A genome-wide association study in progressive multiple sclerosis

Filippo Martinelli-Boneschi, Federica Esposito, Paola Brambilla, Eva Lindström, Giovanni Lavorgna, Jim Stankovich, Mariaemma Rodegher, Ruggero Capra, Angelo Ghezzi, Gabriella Coniglio, Bruno Colombo, Melissa Sorosina, Vittorio Martinelli, David Booth, Annette Bang Oturai, Graeme Stewart, Hanne F. Harbo, Trevor John Kilpatrick, Jan Hillert, Justin P. Rubio & 3 others Hadi Abderrahim, Jerome Wojcik, Giancarlo Comi

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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 (rs3129934T, pcombined=6.7×10-16, OR=2.34, 95% CI=1.90-2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343G, pcombined=2.4×10-5, 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.

Original languageEnglish
Pages (from-to)1384-1394
Number of pages11
JournalMultiple Sclerosis
Volume18
Issue number10
DOIs
Publication statusPublished - 1 Oct 2012
Externally publishedYes

Fingerprint

Genome-Wide Association Study
Multiple Sclerosis
Single Nucleotide Polymorphism
Chronic Progressive Multiple Sclerosis
Chromosomes, Human, Pair 7
Linkage Disequilibrium
Gene Expression Regulation
Glutamic Acid
Chromosomes
Genome
RNA
Cell Line

Keywords

  • association studies in genetics
  • genome-wide association study
  • multiple sclerosis
  • primary progressive
  • single nucleotide polymorphism

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Martinelli-Boneschi, F., Esposito, F., Brambilla, P., Lindström, E., Lavorgna, G., Stankovich, J., ... Comi, G. (2012). A genome-wide association study in progressive multiple sclerosis. Multiple Sclerosis, 18(10), 1384-1394. https://doi.org/10.1177/1352458512439118

A genome-wide association study in progressive multiple sclerosis. / Martinelli-Boneschi, Filippo; Esposito, Federica; Brambilla, Paola; Lindström, Eva; Lavorgna, Giovanni; Stankovich, Jim; Rodegher, Mariaemma; Capra, Ruggero; Ghezzi, Angelo; Coniglio, Gabriella; Colombo, Bruno; Sorosina, Melissa; Martinelli, Vittorio; Booth, David; Oturai, Annette Bang; Stewart, Graeme; Harbo, Hanne F.; Kilpatrick, Trevor John; Hillert, Jan; Rubio, Justin P.; Abderrahim, Hadi; Wojcik, Jerome; Comi, Giancarlo.

In: Multiple Sclerosis, Vol. 18, No. 10, 01.10.2012, p. 1384-1394.

Research output: Contribution to journalArticle

Martinelli-Boneschi, F, Esposito, F, Brambilla, P, Lindström, E, Lavorgna, G, Stankovich, J, Rodegher, M, Capra, R, Ghezzi, A, Coniglio, G, Colombo, B, Sorosina, M, Martinelli, V, Booth, D, Oturai, AB, Stewart, G, Harbo, HF, Kilpatrick, TJ, Hillert, J, Rubio, JP, Abderrahim, H, Wojcik, J & Comi, G 2012, 'A genome-wide association study in progressive multiple sclerosis', Multiple Sclerosis, vol. 18, no. 10, pp. 1384-1394. https://doi.org/10.1177/1352458512439118
Martinelli-Boneschi F, Esposito F, Brambilla P, Lindström E, Lavorgna G, Stankovich J et al. A genome-wide association study in progressive multiple sclerosis. Multiple Sclerosis. 2012 Oct 1;18(10):1384-1394. https://doi.org/10.1177/1352458512439118
Martinelli-Boneschi, Filippo ; Esposito, Federica ; Brambilla, Paola ; Lindström, Eva ; Lavorgna, Giovanni ; Stankovich, Jim ; Rodegher, Mariaemma ; Capra, Ruggero ; Ghezzi, Angelo ; Coniglio, Gabriella ; Colombo, Bruno ; Sorosina, Melissa ; Martinelli, Vittorio ; Booth, David ; Oturai, Annette Bang ; Stewart, Graeme ; Harbo, Hanne F. ; Kilpatrick, Trevor John ; Hillert, Jan ; Rubio, Justin P. ; Abderrahim, Hadi ; Wojcik, Jerome ; Comi, Giancarlo. / A genome-wide association study in progressive multiple sclerosis. In: Multiple Sclerosis. 2012 ; Vol. 18, No. 10. pp. 1384-1394.
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AU - Esposito, Federica

AU - Brambilla, Paola

AU - Lindström, Eva

AU - Lavorgna, Giovanni

AU - Stankovich, Jim

AU - Rodegher, Mariaemma

AU - Capra, Ruggero

AU - Ghezzi, Angelo

AU - Coniglio, Gabriella

AU - Colombo, Bruno

AU - Sorosina, Melissa

AU - Martinelli, Vittorio

AU - Booth, David

AU - Oturai, Annette Bang

AU - Stewart, Graeme

AU - Harbo, Hanne F.

AU - Kilpatrick, Trevor John

AU - Hillert, Jan

AU - Rubio, Justin P.

AU - Abderrahim, Hadi

AU - Wojcik, Jerome

AU - Comi, Giancarlo

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N2 - 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 (rs3129934T, pcombined=6.7×10-16, OR=2.34, 95% CI=1.90-2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343G, pcombined=2.4×10-5, 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.

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