Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

Nikolaos A. Patsopoulos, Federica Esposito, Joachim Reischl, Stephan Lehr, David Bauer, Jürgen Heubach, Rupert Sandbrink, Christoph Pohl, Gilles Edan, Ludwig Kappos, David Miller, Javier Montalbán, Chris H. Polman, Mark S. Freedman, Hans Peter Hartung, Barry G W Arnason, Giancarlo Comi, Stuart Cook, Massimo Filippi, Douglas S. GoodinDouglas Jeffery, Paul O'Connor, George C. Ebers, Dawn Langdon, Anthony T. Reder, Anthony Traboulsee, Frauke Zipp, Sebastian Schimrigk, Jan Hillert, Melanie Bahlo, David R. Booth, Simon Broadley, Matthew A. Brown, Brian L. Browning, Sharon R. Browning, Helmut Butzkueven, William M. Carroll, Caron Chapman, Simon J. Foote, Lyn Griffiths, Allan G. Kermode, Trevor J. Kilpatrick, Jeanette Lechner-Scott, Mark Marriott, Deborah Mason, Pablo Moscato, Robert N. Heard, Michael P. Pender, Victoria M. Perreau, Devindri Perera, Justin P. Rubio, Rodney J. Scott, Mark Slee, Jim Stankovich, Graeme J. Stewart, Bruce V. Taylor, Niall Tubridy, Ernest Willoughby, James Wiley, Paul Matthews, Filippo M. Boneschi, Alastair Compston, Jonathan Haines, Stephen L. Hauser, Jacob L McCauley, Adrian Ivinson, Jorge R. Oksenberg, Margaret A Pericak-Vance, Stephen J. Sawcer, Philip L. De Jager, David A. Hafler, Paul I W de Bakker

Research output: Contribution to journalArticle

224 Citations (Scopus)

Abstract

Objective: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. Methods: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. Results: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934 T at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10-8) near EOMES, rs2150702G in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10-8), and rs6718520A in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10-8). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10-6, some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). Interpretation: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.

Original languageEnglish
Pages (from-to)897-912
Number of pages16
JournalAnnals of Neurology
Volume70
Issue number6
DOIs
StatePublished - Dec 1 2011

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Multiple Sclerosis
Meta-Analysis
Genome
Genome-Wide Association Study
Odds Ratio
Single Nucleotide Polymorphism
Blood Cells
Chromosomes
RNA
HapMap Project
Intergenic DNA
Genetic Association Studies
Demyelinating Diseases
Introns
Alleles
Genes
Datasets

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Patsopoulos, N. A., Esposito, F., Reischl, J., Lehr, S., Bauer, D., Heubach, J., ... de Bakker, P. I. W. (2011). Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Annals of Neurology, 70(6), 897-912. https://doi.org/10.1002/ana.22609

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. / Patsopoulos, Nikolaos A.; Esposito, Federica; Reischl, Joachim; Lehr, Stephan; Bauer, David; Heubach, Jürgen; Sandbrink, Rupert; Pohl, Christoph; Edan, Gilles; Kappos, Ludwig; Miller, David; Montalbán, Javier; Polman, Chris H.; Freedman, Mark S.; Hartung, Hans Peter; Arnason, Barry G W; Comi, Giancarlo; Cook, Stuart; Filippi, Massimo; Goodin, Douglas S.; Jeffery, Douglas; O'Connor, Paul; Ebers, George C.; Langdon, Dawn; Reder, Anthony T.; Traboulsee, Anthony; Zipp, Frauke; Schimrigk, Sebastian; Hillert, Jan; Bahlo, Melanie; Booth, David R.; Broadley, Simon; Brown, Matthew A.; Browning, Brian L.; Browning, Sharon R.; Butzkueven, Helmut; Carroll, William M.; Chapman, Caron; Foote, Simon J.; Griffiths, Lyn; Kermode, Allan G.; Kilpatrick, Trevor J.; Lechner-Scott, Jeanette; Marriott, Mark; Mason, Deborah; Moscato, Pablo; Heard, Robert N.; Pender, Michael P.; Perreau, Victoria M.; Perera, Devindri; Rubio, Justin P.; Scott, Rodney J.; Slee, Mark; Stankovich, Jim; Stewart, Graeme J.; Taylor, Bruce V.; Tubridy, Niall; Willoughby, Ernest; Wiley, James; Matthews, Paul; Boneschi, Filippo M.; Compston, Alastair; Haines, Jonathan; Hauser, Stephen L.; McCauley, Jacob L; Ivinson, Adrian; Oksenberg, Jorge R.; Pericak-Vance, Margaret A; Sawcer, Stephen J.; De Jager, Philip L.; Hafler, David A.; de Bakker, Paul I W.

