Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

被引：283

作者：

Anttila, Verneri ^{[1
,2
]}

Stefansson, Hreinn ^{[3
]}

Kallela, Mikko ^{[4
]}

Todt, Unda ^{[6
,7
]}

Terwindt, Gisela M. ^{[8
]}

Calafato, M. Stella ^{[9
]}

Nyholt, Dale R. ^{[10
]}

Dimas, Antigone S. ^{[11
,12
]}

Freilinger, Tobias ^{[13
,14
]}

Mueller-Myhsok, Bertram ^{[15
]}

Artto, Ville ^{[4
]}

Inouye, Michael ^{[1
,16
]}

Alakurtti, Kirsi ^{[1
,2
]}

Kaunisto, Mari A. ^{[2
,17
]}

Haemaelaeinen, Eija ^{[2
]}

de Vries, Boukje ^{[16
]}

Stam, Anine H. ^{[8
]}

Weller, Claudia M. ^{[16
]}

Heinze, Axel ^{[18
]}

Heinze-Kuhn, Katja ^{[18
]}

Goebel, Ingrid ^{[5
,6
,7
]}

Borck, Guntram ^{[5
,6
,7
]}

Goebel, Hartmut ^{[18
]}

Steinberg, Stacy ^{[3
]}

Wolf, Christiane ^{[15
]}

Bjoernsson, Asgeir ^{[3
]}

Gudmundsson, Gretar ^{[19
]}

Kirchmann, Malene ^{[20
,21
]}

Hauge, Anne ^{[20
,21
]}

Werge, Thomas ^{[22
]}

Schoenen, Jean ^{[23
,24
]}

Eriksson, Johan G. ^{[25
,26
,27
]}

Hagen, Knut ^{[28
]}

Stovner, Lars ^{[28
]}

Wichmann, Erich ^{[29
,30
]}

Meitinger, Thomas ^{[31
,32
]}

Alexander, Michael ^{[33
,34
]}

Moebus, Susanne ^{[35
]}

Schreiber, Stefan ^{[36
,37
]}

Aulchenko, Yurii S. ^{[38
]}

Breteler, Monique M. B. ^{[38
]}

Uitterlinden, Andre G. ^{[39
]}

Hofman, Albert ^{[38
]}

van Duijn, Cornelia M. ^{[38
]}

Tikka-Kleemola, Paevi ^{[40
]}

Vepsaelaeinen, Salli ^{[4
]}

Lucae, Susanne ^{[15
]}

Tozzi, Federica ^{[41
]}

Muglia, Pierandrea ^{[41
,42
]}

Barrett, Jeffrey ^{[1
]}

机构：

[1] Wellcome Trust Sanger Inst, Cambridge, England

[2] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[3] DeCODE genet, Dept Populat Genom, Reykjavik, Iceland

[4] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland

[5] Univ Cologne, Inst Human Genet, Cologne, Germany

[6] Univ Cologne, Inst Genet, D-5000 Cologne, Germany

[7] Univ Cologne, Ctr Mol Med Cologne, D-5000 Cologne, Germany

[8] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands

[9] Cambridge Univ Hosp Natl Hlth Serv Fdn Trust, Cambridge Biomed Res Ctr, Nat Inst Hlth Res, Cambridge, England

[10] Queensland Inst Med Res, Neurogenet Lab, Brisbane, Qld 4006, Australia

[11] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[12] Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland

[13] Univ Munich, Dept Neurol, Klinikum Grosshadern, Munich, Germany

[14] Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany

[15] Max Planck Inst Psychiat, D-80804 Munich, Germany

[16] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands

[17] Folkhalsan Res Ctr, Helsinki, Finland

[18] Kiel Pain & Headache Ctr, Kiel, Germany

[19] Landspitali Univ Hosp, Dept Neurol, Reykjavik, Iceland

[20] Danish Headache Ctr, Glostrup, Denmark

[21] Glostrup Cty Hosp, Dept Neurol, Glostrup, Denmark

[22] Univ Copenhagen, Research Inst Biol Psychiat, Roskilde, Denmark

[23] Univ Liege, Headache Res Unit, Dept Neurol, B-4000 Liege, Belgium

[24] Univ Liege, GIGA, B-4000 Liege, Belgium

[25] Univ Helsinki, Cent Hosp, Dept Gen Practice, Helsinki, Finland

[26] Cent Hosp, Vaasa, Finland

[27] Nat Inst Hlth & Welf, Helsinki, Finland

[28] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway

[29] Inst Epidemiol, Helmholtz Ctr Munich, Neuherberg, Germany

[30] Univ Munich, Inst Med Informationsverarbeitung, Munich, Germany

[31] Inst Human Genet, Helmholtz Ctr Munich, Neuherberg, Germany

[32] Tech Univ Munich, Inst Human Genet, Klinikum Rechts Isar, Munich, Germany

[33] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany

[34] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany

[35] Univ Duisburg Essen, Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany

[36] Univ Kiel, Dept Clin Mol Biol, Kiel, Germany

[37] Univ Kiel, Dept Internal Med 1, Kiel, Germany

[38] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[39] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands

[40] Univ Helsinki, Res Program Mol Med, Helsinki, Finland

[41] GlaxoSmithKline Res & Dev Ltd, Verona, Italy

[42] Univ Toronto, Dept Psychiat, Ctr Addict & Mental Hlth, Toronto, ON, Canada

[43] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland

[44] Broad Inst & Harvard, Boston, MA USA

[45] Oslo Univ Hosp & Univ, Dept Neurol, Oslo, Norway

[46] Univ Cologne, Cologne Excellence Cluster Cellular Stress Resp, Cologne, Germany

[47] Univ Ulm, Inst Human Genet, Ulm, Germany

[48] Univ Helsinki, Dept Med Genet, Helsinki, Finland

[49] Univ Helsinki, Cent Hosp, Dept Med Genet, Helsinki, Finland

来源：

NATURE GENETICS | 2010年 / 42卷 / 10期

基金：

澳大利亚研究理事会; 芬兰科学院; 英国惠康基金; 英国医学研究理事会;

关键词：

FAMILIAL HEMIPLEGIC MIGRAINE; LYMPHOBLASTOID CELL-LINES; EPISODIC ATAXIA; SPREADING DEPRESSION; GENE-EXPRESSION; CONFERS RISK; GLUTAMATE; MUTATION; INVOLVEMENT; MECHANISMS;

D O I：

10.1038/ng.652

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10(-9), odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(-11) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10(-5), permuted threshold for genome-wide significance 7.7 x 10(-5)). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

引用

页码：869 / +

页数：6

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