Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

被引：620

作者：

De Jager, Philip L. ^{[1
,2
,3
,4
]}

Jia, Xiaoming ^{[5
]}

Wang, Joanne ^{[6
,7
]}

de Bakker, Paul I. W. ^{[3
,4
,5
]}

Ottoboni, Linda ^{[1
,2
,3
,4
]}

Aggarwal, Neelum T. ^{[8
,9
]}

Piccio, Laura ^{[10
]}

Raychaudhuri, Soumya ^{[3
,4
,11
]}

Tran, Dong ^{[3
,4
]}

Aubin, Cristin ^{[3
,4
]}

Briskin, Rebeccah ^{[2
]}

Romano, Susan ^{[1
]}

Baranzini, Sergio E. ^{[6
]}

McCauley, Jacob L. ^{[12
]}

Pericak-Vance, Margaret A. ^{[12
]}

Haines, Jonathan L. ^{[13
]}

Gibson, Rachel A. ^{[14
,15
]}

Naeglin, Yvonne ^{[16
]}

Uitdehaag, Bernard ^{[17
]}

Matthews, Paul M. ^{[14
,15
]}

Kappos, Ludwig ^{[16
]}

Polman, Chris ^{[17
]}

McArdle, Wendy L. ^{[18
]}

Strachan, David P. ^{[19
]}

Evans, Denis ^{[8
,9
]}

Cross, Anne H. ^{[10
]}

Daly, Mark J. ^{[3
,4
,20
]}

Compston, Alastair ^{[21
]}

Sawcer, Stephen J. ^{[21
]}

Weiner, Howard L. ^{[1
]}

Hauser, Stephen L. ^{[6
,7
]}

Hafler, David A. ^{[1
,3
,4
]}

Oksenberg, Jorge R. ^{[6
,7
]}

机构：

[1] Brigham & Womens Hosp, Div Mol Immunol, Ctr Neurol Dis, Dept Neurol, Boston, MA 02115 USA

[2] Partners Ctr Personalized Genet Med, Boston, MA USA

[3] Harvard Univ, Program Med & Populat Genet, Broad Inst, Cambridge, MA 02138 USA

[4] MIT, Cambridge, MA 02139 USA

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

[6] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[7] Univ Calif San Francisco, Inst Human Genet, Sch Med, San Francisco, CA 94143 USA

[8] Rush Univ, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[9] Rush Univ, Dept Neurol Sci, Chicago, IL 60612 USA

[10] Washington Univ, Dept Neurol, St Louis, MO USA

[11] Brigham & Womens Hosp, Dept Med, Div Immunol Allergy & Rheumatol, Boston, MA 02115 USA

[12] Univ Miami, Miller Sch Med, Miami Inst Human Genom, Miami, FL 33136 USA

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

[14] Univ London Imperial Coll Sci Technol & Med, Dept Clin Neurosci, London SW7 2AZ, England

[15] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, GlaxoSmithKline Clin Imaging Ctr, London SW7 2AZ, England

[16] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland

[17] Vrije Univ Amsterdam, Med Ctr, Dept Neurol, Amsterdam, Netherlands

[18] Univ Bristol, Dept Social Med, Bristol, Avon, England

[19] Univ London, Div Community Hlth Sci, London, England

[20] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

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

来源：

NATURE GENETICS | 2009年 / 41卷 / 07期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

SYSTEMIC-LUPUS-ERYTHEMATOSUS; PERIPHERAL-BLOOD CELLS; WIDE ASSOCIATION; PERIODIC-SYNDROME; R92Q MUTATION; RHEUMATOID-ARTHRITIS; HAPLOTYPE MAP; INTERFERON; DISEASE; RISK;

D O I：

10.1038/ng.401

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.73 x 10(-9)) and CD6 (P = 3.79 x 10(-9)). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency 0.02; odds ratio 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

引用

页码：776 / U26

页数：10

共 48 条

[1] The tumor-necrosis-factor receptor-associated periodic syndrome:: New mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers [J].

