de Vries Boukje, Anttila Verneri, Freilinger Tobias, Wessman Maija, Kaunisto Mari A, Kallela Mikko, Artto Ville, Vijfhuizen Lisanne S, Göbel Hartmut, Dichgans Martin, Kubisch Christian, Ferrari Michel D, Palotie Aarno, Terwindt Gisela M, van den Maagdenberg Arn Mjm
Department of Human Genetics, Leiden University Medical Center, the Netherlands.
Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, USA Harvard Medical School, USA Stanley Center for Psychiatric Research, Broad Institute for Harvard and MIT, USA.
Cephalalgia. 2016 Jun;36(7):604-14. doi: 10.1177/0333102414566820. Epub 2015 Jan 29.
Before the genome-wide association (GWA) era, many hypothesis-driven candidate gene association studies were performed that tested whether DNA variants in genes that had been selected based on prior knowledge about migraine pathophysiology were associated with migraine. Most studies involved small sample sets without robust replication, thereby making the risk of false-positive findings high. Genome-wide marker data of thousands of migraine patients and controls from the International Headache Genetics Consortium provide a unique opportunity to re-evaluate key findings from candidate gene association studies (and other non-GWA genetic studies) in a much larger data set.
We selected 21 genes from published candidate gene association studies and six additional genes from other non-GWA genetic studies in migraine. Single nucleotide polymorphisms (SNPs) in these genes, as well as in the regions 500 kb up- and downstream, were inspected in IHGC GWAS data from 5175 clinic-based migraine patients with and without aura and 13,972 controls.
None of the SNPs in or near the 27 genes, including the SNPs that were previously found to be associated with migraine, reached the Bonferroni-corrected significance threshold; neither when analyzing all migraine patients together, nor when analyzing the migraine with and without aura patients or males and females separately.
The available migraine GWAS data provide no clear evidence for involvement of the previously reported most promising candidate genes in migraine.
在全基因组关联（GWA）时代之前，进行了许多基于假设驱动的候选基因关联研究，这些研究测试了基于偏头痛病理生理学的先验知识选择的基因中的DNA变异是否与偏头痛相关。大多数研究涉及小样本集且缺乏有力的重复验证，因此假阳性结果的风险很高。来自国际头痛遗传学联盟的数千名偏头痛患者和对照的全基因组标记数据提供了一个独特的机会，可在一个大得多的数据集中重新评估候选基因关联研究（以及其他非GWA基因研究）的关键发现。
我们从已发表的候选基因关联研究中选择了21个基因，并从偏头痛的其他非GWA基因研究中另外选择了6个基因。在来自5175名有或无先兆的门诊偏头痛患者和13972名对照的国际头痛遗传学联盟全基因组关联研究（GWAS）数据中，检查了这些基因以及上下游500 kb区域中的单核苷酸多态性（SNP）。
27个基因内部或附近的SNP，包括先前发现与偏头痛相关的SNP，均未达到Bonferroni校正的显著性阈值；无论是将所有偏头痛患者一起分析，还是分别分析有或无先兆的偏头痛患者或男性和女性时均未达到。
现有的偏头痛GWAS数据没有提供明确证据表明先前报道的最有希望的候选基因参与偏头痛。
