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

F. Esposito, N. A. Patsopoulos, S. Cepok, I. Kockum, V. Leppä, D. R. Booth, R. N. Heard, G. J. Stewart, M. Cox, R. J. Scott, J. Lechner-Scott, A. Goris, R. Dobosi, B. Dubois, J. D. Rioux, A. B. Oturai, H. B. Søndergaard, F. Sellebjerg, P. S. Sørensen, M. Reunanen & 49 others K. Koivisto, I. Cournu-Rebeix, B. Fontaine, J. Winkelmann, C. Gieger, C. Infante-Duarte, F. Zipp, L. Bergamaschi, M. Leone, R. Bergamaschi, P. Cavalla, A. R. Lorentzen, I. L. Mero, E. G. Celius, H. F. Harbo, A. Spurkland, M. Comabella, B. Bryneda, L. Alfredsson, L. Bernardinelli, N. P. Robertson, C. P. Hawkins, L. F. Barcellos, G. Beecham, W. Bush, B. A C Cree, M. J. Daly, A. J. Ivinson, C. Aubin, A. Compston, S. D'Alfonso, J. L. Haines, S. L. Hauser, B. Hemmer, J. Hillert, J. L. McCauley, J. Oksenberg, T. Olsson, A. Palotie, L. Peltonen, M. A. Pericak-Vance, J. Saarela, S. J. Sawcer, B. Stranger, F. M. Boneschi, G. Comi, D. A. Hafler, P. I W De Bakker, P. L. De Jager

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

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 value3.55 × 10-9), IL12A (P3.08 × 10-8) and MPHOSPH9/CDK2AP1 (P3.96 × 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 (P1.18 × 10 5) and in peripheral blood mononuclear cells from subjects with MS (P0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.

Original languageEnglish
Pages (from-to)397-405
Number of pages9
JournalGenes and Immunity
Volume11
Issue number5
DOIs
Publication statusPublished - Jul 2010

Fingerprint

Multiple Sclerosis
Alleles
Celiac Disease
Single Nucleotide Polymorphism
Meta-Analysis
RNA
Blood Cells
Cell Cycle
Cell Proliferation
Genome
Cell Line

Keywords

  • eQTL
  • multiple sclerosis
  • susceptibility loci

ASJC Scopus subject areas

  • Genetics(clinical)
  • Immunology
  • Genetics
  • Medicine(all)

Cite this

Esposito, F., Patsopoulos, N. A., Cepok, S., Kockum, I., Leppä, V., Booth, D. R., ... De Jager, P. L. (2010). IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes and Immunity, 11(5), 397-405. https://doi.org/10.1038/gene.2010.28

IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. / Esposito, F.; Patsopoulos, N. A.; Cepok, S.; Kockum, I.; Leppä, V.; Booth, D. R.; Heard, R. N.; Stewart, G. J.; Cox, M.; Scott, R. J.; Lechner-Scott, J.; Goris, A.; Dobosi, R.; Dubois, B.; Rioux, J. D.; Oturai, A. B.; Søndergaard, H. B.; Sellebjerg, F.; Sørensen, P. S.; Reunanen, M.; Koivisto, K.; Cournu-Rebeix, I.; Fontaine, B.; Winkelmann, J.; Gieger, C.; Infante-Duarte, C.; Zipp, F.; Bergamaschi, L.; Leone, M.; Bergamaschi, R.; Cavalla, P.; Lorentzen, A. R.; Mero, I. L.; Celius, E. G.; Harbo, H. F.; Spurkland, A.; Comabella, M.; Bryneda, B.; Alfredsson, L.; Bernardinelli, L.; Robertson, N. P.; Hawkins, C. P.; Barcellos, L. F.; Beecham, G.; Bush, W.; Cree, B. A C; Daly, M. J.; Ivinson, A. J.; Aubin, C.; Compston, A.; D'Alfonso, S.; Haines, J. L.; Hauser, S. L.; Hemmer, B.; Hillert, J.; McCauley, J. L.; Oksenberg, J.; Olsson, T.; Palotie, A.; Peltonen, L.; Pericak-Vance, M. A.; Saarela, J.; Sawcer, S. J.; Stranger, B.; Boneschi, F. M.; Comi, G.; Hafler, D. A.; De Bakker, P. I W; De Jager, P. L.

In: Genes and Immunity, Vol. 11, No. 5, 07.2010, p. 397-405.