Aksentijevich, I ;

Galon, J ;

Soares, M ;

Mansfield, E ;

Hull, K ;

Oh, HH ;

Goldbach-Mansky, R ;

Dean, J ;

Athreya, B ;

Reginato, AJ ;

Henrickson, M ;

Pons-Estel, B ;

O'Shea, JJ ;

Kastner, DL .

AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 69 (02) :301-314

[2] TNF neutralization in MS - Results of a randomized, placebo-controlled multicenter study [J].

Arnason, BGW ;

Jacobs, G ;

Hanlon, M ;

Clay, BH ;

Noronha, ABC ;

Auty, A ;

Davis, B ;

Nath, A ;

Bouchard, JP ;

Belanger, C ;

Gosselin, F ;

Thibault, M ;

Duquette, P ;

Bourgoin, P ;

DuBois, R ;

Girard, M ;

Ebers, GC ;

Rice, GPA ;

Vandervoort, MK ;

Francis, GS ;

Duncan, L ;

Lapierre, Y ;

Freedman, MS ;

Christie, SN ;

Rabinovitch, HE ;

Patry, D ;

Murphy, WF ;

Peters, S ;

McGuiness, SD ;

Murray, TJ ;

Bhan, V ;

Maxner, CE ;

Van Dorpe, R ;

Oger, JJ ;

Nelson, J ;

Morrison, W ;

Bogle, N ;

Beall, S ;

Vorobeychick, G ;

Hiltbrunner, AV ;

Bock, J ;

Habil ;

Lesslauer, W ;

Li, DKB ;

Paty, DW ;

Zhao, GJ .

NEUROLOGY, 1999, 53 (03) :457-465

[3] Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis [J].

Aulchenko, Yurii S. ;

Hoppenbrouwers, Ilse A. ;

Ramagopalan, Sreeram V. ;

Broer, Linda ;

Jafari, Naghmeh ;

Hillert, Jan ;

Link, Jenny ;

Lundstrom, Wangko ;

Greiner, Eva ;

Sadovnick, A. Dessa ;

Goossens, Dirk ;

Van Broeckhoven, Christine ;

Del-Favero, Jurgen ;

Ebers, George C. ;

Oostra, Ben A. ;

van Duijn, Cornelia M. ;

Hintzen, Rogier Q. .

NATURE GENETICS, 2008, 40 (12) :1402-1403

[4] Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus [J].

Baechler, EC ;

Batliwalla, FM ;

Karypis, G ;

Gaffney, PM ;

Ortmann, WA ;

Espe, KJ ;

Shark, KB ;

Grande, WJ ;

Hughes, KM ;

Kapur, V ;

Gregersen, PK ;

Behrens, TW .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (05) :2610-2615

[5] Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis [J].

Baranzini, Sergio E. ;

Wang, Joanne ;

Gibson, Rachel A. ;

Galwey, Nicholas ;

Naegelin, Yvonne ;

Barkhof, Frederik ;

Radue, Ernst-Wilhelm ;

Lindberg, Raija L. P. ;

Uitdehaag, Bernard M. G. ;

Johnson, Michael R. ;

Angelakopoulou, Aspasia ;

Hall, Leslie ;

Richardson, Jill C. ;

Prinjha, Rab K. ;

Gass, Achim ;

Geurts, Jeroen J. G. ;

Kragt, Jolijn ;

Sombekke, Madeleine ;

Vrenken, Hugo ;

Qualley, Pamela ;

Lincoln, Robin R. ;

Gomez, Refujia ;

Caillier, Stacy J. ;

George, Michaela F. ;

Mousavi, Hourieh ;

Guerrero, Rosa ;

Okuda, Darin T. ;

Cree, Bruce A. C. ;

Green, Ari J. ;

Waubant, Emmanuelle ;

Goodin, Douglas S. ;

Pelletier, Daniel ;

Matthews, Paul M. ;

Hauser, Stephen L. ;

Kappos, Ludwig ;

Polman, Chris H. ;

Oksenberg, Jorge R. .

HUMAN MOLECULAR GENETICS, 2009, 18 (04) :767-778

[6] Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis [J].

