Nature Genetics Advance Online Publication Meta-analysis of 375,000 Individuals Identifies 38 Susceptibility Loci for Migraine-猫眼课题宝

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P. Gormley;V. Anttila;V. Anttila;B. Winsvold;B. Winsvold;P. Palta;T. Esko;T. Esko;T. Esko;T. Pers;Kai-How Farh;Kai-How Farh;Kai-How Farh;E. Cuenca-León;M. Muona;N. Furlotte;Tobias Kurth;Tobias Kurth;A. Ingason;George Mcmahon;L. Ligthart;G. Terwindt;M. Kallela;T. Freilinger;T. Freilinger;C. Ran;S. Gordon;A. Stam;S. Steinberg;G. Borck;M. Koiranen;L. Quaye;H. Adams;T. Lehtimäki;Antti-Pekka Sarin;J. Wedenoja;D. Hinds;Julie E. Buring;Julie E. Buring;M. Schürks;P. Ridker;P. Ridker;M. Hrafnsdottir;H. Stefánsson;S. Ring;J. Hottenga;B. Penninx;M. Färkkilä;V. Artto;M. Kaunisto;Salli Vepsäläinen;R. Malik;A. Heath;P. Madden;N. Martin;G. Montgomery;M. Kurki;M. Kals;R. Mägi;K. Pärn;E. Hämäläinen;Hailiang Huang;Hailiang Huang;Andrea Byrnes;Andrea Byrnes;L. Franke;Jie Huang;E. Stergiakouli;Phil H. Lee;Phil H. Lee;C. Sandor;C. Webber;Zameel M. Cader;Zameel M. Cader;B. Müller-Myhsok;S. Schreiber;T. Meitinger;Jenny Casey Eriksson;J. Eriksson;V. Salomaa;K. Heikkilä;E. Loehrer;E. Loehrer;A. Uitterlinden;A. Hofman;C. Duijn;L. Cherkas;L. Pedersen;A. Stubhaug;A. Stubhaug;Christopher S Nielsen;C. Nielsen;M. Männikkö;E. Mihailov;L. Milani;Hartmut Göbel;A. Esserlind;A. F. Christensen;T. Hansen;T. Werge;T. Werge;T. Werge;Jaakko Kaprio;Jaakko Kaprio;A. Aromaa;Olli T. Raitakari;Olli T. Raitakari;M. Ikram;T. Spector;M. Järvelin;A. Metspalu;C. Kubisch;D. Strachan;M. Ferrari;A. C. Belin;M. Dichgans;M. Wessman;A. M. Maagdenberg;J. Zwart;J. Zwart;D. Boomsma;G. D. Smith;K. Stefánsson;K. Stefánsson;N. Eriksson;M. J. Daly;M. J. Daly;B. Neale;B. Neale;Jes Olesen;D. Chasman;D. Chasman;D. Nyholt;A. Palotie

一个典型的血管变化代表了下游效应，这些效应本身并不是偏头痛的原因4，5。然而，缺乏支持一种理论的遗传学证据。在表型水平上，偏头痛是由国际头痛协会的诊断标准定义的6。有两种流行的亚型：无先兆偏头痛，其特征是与恶心或对光过敏相关的中度或重度头痛的反复发作，偏头痛是一种使人衰弱的神经系统疾病，影响全球约七分之一的人，但其分子机制仍然知之甚少。关于偏头痛是血管功能障碍的疾病还是神经元功能障碍伴继发性血管改变的结果，存在一些争论。全基因组关联（GWA）研究迄今已确定了3个与偏头痛相关的独立基因座。为了确定新的易感基因座，我们对来自22项GWA研究的59，674名受试者和36，078名对照者进行了偏头痛的遗传研究。我们确定了44个独立的单核苷酸多态性（SNP）与偏头痛风险显著相关（P < 5 × 0 −8），映射到38个不同的基因组位点，包括28个以前未报道的位点和一个据我们所知是第一个在X染色体上被确定的位点。在随后的计算分析中，所鉴定的位点显示血管和平滑肌组织中表达的基因富集，这与突出血管病因的偏头痛的主导理论一致。偏头痛是全球第三常见疾病，终生患病率为15- 20%，影响着全球多达10亿人1，2地球仪。它是全球第七大致残性疾病（也是最致残的神经系统疾病），就因残疾而损失的生命年数而言，它是第三大最昂贵的神经系统疾病，仅次于痴呆和中风3。关于偏头痛是一种血管功能障碍性疾病还是一种神经功能障碍性疾病，

A r t i c l e s vascular changes representing downstream effects that are not themselves causative of migraine 4,5. However, genetic evidence favoring one theory over the other is lacking. At the phenotype level, migraine is defined by diagnostic criteria from the International Headache Society 6. There are two prevalent subforms: migraine without aura, which is characterized by recurrent attacks of moderate or severe headache associated with nausea or hypersensitivity to light and Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 3 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 36,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 0 −8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies. Migraine is the third most common disease worldwide, with a lifetime prevalence of 15–20%, affecting up to 1 billion people across the globe 1,2. It ranks as the seventh most disabling disease worldwide (and the most disabling neurological disease) in terms of years of life lost to disability 1 , and it is the third most costly neurological disorder, after dementia and stroke 3. There is debate about whether migraine is a disease of vascular dysfunction or of neuronal dysfunction with

Nature Genetics Advance Online Publication Meta-analysis of 375,000 Individuals Identifies 38 Susceptibility Loci for Migraine

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