Research output: Contribution to journalArticle

Esposito, F, Patsopoulos, NA, Cepok, S, Kockum, I, Leppä, V, Booth, DR, Heard, RN, Stewart, GJ, Cox, M, Scott, RJ, Lechner-Scott, J, Goris, A, Dobosi, R, Dubois, B, Rioux, JD, Oturai, AB, Søndergaard, HB, Sellebjerg, F, Sørensen, PS, Reunanen, M, Koivisto, K, Cournu-Rebeix, I, Fontaine, B, Winkelmann, J, Gieger, C, Infante-Duarte, C, Zipp, F, Bergamaschi, L, Leone, M, Bergamaschi, R, Cavalla, P, Lorentzen, AR, Mero, IL, Celius, EG, Harbo, HF, Spurkland, A, Comabella, M, Bryneda, B, Alfredsson, L, Bernardinelli, L, Robertson, NP, Hawkins, CP, Barcellos, LF, Beecham, G, Bush, W, Cree, BAC, Daly, MJ, Ivinson, AJ, Aubin, C, Compston, A, D'Alfonso, S, Haines, JL, Hauser, SL, Hemmer, B, Hillert, J, McCauley, JL, Oksenberg, J, Olsson, T, Palotie, A, Peltonen, L, Pericak-Vance, MA, Saarela, J, Sawcer, SJ, Stranger, B, Boneschi, FM, Comi, G, Hafler, DA, De Bakker, PIW & De Jager, PL 2010, 'IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci', Genes and Immunity, vol. 11, no. 5, pp. 397-405. https://doi.org/10.1038/gene.2010.28
Esposito, F. ; Patsopoulos, N. A. ; Cepok, S. ; Kockum, I. ; Leppä, V. ; Booth, D. R. ; Heard, R. N. ; Stewart, G. J. ; Cox, M. ; Scott, R. J. ; Lechner-Scott, J. ; Goris, A. ; Dobosi, R. ; Dubois, B. ; Rioux, J. D. ; Oturai, A. B. ; Søndergaard, H. B. ; Sellebjerg, F. ; Sørensen, P. S. ; Reunanen, M. ; Koivisto, K. ; Cournu-Rebeix, I. ; Fontaine, B. ; Winkelmann, J. ; Gieger, C. ; Infante-Duarte, C. ; Zipp, F. ; Bergamaschi, L. ; Leone, M. ; Bergamaschi, R. ; Cavalla, P. ; Lorentzen, A. R. ; Mero, I. L. ; Celius, E. G. ; Harbo, H. F. ; Spurkland, A. ; Comabella, M. ; Bryneda, B. ; Alfredsson, L. ; Bernardinelli, L. ; Robertson, N. P. ; Hawkins, C. P. ; Barcellos, L. F. ; Beecham, G. ; Bush, W. ; Cree, B. A C ; Daly, M. J. ; Ivinson, A. J. ; Aubin, C. ; Compston, A. ; D'Alfonso, S. ; Haines, J. L. ; Hauser, S. L. ; Hemmer, B. ; Hillert, J. ; McCauley, J. L. ; Oksenberg, J. ; Olsson, T. ; Palotie, A. ; Peltonen, L. ; Pericak-Vance, M. A. ; Saarela, J. ; Sawcer, S. J. ; Stranger, B. ; Boneschi, F. M. ; Comi, G. ; Hafler, D. A. ; De Bakker, P. I W ; De Jager, P. L. / IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. In: Genes and Immunity. 2010 ; Vol. 11, No. 5. pp. 397-405.
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T1 - IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

AU - Esposito, F.

AU - Patsopoulos, N. A.

AU - Cepok, S.

AU - Kockum, I.

AU - Leppä, V.

AU - Booth, D. R.

AU - Heard, R. N.

AU - Stewart, G. J.

AU - Cox, M.

AU - Scott, R. J.

AU - Lechner-Scott, J.

AU - Goris, A.

AU - Dobosi, R.

AU - Dubois, B.

AU - Rioux, J. D.

AU - Oturai, A. B.

AU - Søndergaard, H. B.

AU - Sellebjerg, F.

AU - Sørensen, P. S.

AU - Reunanen, M.

AU - Koivisto, K.

AU - Cournu-Rebeix, I.

AU - Fontaine, B.

AU - Winkelmann, J.

AU - Gieger, C.

AU - Infante-Duarte, C.

AU - Zipp, F.

AU - Bergamaschi, L.

AU - Leone, M.

AU - Bergamaschi, R.

AU - Cavalla, P.

AU - Lorentzen, A. R.

AU - Mero, I. L.

AU - Celius, E. G.

AU - Harbo, H. F.

AU - Spurkland, A.

AU - Comabella, M.

AU - Bryneda, B.

AU - Alfredsson, L.

AU - Bernardinelli, L.

AU - Robertson, N. P.

AU - Hawkins, C. P.

AU - Barcellos, L. F.

AU - Beecham, G.

AU - Bush, W.

AU - Cree, B. A C

AU - Daly, M. J.

AU - Ivinson, A. J.

AU - Aubin, C.

AU - Compston, A.

AU - D'Alfonso, S.

AU - Haines, J. L.

AU - Hauser, S. L.

AU - Hemmer, B.

AU - Hillert, J.

AU - McCauley, J. L.

AU - Oksenberg, J.

AU - Olsson, T.

AU - Palotie, A.

AU - Peltonen, L.

AU - Pericak-Vance, M. A.

AU - Saarela, J.

AU - Sawcer, S. J.

AU - Stranger, B.

AU - Boneschi, F. M.

AU - Comi, G.

AU - Hafler, D. A.

AU - De Bakker, P. I W

AU - De Jager, P. L.

PY - 2010/7

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N2 - 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 value3.55 × 10-9), IL12A (P3.08 × 10-8) and MPHOSPH9/CDK2AP1 (P3.96 × 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 (P1.18 × 10 5) and in peripheral blood mononuclear cells from subjects with MS (P0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.

AB - 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 value3.55 × 10-9), IL12A (P3.08 × 10-8) and MPHOSPH9/CDK2AP1 (P3.96 × 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 (P1.18 × 10 5) and in peripheral blood mononuclear cells from subjects with MS (P0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.

KW - eQTL

KW - multiple sclerosis

KW - susceptibility loci

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