Barcellos, Lisa F. ;

Sawcer, Stephen ;

Ramsay, Patricia P. ;

Baranzini, Sergio E. ;

Thomson, Glenys ;

Briggs, Farren ;

Cree, Bruce C. A. ;

Begovich, Ann B. ;

Villoslada, Pablo ;

Montalban, Xavier ;

Uccelli, Antonio ;

Savettieri, Giovanni ;

Lincoln, Robin R. ;

DeLoa, Carolyn ;

Haines, Jonathan L. ;

Pericak-Vance, Margaret A. ;

Compston, Alastair ;

Hauser, Stephen L. ;

Oksenberg, Jorge R. .

HUMAN MOLECULAR GENETICS, 2006, 15 (18) :2813-2824

[7] Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].

Barrett, Jeffrey C. ;

Hansoul, Sarah ;

Nicolae, Dan L. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Rioux, John D. ;

Brant, Steven R. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Barmada, M. Michael ;

Bitton, Alain ;

Dassopoulos, Themistocles ;

Datta, Lisa Wu ;

Green, Todd ;

Griffiths, Anne M. ;

Kistner, Emily O. ;

Murtha, Michael T. ;

Regueiro, Miguel D. ;

Rotter, Jerome I. ;

Schumm, L. Philip ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Xavier, Ramnik J. ;

Libioulle, Cecile ;

Sandor, Cynthia ;

Lathrop, Mark ;

Belaiche, Jacques ;

Dewit, Olivier ;

Gut, Ivo ;

Heath, Simon ;

Laukens, Debby ;

Mni, Myriam ;

Rutgeerts, Paul ;

Van Gossum, Andre ;

Zelenika, Diana ;

Franchimont, Denis ;

Hugot, Jean-Pierre ;

de Vos, Martine ;

Vermeire, Severine ;

Louis, Edouard ;

Cardon, Lon R. ;

Anderson, Carl A. ;

Drummond, Hazel ;

Nimmo, Elaine ;

Ahmad, Tariq ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fisher, Sheila A. ;

Marchini, Jonathan ;

Ghori, Jilur .

NATURE GENETICS, 2008, 40 (08) :955-962

[8] Design of the Chicago Health and Aging Project (CHAP) [J].

Bienias, Julia L. ;

Beckett, Laurel A. ;

Bennett, David A. ;

Wilson, Robert S. ;

Evans, Denis A. .

JOURNAL OF ALZHEIMERS DISEASE, 2003, 5 (05) :349-355

[9] Extracellular Isoforms of CD6 generated by alternative splicing regulate targeting of CD6 to the immunological synapse [J].

Castro, Monica A. A. ;

Oliveira, Marta I. ;

Nunes, Raquel J. ;

Fabre, Stephanie ;

Barbosa, Rita ;

Peixoto, Antonio ;

Brown, Marion H. ;

Parnes, Jane R. ;

Bismuth, Georges ;

Moreira, Alexandra ;

Rocha, Benedita ;

Carmo, Alexandre M. .

JOURNAL OF IMMUNOLOGY, 2007, 178 (07) :4351-4361

[10] A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC [J].

de Bakker, Paul I. W. ;

McVean, Gil ;

Sabeti, Pardis C. ;

Miretti, Marcos M. ;

Green, Todd ;

Marchini, Jonathan ;

Ke, Xiayi ;

Monsuur, Alienke J. ;

Whittaker, Pamela ;

Delgado, Marcos ;

Morrison, Jonathan ;

Richardson, Angela ;

Walsh, Emily C. ;

Gao, Xiaojiang ;

Galver, Luana ;

Hart, John ;

Hafler, David A. ;

Pericak-Vance, Margaret ;

Todd, John A. ;

Daly, Mark J. ;

Trowsdale, John ;

Wijmenga, Cisca ;

Vyse, Tim J. ;

Beck, Stephan ;

Murray, Sarah Shaw ;

Carrington, Mary ;

Gregory, Simon ;

Deloukas, Panos ;

Rioux, John D. .

NATURE GENETICS, 2006, 38 (10) :1166-1172

← 1 2 3 4 5 →