A genome-wide association study in progressive multiple sclerosis

被引：39

作者：

Martinelli-Boneschi, Filippo ^{[1
,2
]}

Esposito, Federica ^{[1
,2
]}

Brambilla, Paola ^{[1
,2
]}

Lindstrom, Eva ^{[3
]}

Lavorgna, Giovanni ^{[4
]}

Stankovich, Jim ^{[5
]}

Rodegher, Mariaemma ^{[1
,2
]}

Capra, Ruggero

Ghezzi, Angelo

Coniglio, Gabriella ^{[6
]}

Colombo, Bruno ^{[1
,2
]}

Sorosina, Melissa ^{[1
,2
]}

Martinelli, Vittorio ^{[1
,2
]}

Booth, David ^{[7
]}

Oturai, Annette Bang ^{[8
]}

Stewart, Graeme ^{[7
]}

Harbo, Hanne F. ^{[9
,10
]}

Kilpatrick, Trevor John ^{[11
]}

Hillert, Jan ^{[3
]}

Rubio, Justin P. ^{[11
]}

Abderrahim, Hadi ^{[12
]}

Wojcik, Jerome ^{[12
]}

Comi, Giancarlo ^{[1
,2
]}

机构：

[1] Ist Sci San Raffaele, Inst Expt Neurol INSPE, Div Neurosci, I-20132 Milan, Italy

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

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

[4] Ist Sci San Raffaele, DIBIT, I-20132 Milan, Italy

[5] Univ Tasmania, Menzies Res Inst, Hobart, Tas 7001, Australia

[6] San Carlo Hosp, Dept Neurol, Potenza, Italy

[7] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia

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

[9] Univ Oslo, Dept Neurol, N-0316 Oslo, Norway

[10] Hosp & Univ Oslo, Oslo, Norway

[11] Univ Melbourne, Florey Neurosci Inst, Melbourne, Vic 3010, Australia

[12] Merck Serono Genet Res Ctr, Geneva, Switzerland

来源：

MULTIPLE SCLEROSIS JOURNAL | 2012年 / 18卷 / 10期

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

multiple sclerosis; association studies in genetics; single nucleotide polymorphism; genome-wide association study; primary progressive; GENE-EXPRESSION; SUSCEPTIBILITY; IDENTIFICATION; CNTNAP2; RISK; HLA; FAMILIES; RECEPTOR; LINKAGE; REGION;

D O I：

10.1177/1352458512439118

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background: The role played by genetic factors in influencing the clinical course of multiple sclerosis (MS) is not yet well established. Objective: We aimed to identify genetic variants associated with progressive MS (PrMS). Methods: We conducted a genome-wide association study (GWAS) in 197 patients with PrMS and 234 controls of Italian origin. We tested the top 20 single nucleotide polymorphisms (SNPs) with suggestive evidence of association (p-value < 10(-4)) in two independent sets of primary progressive MS cases and controls. Results: We identified a risk-associated SNP in the HLA region in linkage disequilibrium (LD) with DRB1*1501 and DQB*0602 loci, with genome-wide significance (rs3129934(T), p(combined)=6.7x10(-16), OR=2.34, 95% CI=1.90-2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343(G), p(combined)=2.4x10(-5), OR=0.70, 95% CI=0.59-0.83) which maps within a human endogenous retroviral (HERV) element. The new locus did not have a 'cis' effect on RNA expression in lymphoblastic cell lines, but pathway analyses of 'trans' effects point to an expression regulation of genes involved in neurodegeneration, including glutamate metabolism (p < 0.01) and axonal guidance signalling (p < 0.02). Conclusions: We have confirmed the established association with the HLA region and, despite the low statistical power of the study, we found suggestive evidence for association with a novel locus on chromosome 7, with a putative regulatory role.

引用

页码：1384 / 1394

页数：11

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