Genome-wide significant association with seven novel multiple sclerosis risk loci

Christina M. Lill; Felix Luessi; Antonio Alcina; Ekaterina A. Sokolova; Nerea Ugidos; Belén de la Hera; Léna Guillot-Noël; Sunny Malhotra; Eva Reinthaler; Brit Maren M. Schjeide; Julia Y. Mescheriakova; Andriy Mashychev; Inken Wohlers; Denis A. Akkad; Orhan Aktas; Iraide Alloza; Alfredo Antigüedad; Rafa Arroyo; Ianire Astobiza; Paul Blaschke; Alexei N. Boyko; Mathias Buttmann; Andrew Chan; Thomas Dörner; Joerg T. Epplen; Olga O. Favorova; Maria Fedetz; Oscar Fernández; Angel García-Martínez; Lisa Ann Gerdes; Christiane Graetz; Hans Peter Hartung; Sabine Hoffjan; Guillermo Izquierdo; Denis S. Korobko; Antje Kroner; Christian Kubisch; Tania Kümpfel; Laura Leyva; Peter Lohse; Nadezhda A. Malkova; Xavier Montalban; Ekaterina V. Popova; Peter Rieckmann; Alexei S. Rozhdestvenskii; Christiane Schmied; Inna V. Smagina; Ekaterina Y. Tsareva; Alexander Winkelmann; Uwe K. Zettl; Harald Binder; Isabelle Cournu-Rebeix; Rogier Hintzen; Alexander Zimprich; Manuel Comabella; Bertrand Fontaine; Elena Urcelay; Koen Vandenbroeck; Maxim Filipenko; Fuencisla Matesanz; Frauke Zipp; Lars Bertram

doi:10.1136/jmedgenet-2015-103442

Genome-wide significant association with seven novel multiple sclerosis risk loci

Christina M. Lill^*
, Felix Luessi
, Antonio Alcina
, Ekaterina A. Sokolova
, Nerea Ugidos
, Belén de la Hera
, Léna Guillot-Noël
, Sunny Malhotra
, Eva Reinthaler
, Brit Maren M. Schjeide
, Julia Y. Mescheriakova
, Andriy Mashychev
, Inken Wohlers
, Denis A. Akkad
, Orhan Aktas
, Iraide Alloza
, Alfredo Antigüedad
, Rafa Arroyo
, Ianire Astobiza
, Paul Blaschke

Alexei N. Boyko, Mathias Buttmann, Andrew Chan, Thomas Dörner, Joerg T. Epplen, Olga O. Favorova, Maria Fedetz, Oscar Fernández, Angel García-Martínez, Lisa Ann Gerdes, Christiane Graetz, Hans Peter Hartung, Sabine Hoffjan, Guillermo Izquierdo, Denis S. Korobko, Antje Kroner, Christian Kubisch, Tania Kümpfel, Laura Leyva, Peter Lohse, Nadezhda A. Malkova, Xavier Montalban, Ekaterina V. Popova, Peter Rieckmann, Alexei S. Rozhdestvenskii, Christiane Schmied, Inna V. Smagina, Ekaterina Y. Tsareva, Alexander Winkelmann, Uwe K. Zettl, Harald Binder, Isabelle Cournu-Rebeix, Rogier Hintzen, Alexander Zimprich, Manuel Comabella, Bertrand Fontaine, Elena Urcelay, Koen Vandenbroeck, Maxim Filipenko, Fuencisla Matesanz, Frauke Zipp, Lars Bertram