In: Annals of Neurology, Vol. 70, No. 6, 01.12.2011, p. 897-912.

Research output: Contribution to journalArticle

Patsopoulos, NA, Esposito, F, Reischl, J, Lehr, S, Bauer, D, Heubach, J, Sandbrink, R, Pohl, C, Edan, G, Kappos, L, Miller, D, Montalbán, J, Polman, CH, Freedman, MS, Hartung, HP, Arnason, BGW, Comi, G, Cook, S, Filippi, M, Goodin, DS, Jeffery, D, O'Connor, P, Ebers, GC, Langdon, D, Reder, AT, Traboulsee, A, Zipp, F, Schimrigk, S, Hillert, J, Bahlo, M, Booth, DR, Broadley, S, Brown, MA, Browning, BL, Browning, SR, Butzkueven, H, Carroll, WM, Chapman, C, Foote, SJ, Griffiths, L, Kermode, AG, Kilpatrick, TJ, Lechner-Scott, J, Marriott, M, Mason, D, Moscato, P, Heard, RN, Pender, MP, Perreau, VM, Perera, D, Rubio, JP, Scott, RJ, Slee, M, Stankovich, J, Stewart, GJ, Taylor, BV, Tubridy, N, Willoughby, E, Wiley, J, Matthews, P, Boneschi, FM, Compston, A, Haines, J, Hauser, SL, McCauley, JL, Ivinson, A, Oksenberg, JR, Pericak-Vance, MA, Sawcer, SJ, De Jager, PL, Hafler, DA & de Bakker, PIW 2011, 'Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci', Annals of Neurology, vol. 70, no. 6, pp. 897-912. https://doi.org/10.1002/ana.22609
Patsopoulos NA, Esposito F, Reischl J, Lehr S, Bauer D, Heubach J et al. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Annals of Neurology. 2011 Dec 1;70(6):897-912. https://doi.org/10.1002/ana.22609
Patsopoulos, Nikolaos A. ; Esposito, Federica ; Reischl, Joachim ; Lehr, Stephan ; Bauer, David ; Heubach, Jürgen ; Sandbrink, Rupert ; Pohl, Christoph ; Edan, Gilles ; Kappos, Ludwig ; Miller, David ; Montalbán, Javier ; Polman, Chris H. ; Freedman, Mark S. ; Hartung, Hans Peter ; Arnason, Barry G W ; Comi, Giancarlo ; Cook, Stuart ; Filippi, Massimo ; Goodin, Douglas S. ; Jeffery, Douglas ; O'Connor, Paul ; Ebers, George C. ; Langdon, Dawn ; Reder, Anthony T. ; Traboulsee, Anthony ; Zipp, Frauke ; Schimrigk, Sebastian ; Hillert, Jan ; Bahlo, Melanie ; Booth, David R. ; Broadley, Simon ; Brown, Matthew A. ; Browning, Brian L. ; Browning, Sharon R. ; Butzkueven, Helmut ; Carroll, William M. ; Chapman, Caron ; Foote, Simon J. ; Griffiths, Lyn ; Kermode, Allan G. ; Kilpatrick, Trevor J. ; Lechner-Scott, Jeanette ; Marriott, Mark ; Mason, Deborah ; Moscato, Pablo ; Heard, Robert N. ; Pender, Michael P. ; Perreau, Victoria M. ; Perera, Devindri ; Rubio, Justin P. ; Scott, Rodney J. ; Slee, Mark ; Stankovich, Jim ; Stewart, Graeme J. ; Taylor, Bruce V. ; Tubridy, Niall ; Willoughby, Ernest ; Wiley, James ; Matthews, Paul ; Boneschi, Filippo M. ; Compston, Alastair ; Haines, Jonathan ; Hauser, Stephen L. ; McCauley, Jacob L ; Ivinson, Adrian ; Oksenberg, Jorge R. ; Pericak-Vance, Margaret A ; Sawcer, Stephen J. ; De Jager, Philip L. ; Hafler, David A. ; de Bakker, Paul I W. / Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. In: Annals of Neurology. 2011 ; Vol. 70, No. 6. pp. 897-912.
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abstract = "Objective: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. Methods: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. Results: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934 T at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10-8) near EOMES, rs2150702G in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10-8), and rs6718520A in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10-8). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10-6, some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). Interpretation: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.",
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T1 - Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

