Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci

被引：87

作者：

McCauley, Jacob L. ^{[1
]}

Zuvich, Rebecca L. ^{[2
]}

Beecham, Ashley H. ^{[1
]}

De Jager, Philip L. ^{[3
,4
,5
,6
]}

Konidari, Ioanna ^{[1
]}

Whitehead, Patrice L. ^{[1
]}

Aubin, Cristin ^{[5
,6
]}

Ban, Maria ^{[7
]}

Pobywajlo, Susan ^{[5
,6
]}

Briskin, Rebeccah ^{[5
,6
]}

Romano, Susan ^{[3
,4
]}

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

Piccio, Laura ^{[10
]}

McArdle, Wendy L. ^{[11
]}

Strachan, David P. ^{[12
]}

Evans, Denis ^{[8
,9
]}

Cross, Anne H. ^{[10
]}

Cree, Bruce ^{[13
]}

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

Barcellos, Lisa F. ^{[16
]}

Ivinson, Adrian J. ^{[17
]}

Compston, Alastair ^{[7
]}

Hafler, David A. ^{[5
,6
,18
]}

Hauser, Stephen L. ^{[13
,19
]}

Oksenberg, Jorge R. ^{[13
,19
]}

Sawcer, Stephen J. ^{[7
]}

Pericak-Vance, Margaret A. ^{[1
]}

Haines, Jonathan L. ^{[2
]}

机构：

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

[2] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37232 USA

[3] Brigham & Womens Hosp, Program NeuroPsychiat Genom, Dept Neurol, Ctr Neurol Dis, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Boston, MA 02115 USA

[5] Harvard Univ, Program Med & Populat Genet, Broad Inst, Cambridge, MA 02139 USA

[6] MIT, Cambridge, MA 02139 USA

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

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

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

[10] Washington Univ, Dept Neurol, St Louis, MO 63110 USA

[11] Univ Bristol, Dept Social Med, Bristol BS8 2BN, Avon, England

[12] Univ London, Div Community Hlth Sci, London SW17 ORE, England

[13] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA 94143 USA

[14] Univ Montreal, Lab Genet & Genom Med Inflammat, Montreal, PQ H1T 1C8, Canada

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

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

[17] Harvard Univ, Harvard NeuroDiscovery Ctr, Sch Med, Boston, MA 02155 USA

[18] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA

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

来源：

HUMAN MOLECULAR GENETICS | 2010年 / 19卷 / 05期

基金：

英国惠康基金; 英国医学研究理事会; 美国国家卫生研究院;

关键词：

INTERLEUKIN-7; RECEPTOR; REPLICATION; LINKAGE; GENES; IL2RA; RISK; CD58;

D O I：

10.1093/hmg/ddp542

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Genome-wide association studies (GWASs) have proven highly effective, identifying hundreds of associations across numerous complex diseases. These studies typically test hundreds of thousands of variations and identify hundreds of potential associations. However, to date, follow-up attempts have generally only concentrated on just the few most significant initial associations, leaving the majority of true associations in any GWAS study without replication. Here, we present a substantially more comprehensive follow-up of the first genome-wide association screen performed in multiple sclerosis (MS), a complex genetic disease with central nervous system inflammation. We genotyped approximately 30 000 single-nucleotide polymorphisms (SNPs) that demonstrated mild-to-moderate levels of significance (P < 0.10) in the initial GWAS in an independent set of 1343 MS cases and 1379 controls. We further replicated several of the most significant findings in another independent data set of 2164 MS cases and 2016 controls. We find considerable evidence for a number of novel susceptibility loci including KIF21B [rs12122721, combined P = 6.56 x 10(-10), odds ratio (OR) = 1.22] and TMEM39A (rs1132200, P = 3.09 x 10(-8), OR = 1.24), both of which meet genome-wide significance. Both of these loci were overlooked in the initial replication, despite being among the top 3000 (similar to 1%) SNP hits in the original screen.

引用

页码：953 / 962

页数：10

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