Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Department of Neurology, Leiden University Medical Centre, 9600, 2300 RC, Leiden, The Netherlands.
J Headache Pain. 2019 Jan 11;20(1):5. doi: 10.1186/s10194-018-0956-x.
Recent technical advances in genetics made large-scale genome-wide association studies (GWAS) in migraine feasible and have identified over 40 common DNA sequence variants that affect risk for migraine types. Most of the variants, which are all single nucleotide polymorphisms (SNPs), show robust association with migraine as evidenced by the fact that the vast majority replicate in subsequent independent studies. However, despite thorough bioinformatic efforts aimed at linking the migraine risk SNPs with genes and their molecular pathways, there remains quite some discussion as to how successful this endeavour has been, and their current practical use for the diagnosis and treatment of migraine patients. Although existing genetic information seems to favour involvement of vascular mechanisms, but also neuronal and other mechanisms such as metal ion homeostasis and neuronal migration, the complexity of the underlying genetic pathophysiology presents challenges to advancing genetic knowledge to clinical use. A major issue is to what extent one can rely on bioinformatics to pinpoint the actual disease genes, and from this the linked pathways. In this Commentary, we will provide an overview of findings from GWAS in migraine, current hypotheses of the disease pathways that emerged from these findings, and some of the major drawbacks of the approaches used to identify the genes and pathways. We argue that more functional research is urgently needed to turn the hypotheses that emerge from GWAS in migraine to clinically useful information.
近年来遗传学领域的技术进步使得大规模全基因组关联研究（GWAS）在偏头痛研究中成为可能，并确定了超过 40 个常见的 DNA 序列变异，这些变异会影响偏头痛的发病风险。大多数变异均为单核苷酸多态性（SNP），与偏头痛具有很强的相关性，这一事实表明，绝大多数变异在随后的独立研究中得到了复制。然而，尽管人们进行了彻底的生物信息学研究，旨在将偏头痛风险 SNP 与基因及其分子途径联系起来，但对于这项研究的成功程度以及它们目前在偏头痛患者的诊断和治疗中的实际应用，仍存在相当大的争议。尽管现有遗传信息似乎支持血管机制的参与，但也涉及神经元和其他机制，如金属离子内稳态和神经元迁移，潜在遗传病理生理学的复杂性给将遗传知识推进到临床应用带来了挑战。一个主要问题是，在多大程度上可以依赖生物信息学来确定实际的疾病基因，以及由此确定相关途径。在本评论中，我们将概述偏头痛 GWAS 的研究结果、从这些发现中出现的疾病途径的当前假设，以及用于识别基因和途径的方法的一些主要缺点。我们认为，迫切需要更多的功能研究，将偏头痛 GWAS 中出现的假设转化为临床有用的信息。