^*Corresponding author for this work

Department of Neurology
Johannes Gutenberg University Mainz
Department of Cell Biology and Immunology
Institute of Parasitology and Biomedicine López-Neyra
Novosibirsk State University
Neurogenomiks Laboratory
Universidad del País Vasco (UPV/EHU)
Achucarro Basque Center for Neuroscience
Instituto de Investigacion Sanitaria Del Hospital Universario la Paz (IdiPAZ)
Institute for Cardiometabolism and Nutrition (ICAN)
Universitari Vall d'Hebrón
University of Vienna
Department of Vertebrate Genomics
MPI Molekulare Genetik
Erasmus University Medical Center
Ruhr-University Bochum
Department of Neurology
University of Düsseldorf
Basque Foundation for Science
Servicio de Neurología
Hospital Universitario de Basurto
Multiple Sclerosis Unit
University of Rostock
Moscow State University
University of Würzburg
Department of Neurology
Charite - Universitatsmedizin Berlin
Faculty of Health
University Witten/Herdecke
Unidad de Gestión Clínica de Neurociencias
Hospital Regional Universitario Carlos Haya
Ludwig-Maximilians-Universität
Unidad de Esclerosis Múltiple
Hospital Universitario Virgen Macarena
University of Wisconsin-Madison
University Hospital Hamburg-Eppendorf
Department of Clinical Chemistry
University of Tubingen
Sozialstiftung Bamberg Hospital
Omsk State Medical Academy
Altai State Medical University
Institute for Medical Biostatistics
Département des Maladies du Système Nerveux
Hôpital de la Pitié-Salpêtrière
Department of Neurology
Department of Neurology

36 Citations (Scopus)

Abstract

Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect metaanalysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10^-8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10^-12), CD28 (rs6435203, p=1.35×10^-9), LPP (rs4686953, p=3.35×10^-8), ETS1 (rs3809006, p=7.74×10^-9), DLEU1 (rs806349, p=8.14×10^-12), LPIN3 (rs6072343, p=7.16×10^-12) and IFNGR2 (rs9808753, p=4.40×10^-10). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.

Original language	English
Journal	Journal of Medical Genetics
Volume	52
Issue number	12
Pages (from-to)	848-855
Number of pages	8
ISSN	0022-2593
DOIs	https://doi.org/10.1136/jmedgenet-2015-103442
Publication status	Published - 01.01.2015

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

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10.1136/jmedgenet-2015-103442

Cite this

Lill, C. M., Luessi, F., Alcina, A., Sokolova, E. A., Ugidos, N., de la Hera, B., Guillot-Noël, L., Malhotra, S., Reinthaler, E., Schjeide, B. M. M., Mescheriakova, J. Y., Mashychev, A., Wohlers, I., Akkad, D. A., Aktas, O., Alloza, I., Antigüedad, A., Arroyo, R., Astobiza, I., ... Bertram, L. (2015). Genome-wide significant association with seven novel multiple sclerosis risk loci. Journal of Medical Genetics, 52(12), 848-855. https://doi.org/10.1136/jmedgenet-2015-103442

@article{a47a06c52bb5405dbf86147fb4e8deb2,

title = "Genome-wide significant association with seven novel multiple sclerosis risk loci",

abstract = "Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect metaanalysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5{\texttimes}10-8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03{\texttimes}10-12), CD28 (rs6435203, p=1.35{\texttimes}10-9), LPP (rs4686953, p=3.35{\texttimes}10-8), ETS1 (rs3809006, p=7.74{\texttimes}10-9), DLEU1 (rs806349, p=8.14{\texttimes}10-12), LPIN3 (rs6072343, p=7.16{\texttimes}10-12) and IFNGR2 (rs9808753, p=4.40{\texttimes}10-10). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.",

