IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

被引：59

作者：

Esposito, F. ^{[1
,2
]}

Patsopoulos, N. A. ^{[3
,4
,5
]}

Cepok, S. ^{[6
]}

Kockum, I. ^{[7
,8
]}

Leppa, V. ^{[9
,10
]}

Booth, D. R. ^{[11
]}

Heard, R. N. ^{[11
]}

Stewart, G. J. ^{[11
]}

Cox, M. ^{[12
]}

Scott, R. J. ^{[12
]}

Lechner-Scott, J. ^{[12
]}

Goris, A. ^{[13
]}

Dobosi, R. ^{[13
]}

Dubois, B. ^{[13
]}

Rioux, J. D. ^{[14
,15
]}

Oturai, A. B. ^{[16
]}

Sondergaard, H. B. ^{[16
]}

Sellebjerg, F. ^{[16
]}

Sorensen, P. S. ^{[16
]}

Reunanen, M. ^{[17
]}

Koivisto, K. ^{[18
]}

Cournu-Rebeix, I. ^{[19
,20
,21
]}

Fontaine, B. ^{[19
,20
,21
]}

Winkelmann, J. ^{[22
,23
,24
]}

Gieger, C. ^{[25
]}

Infante-Duarte, C. ^{[26
]}

Zipp, F. ^{[27
]}

Bergamaschi, L. ^{[28
,29
]}

Leone, M. ^{[30
]}

Bergamaschi, R. ^{[31
]}

Cavalla, P. ^{[32
]}

Lorentzen, A. R. ^{[33
,34
]}

Mero, I-L ^{[34
,35
]}

Celius, E. G. ^{[35
]}

Harbo, H. F. ^{[33
,35
]}

Spurkland, A. ^{[36
]}

Comabella, M. ^{[37
]}

Brynedal, B.

Alfredsson, L. ^{[38
]}

Bernardinelli, L. ^{[39
,40
]}

Robertson, N. P. ^{[41
]}

Hawkins, C. P. ^{[42
,43
]}

Barcellos, L. F. ^{[44
]}

Beecham, G. ^{[45
]}

Bush, W. ^{[46
]}

Cree, B. A. C. ^{[47
]}

Daly, M. J. ^{[48
,49
,50
]}

Ivinson, A. J. ^{[51
]}

Aubin, C. ^{[49
,50
]}

Compston, A. ^{[52
]}

机构：

[1] Ist Sci San Raffaele, Dept Neurol, I-20132 Milan, Italy

[2] Ist Sci San Raffaele, Inst Expt Neurol, I-20132 Milan, Italy

[3] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

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

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

[6] Tech Univ Munich, Klinikum Rechts Isar, D-8000 Munich, Germany

[7] Karolinska Inst, Karolinska Univ Hosp, Dept Clin Neurosci, Neuroimmunol Unit, Solna, Sweden

[8] Karolinska Inst, Karolinska Univ Hosp, Ctr Mol Med, Solna, Sweden

[9] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland

[10] Univ Helsinki, FIMM, Helsinki, Finland

[11] Univ Sydney, Westmead Hosp, Inst Immunol & Allergy Res, Westmead Millennium Inst, Sydney, NSW 2006, Australia

[12] Univ Newcastle, Callaghan, NSW 2308, Australia

[13] Katholieke Univ Leuven, Sect Expt Neurol, Leuven, Belgium

[14] Univ Montreal, Montreal, PQ, Canada

[15] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada

[16] Copenhagen Univ Hosp, Rigshosp, Danish Multiple Sclerosis Res Ctr, DK-2100 Copenhagen, Denmark

[17] Oulu Univ Hosp, Dept Neurol, Oulu, Finland

[18] Cent Hosp Seinajoki, Seinajoki, Finland

[19] INSERM, UMR S975, Paris, France

[20] Univ Paris 06, Ctr Rech Inst Cerveau & Moelle, CNRS 7225, UMR S975, Paris, France

[21] Hop La Pitie Salpetriere, AP HP, Dept Neurol, F-75651 Paris, France

[22] Tech Univ Munich, Neurol Klin, Munich, Germany

[23] Tech Univ Munich, Inst Humangenet, Munich, Germany

[24] Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany

[25] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, Munich, Germany

[26] Charite, Cecilie Vogt Clin Neurol, D-13353 Berlin, Germany

[27] Johannes Gutenberg Univ Mainz, Univ Med Mainz, Dept Neurol, Mainz, Germany

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

[29] Univ Piemonte Orientale, Dept Med Sci, Novara, Italy

[30] AOU Maggiore Carita, Neurol Clin, Novara, Italy

[31] IRCCS, Neurol Inst C Mondino, Pavia, Italy

[32] Osped San Giovanni Battista Torino, Dept Neurol, Turin, Italy

[33] Univ Oslo, Ulleval Univ Hosp, Fac Div, Dept Neurol, Oslo, Norway

[34] Oslo Univ Hosp, Rikshosp, Inst Immunol, Oslo, Norway

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

[36] Univ Oslo, Inst Basal Med Sci, Oslo, Norway

[37] Hosp Univ Vall Hebron, CEM Cat, Unitat Neuroimmunol Clin, Barcelona, Spain

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

[39] Univ Pavia, Dept Appl Sci, I-27100 Pavia, Italy

[40] Univ Cambridge, Stat Lab, Ctr Math Sci, Cambridge CB2 1SB, England

[41] Univ Wales Hosp, Dept Neurol, Cardiff CF4 4XW, S Glam, Wales

[42] Keele Univ, Human Genom Res Grp, Stoke On Trent, Staffs, England

[43] Univ Hosp N Staffordshire, Dept Neurol, Stoke On Trent, Staffs, England

[44] Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Berkeley, CA 94720 USA

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

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

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

[48] Massachusetts Gen Hosp, Boston, MA 02114 USA

[49] MIT, Cambridge, MA 02139 USA

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

来源：

GENES AND IMMUNITY | 2010年 / 11卷 / 05期

基金：

瑞典研究理事会; 英国医学研究理事会;

关键词：

multiple sclerosis; susceptibility loci; eQTL; GENOME-WIDE ASSOCIATION; DIAGNOSTIC-CRITERIA; RISK; METAANALYSIS; VARIANTS; DISEASE; GENE; P12(DOC-1); NUCLEOTIDE; ISOLATE;

D O I：

10.1038/gene.2010.28

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value = 3.55 x 10(-9)), IL12A (P = 3.08 x 10(-8)) and MPHOSPH9/CDK2AP1 (P = 3.96 x 10(-8)). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P - 1.18 x 10(-5)) and in peripheral blood mononuclear cells from subjects with MS (P - 0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation. Genes and Immunity (2010) 11, 397-405; doi: 10.1038/gene.2010.28; published online 17 June 2010

引用

页码：397 / 405

页数：9

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