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. Goodin; Douglas 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 McCauley; Adrian Ivinson; Jorge R. Oksenberg; Margaret Pericak-Vance; Stephen J. Sawcer; Philip L. De Jager; David A. Hafler; Paul I.W. de Bakker

doi:10.1002/ana.22609

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 McCauley, Adrian Ivinson, Jorge R. Oksenberg, Margaret Pericak-Vance, Stephen J. Sawcer, Philip L. De Jager, David A. Hafler, Paul I.W. de Bakker

Research output: Contribution to journal › Article › peer-review

286 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, rs2150702^G in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10^-8), and rs6718520^A 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 language	English
Pages (from-to)	897-912
Number of pages	16
Journal	Annals of Neurology
Volume	70
Issue number	6
DOIs	https://doi.org/10.1002/ana.22609
Publication status	Published - Dec 2011
Externally published	Yes

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Patsopoulos, N. A., Esposito, F., Reischl, J., Lehr, S., Bauer, D., Heubach, J., Sandbrink, R., Pohl, C., Edan, G., Kappos, L., Miller, D., Montalbán, J., Polman, C. H., Freedman, M. S., Hartung, H. P., Arnason, B. G. W., Comi, G., Cook, S., Filippi, M., ... 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

@article{b66f3b24513a4f06a97cff14baae6867,

title = "Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci",

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.",

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

year = "2011",

month = dec,

doi = "10.1002/ana.22609",

language = "English",

volume = "70",

pages = "897--912",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "6",

}

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, J, Ivinson, A, Oksenberg, JR, Pericak-Vance, M, 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

TY - JOUR

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

AU - Ivinson, Adrian

AU - Oksenberg, Jorge R.

AU - Pericak-Vance, Margaret

AU - Sawcer, Stephen J.

AU - De Jager, Philip L.

AU - Hafler, David A.

AU - de Bakker, Paul I.W.

PY - 2011/12

Y1 - 2011/12

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.

UR - http://www.scopus.com/inward/record.url?scp=84255194782&partnerID=8YFLogxK

U2 - 10.1002/ana.22609

DO - 10.1002/ana.22609

M3 - Article

SN - 0364-5134

VL - 70

SP - 897

EP - 912

JO - Annals of Neurology

JF - Annals of Neurology

IS - 6

ER -

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

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