“We are working hard on identifying clinically meaningful biomarkers, but we are not there yet.”
– Bendik S. Winsvold (Oslo University Hospital, Norway)
Dr Winsvold started his presentation by defining biomarkers as measurable indicators of a condition. According to Dr Winsvold, biomarkers can be divided in clinically applicable biomarkers and biomarkers that increase our understanding of the disease.
Insights from monogenic disorders
Recent advances in genetic studies, particularly genome-wide association studies (GWAS), have contributed substantially to the identification of common genetic variants in migraine.2 Dr Winsvold discussed three subtypes of migraine with identified genetic components: familial hemiplegic migraine, associated with mutations in CACNA1A, ATP1A2 and SCN1A; hemiplegic migraine, associated with mutations in PRRT2; and monogenic typical migraine with aura, associated with mutations in KCNK18 (encoding TRESK). The common denominator for impaired function of the involved genes is neuronal hyperexcitability, with resulting increased susceptibility to cortical spreading depression (CSD).3
In addition to monogenic migraine disorders, Dr Winsvold noted that a number of primarily vascular disorders are caused by mutations in single genes, which often are accompanied by migraine features.4 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebrovascular disease caused by mutations in NOTCH3. CADASIL is characterized by ischemic strokes and dementia, but up to 40% of patients also experience migraine.4 Mutations in the TREX1 and COL4A1 also cause vascular disorders that are often associated with migraine.
Insights from common migraine
The GWAS approach has been used to identify several new independent loci associated with common migraine. Dr Winsvold presented a study conducted on 59,674 patients with migraine and 316,078 controls that identified 44 independent single-nucleotide polymorphisms (SNPs) mapped to 38 distinct genomic loci significantly associated with migraine.5 Several of these loci are enriched for genes that are expressed in vascular and smooth muscle tissues. However, Dr Winsvold mentioned a yet unpublished large migraine study by the International Headache Genetics Consortium that identified several new independent SNPs within non-vascular genes.
Exploring other primary headache disorders
The current use of genetic biomarkers is mainly limited to monogenic forms of migraine, but the search for biomarkers in other headache disorders is ongoing. Dr Winsvold is part of the International Consortium for Genetic Studies in Cluster Headache that includes research groups from more than 10 countries. The Consortium is currently analysing clinically diagnosed patients with cluster headache using the GWAS approach with the hope of identifying clinically meaningful biomarkers.
Dr Winsvold concluded his presentation by stating that GWAS findings have no direct clinical application yet. Identification of robust and clinically meaningful biomarkers for migraine and other headache disorders is a challenging but highly important task. Dr Winsvold is hopeful that genetic biomarkers could in the future be used to identify genetic subtypes of migraine, as well as to predict treatment effects of migraine drugs.
GDB 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–1858.
De Boer I, et al. Advance in genetics of migraine. Curr Opin Neurol. 2019;32:413–21.
Pellacani S, et al. The Revolution in Migraine Genetics: From Aching Channels Disorders to a Next-Generation Medicine. Front Cell Neurosci. 2016;10:156.
Sutherland HG et al. Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders. Headache. 2017;57:537–569.
Gormley P, et al. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet. 2016;48:856–66.