AU - Patsopoulos, Nikolaos A.

AU - Esposito, Federica

AU - Reischl, Joachim

AU - Lehr, Stephan

AU - Bauer, David

AU - Heubach, Jürgen

AU - Sandbrink, Rupert

AU - Pohl, Christoph

AU - Edan, Gilles

AU - Kappos, Ludwig

AU - Miller, David

AU - Montalbán, Javier

AU - Polman, Chris H.

AU - Freedman, Mark S.

AU - Hartung, Hans Peter

AU - Arnason, Barry G W

AU - Comi, Giancarlo

AU - Cook, Stuart

AU - Filippi, Massimo

AU - Goodin, Douglas S.

AU - Jeffery, Douglas

AU - O'Connor, Paul

AU - Ebers, George C.

AU - Langdon, Dawn

AU - Reder, Anthony T.

AU - Traboulsee, Anthony

AU - Zipp, Frauke

AU - Schimrigk, Sebastian

AU - Hillert, Jan

AU - Bahlo, Melanie

AU - Booth, David R.

AU - Broadley, Simon

AU - Brown, Matthew A.

AU - Browning, Brian L.

AU - Browning, Sharon R.

AU - Butzkueven, Helmut

AU - Carroll, William M.

AU - Chapman, Caron

AU - Foote, Simon J.

AU - Griffiths, Lyn

AU - Kermode, Allan G.

AU - Kilpatrick, Trevor J.

AU - Lechner-Scott, Jeanette

AU - Marriott, Mark

AU - Mason, Deborah

AU - Moscato, Pablo

AU - Heard, Robert N.

AU - Pender, Michael P.

AU - Perreau, Victoria M.

AU - Perera, Devindri

AU - Rubio, Justin P.

AU - Scott, Rodney J.

AU - Slee, Mark

AU - Stankovich, Jim

AU - Stewart, Graeme J.

AU - Taylor, Bruce V.

AU - Tubridy, Niall

AU - Willoughby, Ernest

AU - Wiley, James

AU - Matthews, Paul

AU - Boneschi, Filippo M.

AU - Compston, Alastair

AU - Haines, Jonathan

AU - Hauser, Stephen L.

AU - McCauley, Jacob L

AU - Ivinson, Adrian

AU - Oksenberg, Jorge R.

AU - Pericak-Vance, Margaret A

AU - Sawcer, Stephen J.

AU - De Jager, Philip L.

AU - Hafler, David A.

AU - de Bakker, Paul I W

PY - 2011/12/1

Y1 - 2011/12/1

N2 - Objective: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. Methods: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. Results: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934 T at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10-8) near EOMES, rs2150702G in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10-8), and rs6718520A in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10-8). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10-6, some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). Interpretation: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.

AB - Objective: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. Methods: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. Results: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934 T at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10-8) near EOMES, rs2150702G in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10-8), and rs6718520A in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10-8). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10-6, some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). Interpretation: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.

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