomedical Innovation, QUT, Musk Ave, Kelvin Grove, QLD 4059, Australia The authors declare no conflicts of interest. Acknowledgements: We wish to acknowledge the support of the Australian National Health and Medical Research Council and the Migraine Research Foundation, NY, USA for supporting our migraine genetic and diagnostic research. Key words: Migraine; genetics; hemiplegic migraine; genome-wide association study ABSTRACT Migraine is a complex, debilitating neurovascular disorder, typically characterised by recurring, incapacitating attacks of severe headache often accompanied by nausea and neurological disturbances. It has a strong genetic basis demonstrated by rare migraine disorders caused by mutations in single genes (monogenic), as well as familial clustering of common migraine which is associated with polymorphisms in many genes (polygenic). Hemiplegic migraine is a dominantly inherited, severe form of migraine with associated motor weakness. Family studies have found that mutations in three different ion channels genes, CACNA1A, ATP1A2 and SCN1A can be causal. Functional studies of these mutations has shown that they can result in defective regulation of glutamatergic neurotransmission and the excitatory/inhibitory balance in the brain, which lowers the threshold for cortical spreading depression, a wave of cortical depolarisation thought to be involved in headache initiation mechanisms. Other putative genes for monogenic migraine include KCKN18, PRRT2, and CSNK1D, which can also be involved with other disorders. There are a number of primarily vascular disorders caused by mutations in single genes, which are often accompanied by migraine symptoms. Mutations in NOTCH3 causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) a hereditary cerebrovascular disease that leads to ischemic strokes and dementia, but in which migraine is often present, sometimes long before the onset of other symptoms. Mutations in the TREX1 and COL4A1 also cause vascular disorders, but often feature migraine. With respect to common polygenic migraine, genome-wide association studies have now identified single nucleotide polymorphisms at 38 loci significantly associated with migraine risk. Functions assigned to the genes in proximity to these loci suggest that both neuronal and vascular pathways also contribute to the pathophysiology of common migraine. Further studies are required to fully understand these findings and translate them into treatment options for migraine patients. INTRODUCTION Migraine symptoms and diagnosis Migraine is a complex, debilitating neurovascular disorder, typically characterized by recurring, incapacitating attacks of moderate or severe headache for 1-3 days and often accompanied by autonomic dysfunction, nausea and sometimes aura symptoms. The disorder affects at least 12% of the general population, including young children, with a marked preponderance of females (~3:1 ratio) [1, 2]. In addition to individual suffering, migraine has severe social and economic impacts. Data from the recent Global Burden of Disease study (2013) ranks migraine as the most burdensome neurological disorder, and 6th highest cause of disability worldwide [3]. It ranks among the World Health Organisation top 12 of most disabling and undertreated disorders and is responsible for one of the highest socio-economic burdens of any brain ailment. It is often misdiagnosed because of lack of objective diagnostic tests and current treatments are not satisfactory or effective for everyone. Migraine presents with variable clinical phenotypes which can be heterogeneous in the population. Characteristic clinical features of migraine include throbbing head pain (usually unilateral), nausea, vomiting, photophobia, phonophobia and often severe, neurological disturbances [4]. It is currently clinically diagnosed based on the International Classification of Headache Disorders 3rd Edition (ICHD-III) [4] which formally classifies migraine into two main subtypes; Migraine without Aura (MO) and Migraine with Aura (MA). These have substantial symptomatic overlap, however MA sufferers also experience distinguishing neurological phenomena that precede the headache phase of an attack. The aura can encompass various neurological symptoms, often visual, such as scintillating shapes, hallucinations or black spots, but can also affect sensory, speech, motor, brainstem and retinal functions. Overall, MO and MA sufferers account for ~70% and 20-30% of migraineurs, respectively. ICHD-III also describes other migraine sub-types: chronic migraine is diagnosed in patients who experience frequent or almost continuous migraine symptoms, and is often linked with medication overuse; more than 50% of females suffering from MO report a menstrual association which has led to the further classification of menstrual migraine [5, 6]; and hemiplegic migraine (HM) is a rare severe form of MA that also features motor weakness. Pathophysiology of Migraine Activation of the trigeminovascular system The pathophysiology of migraine is only partially understood, but is believed to be caused by activation of the trigeminovascular system [7]. The headache phase of a migraine attack is thought to result from activation of nociceptors innervating the cranial blood vessels, which transmits a signal to the trigeminal bipolar neurons; this is further relayed to thalamic and cortical areas, producing the sensation of pain [8]. The signal from the perivascular neurons is transmitted by the vasoactive neuropeptides calcitonin gene-related peptide (CGRP), substance P (SP) and nitric oxide, resulting in a downstream cascade of events that leads to the release of vasoactive inflammatory mediators, inflammation in the meninges and sensitization of pain relevant brainstem regions [9]. Cortical Spreading Depression Trigeminal activation is a downstream event; how it is triggered is not well understood, but there is accumulating evidence that cortical spreading depression (CSD) is one route. CSD is a slowly propagating wave of neuronal and glial depolarisation accompanied by massive ion fluxes, that spreads across the brain cortex, and which is followed by a long-lasting suppression of neuronal activity [10, 11]. It coincides with, and is thought to underlie, the migraine aura [12, 13]. The onset of CSD has been demonstrated experimentally following noxious stimuli which lead to a build-up of glutamate in the neuronal environment, which then pathologically activates calcium and sodium channels, particularly the N-methyl-D- aspartate (NMDA) receptors [11]. Evidence from experimental animals suggests that CSD might not only cause migraine auras, but also play a pivotal role in headache initiation mechanisms [12-14]. CSD is associated with opening of Pannexin1 mega channels causing caspase-1 activation and HMGB1 release which initiates parenchymal inflammatory pathways and may provide the stimulus for sustained trigeminal activation [15]. Proof of a direct link between CSD and migraine in humans is still lacking, and the question of how CSD itself is triggered, and details of the downstream effects needs further investigation. Furthermore, the majority of migraine patients do not experience aura, so alternative triggers for trigeminovascular activation may also be important, such as cortical hyperexcitability or brain stem or hypothalamic dysfunction [16]. Clinical and neurophysiological studies have confirmed that individuals suffering from migraine display chronic hypersensitivity to sensory stimuli and or abnormal processing of sensory information [17-19]. Migraineurs exhibit cortical excitability [19, 20], which may make them more susceptible to CSD. Dissection of the genetics of migraine, particularly the severe monogenic forms, has added support to this and animal models have aided in understanding some of the mechanisms. Genetics of Migraine Migraine is a complex disorder with many factors contributing