Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

被引：923

作者：

Patsopoulos, Nikolas A. ^{[1
,2
,3
,4
]}

Baranzini, Sergio E. ^{[5
]}

Santaniello, Adams ^{[5
]}

Shoostari, Parisa ^{[6
,7
,107
]}

Cotsapas, Chris ^{[4
,6
,7
]}

Wong, Garrett ^{[1
,3
]}

Beecham, Ashley H. ^{[8
]}

James, Tojo ^{[9
]}

Replogle, Joseph ^{[2
,3
,4
,10
]}

Vlachos, Ioannis S. ^{[1
,3
,4
]}

McCabe, Cristin ^{[4
]}

Pers, Tune H. ^{[11
]}

Brandes, Aaron ^{[4
]}

White, Charles ^{[4
,10
]}

Keenan, Brendan ^{[12
]}

Cimpean, Maria ^{[10
]}

Winn, Phoebe ^{[10
]}

Panteliadis, Ioannis-Pavlos ^{[1
,4
]}

Robbins, Allison ^{[10
]}

Andlauer, Till F. M. ^{[13
,14
,15
]}

Zarzycki, Onigiusz ^{[1
,4
]}

Dubois, Bénédicte ^{[16
]}

Goris, An ^{[16
]}

Sondergaard, Helle Bach ^{[17
]}

Sellebjerg, Finn ^{[17
]}

Sorensen, Per Soelberg ^{[17
]}

Ullum, Henrik ^{[18
]}

Thorner, Lise Wegner ^{[18
]}

Saarela, Janna ^{[19
]}

Cournu-Rebeix, Isabelle ^{[20
]}

Damotte, Vincent ^{[20
,21
]}

Fontaine, Bertrand ^{[20
,22
]}

Guillot-Noel, Lena ^{[20
]}

Lathrop, Mark ^{[23
,24
,25
,26
]}

Vukusic, Sandra ^{[27
,28
,29
,30
,31
]}

Berthele, Achim ^{[14
,15
]}

Pongratz, Viola ^{[14
,15
]}

Gasperi, Christiane ^{[14
,15
]}

Graetz, Christiane ^{[15
,32
]}

Grummel, Verena ^{[14
,15
]}

Hemmer, Bernhard ^{[14
,15
,33
]}

Hoshi, Muni ^{[14
,15
]}

Knier, Benjamin ^{[14
,15
]}

Korn, Thomas ^{[14
,15
,33
]}

Lill, Christina M. ^{[15
,34
,35
]}

Luessi, Felix ^{[15
,34
]}

Muehlau, Mark ^{[14
,15
]}

Zipp, Frauke ^{[15
,34
]}

Dardiotis, Efthimios ^{[36
]}

机构：

[1] Brigham & Womens Hosp, Dept Neurol, Ann Ramsey Ctr far Neurol Dis, Syst Biol & Comp Sci Program, 75 Francis St, Boston, MA 02115 USA

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

[3] Harvard Med Sch, Boston, MA 02115 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Univ Calif San Francisco, Sandler Nearosci Ctr, Dept Neurol, 676 Nelson Rising Lane, San Francisco, CA 94158 USA

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

[7] Yale Univ, Yale Sch Med, Dept Genet, New Haven, CT 06520 USA

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

[9] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden

[10] Columbia Univ, Med Ctr, Ctr Translat & Computat Neuoimmunol, Multiple Sclerosis Ctr,Dept Neurol, New York, NY USA

[11] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metabol Res, DK-2100 Copenhagen, Denmark

[12] Univ Penn, Perelman Sch Med, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA 19104 USA

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

[14] Tech Univ Munich, Klinikum Rechts Isar, Dept Neurol, D-81675 Munich, Germany

[15] Germa Competence Network Multiple Sclerosis, B-3000 Leuven, Belgium

[16] Katholieke Univ Leuven, Dept Nearosci, Lab Neuroimmunol, Herestr 49 Bus 1022, B-3000 Leuven, Belgium

[17] Univ Copenhagen, Rigshosp, Dept Neurol, Danish Multiple Sclerosis Ctr, Sect 6311, DK-2100 Copenhagen, Denmark

