Helsinki - The largest genome-wide association study on migraine to date has discovered gene variants in 38 sections of the genome that provide important clues about the possible causes of the disease. According to the publication in Nature Genetics (2016; doi:), many variants are found in genes that are activated in blood vessels and smooth muscles, which suggests vascular genesis.
According to family and twin studies, 42 Percent of all migraine diseases are genetic. The genes responsible are not yet known. An exception was the rare familial hemiplegic migraine (FHM), which is triggered by defects in ion transport in nerve cells, which supports the so-called neurogenic hypothesis of migraines. According to this, dysfunction of nerve cells triggers the headache attacks, which in some patients are announced by visual or sensory symptoms called aura.
Migraine was the subject of earlier genome-wide association studies (GWAS). There, gene variants have already been discovered at 13 locations in the genetic make-up, including those that are more likely to arise in the blood vessels of the brain. According to the vascular hypothesis, the headache is caused by dilation of the blood vessels. It is currently the predominant view, as some vasodilators such as glycerol trinitrate can trigger migraine attack and most migraine therapeutics - from ergot alkaloids to triptans to the developing CGRP receptor antagonists - achieve their effect by contracting the blood vessels.
The new GWAS now presented by Aarno Palotie, University of Helsinki, predominantly supports the vascular hypothesis. The researchers compared the genes of 59,674 migraine patients and 36,078 healthy controls. They came across 44 gene variants, so-called single nucleotide polymorphisms (SNP), which were located on 38 gene locations.
Numerous genes were located on these gene locations (PHACTR1, TGFBR2, LRP1, PRDM16, RNF213, JAG1, HEY2 , GJA1 and ARMS2), which influence the contractility of smooth muscle cells or otherwise interfere with the regulation of the vessel diameter (MRVI1, GJA1, SLC24A3 and NRP1). Six other genes (REST, GJA1, YAP1, PRDM16, LRP1 and MRVI1) are connected to oxidative stress and NO signaling pathways, which also indirectly influence the function of blood vessels.
Palotie also found two SNPs in Genes that contain the blueprint for membrane channels (KCNK5 and TRPM8). For the researchers, however, the influence is of minor importance. However, the study is far from explaining the genetic risk of migraines, so that newerogenic influence on migraines cannot be ruled out. In one form or another, channelopathy, i.e. malfunction of the ion channels that are responsible for the transmission of signals, could also play role.
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