Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

被引：1032

作者：

Beecham, Ashley H. ^{[1
]}

Patsopoulos, Nikolaos A. ^{[2
,3
,4
,5
,6
]}

Xifara, Dionysia K. ^{[7
]}

Davis, Mary F. ^{[8
]}

Kemppinen, Anu ^{[9
]}

Cotsapas, Chris ^{[10
,11
,12
]}

Shah, Tejas S. ^{[13
]}

Spencer, Chris ^{[7
]}

Booth, David ^{[14
]}

Goris, An ^{[15
]}

Oturai, Annette ^{[16
]}

Saarela, Janna ^{[17
]}

Fontaine, Bertrand ^{[18
]}

Hemmer, Bernhard ^{[19
,20
,21
]}

Martin, Claes ^{[22
]}

Zipp, Frauke ^{[23
]}

D'Alfonso, Sandra ^{[24
,25
]}

Martinelli-Boneschi, Filippo ^{[26
,27
]}

Taylor, Bruce ^{[28
]}

Harbo, Hanne F. ^{[29
,30
]}

Kockum, Ingrid ^{[31
]}

Hillert, Jan ^{[31
]}

Olsson, Tomas ^{[31
]}

Ban, Maria ^{[9
]}

Oksenberg, Jorge R. ^{[32
]}

Hintzen, Rogier ^{[33
]}

Barcellos, Lisa F. ^{[34
,35
,36
]}

Agliardi, Cristina ^{[37
]}

Alfredsson, Lars ^{[38
]}

Alizadeh, Mehdi ^{[39
]}

Anderson, Carl ^{[13
]}

Andrews, Robert ^{[13
]}

Sondergaard, Helle Bach ^{[16
]}

Baker, Amie ^{[9
]}

Band, Gavin ^{[7
]}

Baranzini, Sergio E. ^{[32
]}

Barizzone, Nadia ^{[24
,25
]}

Barrett, Jeffrey ^{[13
]}

Bellenguez, Celine ^{[7
]}

Bergamaschi, Laura ^{[24
,25
]}

Bernardinelli, Luisa ^{[40
]}

Berthele, Achim ^{[19
]}

Biberacher, Viola ^{[19
]}

Binder, Thomas M. C. ^{[41
]}

Blackburn, Hannah ^{[13
]}

Bomfim, Izaura L. ^{[31
]}

Brambilla, Paola ^{[26
]}

Broadley, Simon ^{[42
]}

Brochet, Bruno ^{[43
]}

Brundin, Lou ^{[31
]}

机构：

[1] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA

[2] Brigham & Womens Hosp, Inst Neurosci, Dept Neurol, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA

[3] Brigham & Womens Hosp, Inst Neurosci, Dept Psychiat, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA

[4] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Genet, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Boston, MA USA

[6] Broad Inst Harvard & MIT, Cambridge, MA USA

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

[8] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA

[9] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England

[10] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA

[11] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA

[12] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[13] Wellcome Trust Sanger Inst, Cambridge, England

[14] Univ Sydney, Westmead Millennium Inst, Westmead, NSW 2145, Australia

[15] Katholieke Univ Leuven, Lab Neuroimmunol, Sect Expt Neurol, Louvain, Belgium

[16] Copenhagen Univ Hosp, Danish Multiple Sclerosis Ctr, Dept Neurol, Copenhagen, Denmark

[17] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[18] Univ Paris 06, Ctr Rech Inst Cerveau & Moelle Epiniere CRICM, INSERM UMRS 975, Dept Neurol, Paris, France

[19] Tech Univ Munich, Klinikum Rechts Isar, Dept Neurol, D-80290 Munich, Germany

[20] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[21] German Competence Network Multiple Sclerosis KKNM, Munich, Germany

[22] Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Stockholm, Sweden

[23] Johannes Gutenberg Univ Mainz, Med Ctr, Rhine Main Neuroscience Network Rmn2, Focus Program Translat Neurosci FTN, D-55122 Mainz, Germany

[24] Univ Piemonte Orientale, Dept Hlth Sci, Novara, Italy

[25] Univ Piemonte Orientale, Interdisciplinary Res Ctr Autoimmune Dis IRCAD, Novara, Italy

[26] Ist Sci San Raffaele, Div Neurosci, Inst Expt Neurol INSPE, Lab Genet Neurol Complex Disorders, I-20132 Milan, Italy

[27] Ist Sci San Raffaele, Div Neurosci, INSPE, Dept Neurol, I-20132 Milan, Italy

[28] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas, Australia

[29] Oslo Univ Hosp, Dept Neurol, Oslo, Norway

[30] Univ Oslo, Oslo, Norway

[31] Karolinska Inst, Dept Neurosci, Stockholm, Sweden

[32] Univ Calif San Francisco, Dept Neurol, Sandler Neurosci Ctr, San Francisco, CA USA

[33] Erasmus Univ, Med Ctr, Erasmus MC, Dept Neurol, Rotterdam, Netherlands

[34] Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Genet Epidemiol & Genom Lab, Berkeley, CA 94720 USA

[35] Univ Calif Berkeley, Calif Inst Quantitat Biosci QB3, Berkeley, CA 94720 USA

[36] Kaiser Permanente Div Res, Oakland, CA USA

[37] IRCCS Santa Maria Nascente, Don C Gnocchi Fdn Org Non Lucrativa Utilita Socia, Lab Mol Med & Biotechnol, Milan, Italy

[38] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden

[39] Univ Rennes 1, Immunol Lab, Rennes, France

[40] MRC, Biostat Unit, Cambridge CB2 2BW, England

[41] Univ Med Ctr Hamburg Eppendorf, Dept Transfus Med, Hamburg, Germany

[42] Griffith Univ, Sch Med, Gold Coast, Qld, Australia

[43] Univ Bordeaux 2, Ctr Hosp Univ CHU Pellegrin, F-33076 Bordeaux, France

[44] Univ Melbourne, Dept Med, Melbourne, Vic, Australia

[45] Monash Univ, Box Hill Hosp, Dept Neurol, Box Hill, Vic, Australia

[46] Ctr Hosp Univ Reg Montpellier, Serv Neurol, Montpellier, France

[47] Univ Paris 06, INSERM, Plateforme Postgen P3S, Paris, France

[48] Azienda Osped Citta Salute & Sci Torino, Multiple Sclerosis Ctr, Dept Neurosci, Turin, Italy

[49] Univ Turin, Dept Neurosci, Turin, Italy

[50] Hop Avicenne, Serv Neurol, F-93009 Bobigny, France

来源：

NATURE GENETICS | 2013年 / 45卷 / 11期

基金：

英国医学研究理事会; 美国国家卫生研究院; 英国惠康基金; 瑞典研究理事会;

关键词：

GENOTYPE IMPUTATION; ASSOCIATION; RISK; METAANALYSIS; INFORMATION; AUTOIMMUNE; GENETICS; COMMON; RARE; TOOL;

D O I：

10.1038/ng.2770

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 x 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 x 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

引用

页码：1353 / +

页数：10

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