[18] Univ Copenhagen, Rigshosp, Dept Clin Immunol, Sect 2082, DK-2100 Copenhagen, Denmark

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

[20] Sorbonne Univ, Hop Univ Pitie Salpetriere, INSERM, ICM UMR 1127, 47 Blvd Hop, F-75013 Paris, France

[21] Univ Lille, CHU Lille, Inst Pasteur Lille, INSERM,UMR1167, Lille, France

[22] Hop Univ Pitie Salpetriere, Dept Neurol, CRM UMR974, 47 Blvd Hop, F-75013 Paris, France

[23] Ctr Natl Genotypage, Inst Genom, Commissariat Energie Atom, Evry, France

[24] Fdn Jean Dausset, Ctr Etud Polymorphisme Humain, Paris, France

[25] McGill Univ, Montreal, PQ, Canada

[26] Genome Quebec Innovat Ctr, Montreal, PQ, Canada

[27] Hosp Civils Lyon, Serv Neurol Sclerose Plaques Pathol Myeline & Neu, F-69677 Bron, France

[28] Ctr Rech Neurosci Lyon, Observ Francais Sci Plaques, INSERM 1028, F-69003 Lyon, France

[29] CNRS, UMR 5292, F-69003 Lyon, France

[30] Univ Claude Bernard Lyon 1, Univ Lyon, F-69000 Lyon, France

[31] Eugene Dev EDMUS Fdn Multiple Sclerosis, F-69677 Bron, France

[32] Johannes Gutenberg Univ Mainz, Med Ctr, Rmn2, Focus Program Translat Neurosci FTN, Mainz, Germany

[33] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany

[34] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Focus Program Translat Neuosci FTN Immunol FZI, Rmn2,Dept Neurol, Mainz, Germany

[35] Univ Lubeck, Inst Neurogenet, Genet & Mol Epidemiol Grp, Lubeck, Germany

[36] Univ Hosp Larissa, Nearogenet Lah, Neurol Dept, Larisa, Greece

[37] IRCCS S Maria Nascente, Don C Gnocchi Fdn ONLUS, Lab Mol Med & Biotechnol, Milan, Italy

[38] Torino Univ, Dept Med Sci, Turin, Italy

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

[40] Univ Piemonte Orientale, IRCAD, Novara, Italy

[41] AOU Verona, Ctr Reg Sclerosi Multipla, Nearol B, Verona, Italy

[42] Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Milan, Italy

[43] Med Res Council Biostat Unit, Rohinson Way, Cambridge CB2 0SR, England

[44] AO Citta Salute & Sci Torino, Dept Neurosci, MS Ctr, Turin, Italy

[45] Univ Turin, Turin, Italy

[46] Ist Sci San Raffaele, Div Neurosci, Inst Expt Neurol INSPE, Lab Human Genet Neurol Complex Disorder, Via Olgettina 58, I-20132 Milan, Italy

[47] Univ Milan, Dept Biomed Sci Hlth, Milan, Italy

[48] Univ Milan, Dept Hlth Sci, San Paolo Hosp & Filarete Fdn, Viale Ortles 22-4, I-20139 Milan, Italy

[49] Ist Sci San Raffaele, Div Neuosci, Inst Expt Neurol INSPE, Dept Neurol, Via Olgettina 58, I-20132 Milan, Italy

[50] Univ Milan, Dept Pathophysiol & Transplantat, Neurol Unit, Milan, Italy

来源：

SCIENCE | 2019年 / 365卷 / 6460期

基金：

英国医学研究理事会; 英国惠康基金; 瑞典研究理事会;

关键词：

GENE-EXPRESSION; DIAGNOSTIC-CRITERIA; COMPLEX TRAITS; RISK ALLELES; ASSOCIATION; AUTOIMMUNE; HERITABILITY; ARCHITECTURE; METAANALYSIS; MECHANISMS;

D O I：

10.1126/science.aav7188

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses. © 2019 American Association for the Advancement of Science. All rights reserved.

引用

页码：1417 / +

页数：99

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