author = "Lill, \{Christina M.\} and Felix Luessi and Antonio Alcina and Sokolova, \{Ekaterina A.\} and Nerea Ugidos and \{de la Hera\}, Bel{\'e}n and L{\'e}na Guillot-No{\"e}l and Sunny Malhotra and Eva Reinthaler and Schjeide, \{Brit Maren M.\} and Mescheriakova, \{Julia Y.\} and Andriy Mashychev and Inken Wohlers and Akkad, \{Denis A.\} and Orhan Aktas and Iraide Alloza and Alfredo Antig{\"u}edad and Rafa Arroyo and Ianire Astobiza and Paul Blaschke and Boyko, \{Alexei N.\} and Mathias Buttmann and Andrew Chan and Thomas D{\"o}rner and Epplen, \{Joerg T.\} and Favorova, \{Olga O.\} and Maria Fedetz and Oscar Fern{\'a}ndez and Angel Garc{\'i}a-Mart{\'i}nez and Gerdes, \{Lisa Ann\} and Christiane Graetz and Hartung, \{Hans Peter\} and Sabine Hoffjan and Guillermo Izquierdo and Korobko, \{Denis S.\} and Antje Kroner and Christian Kubisch and Tania K{\"u}mpfel and Laura Leyva and Peter Lohse and Malkova, \{Nadezhda A.\} and Xavier Montalban and Popova, \{Ekaterina V.\} and Peter Rieckmann and Rozhdestvenskii, \{Alexei S.\} and Christiane Schmied and Smagina, \{Inna V.\} and Tsareva, \{Ekaterina Y.\} and Alexander Winkelmann and Zettl, \{Uwe K.\} and Harald Binder and Isabelle Cournu-Rebeix and Rogier Hintzen and Alexander Zimprich and Manuel Comabella and Bertrand Fontaine and Elena Urcelay and Koen Vandenbroeck and Maxim Filipenko and Fuencisla Matesanz and Frauke Zipp and Lars Bertram",

year = "2015",

month = jan,

day = "1",

doi = "10.1136/jmedgenet-2015-103442",

language = "English",

volume = "52",

pages = "848--855",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "12",

}

Lill, CM, Luessi, F, Alcina, A, Sokolova, EA, Ugidos, N, de la Hera, B, Guillot-Noël, L, Malhotra, S, Reinthaler, E, Schjeide, BMM, Mescheriakova, JY, Mashychev, A, Wohlers, I, Akkad, DA, Aktas, O, Alloza, I, Antigüedad, A, Arroyo, R, Astobiza, I, Blaschke, P, Boyko, AN, Buttmann, M, Chan, A, Dörner, T, Epplen, JT, Favorova, OO, Fedetz, M, Fernández, O, García-Martínez, A, Gerdes, LA, Graetz, C, Hartung, HP, Hoffjan, S, Izquierdo, G, Korobko, DS, Kroner, A, Kubisch, C, Kümpfel, T, Leyva, L, Lohse, P, Malkova, NA, Montalban, X, Popova, EV, Rieckmann, P, Rozhdestvenskii, AS, Schmied, C, Smagina, IV, Tsareva, EY, Winkelmann, A, Zettl, UK, Binder, H, Cournu-Rebeix, I, Hintzen, R, Zimprich, A, Comabella, M, Fontaine, B, Urcelay, E, Vandenbroeck, K, Filipenko, M, Matesanz, F, Zipp, F & Bertram, L 2015, 'Genome-wide significant association with seven novel multiple sclerosis risk loci', Journal of Medical Genetics, vol. 52, no. 12, pp. 848-855. https://doi.org/10.1136/jmedgenet-2015-103442

TY - JOUR

T1 - Genome-wide significant association with seven novel multiple sclerosis risk loci

AU - Lill, Christina M.

AU - Luessi, Felix

AU - Alcina, Antonio

AU - Sokolova, Ekaterina A.

AU - Ugidos, Nerea

AU - de la Hera, Belén

AU - Guillot-Noël, Léna

AU - Malhotra, Sunny

AU - Reinthaler, Eva

AU - Schjeide, Brit Maren M.

AU - Mescheriakova, Julia Y.

AU - Mashychev, Andriy

AU - Wohlers, Inken

AU - Akkad, Denis A.

AU - Aktas, Orhan

AU - Alloza, Iraide

AU - Antigüedad, Alfredo

AU - Arroyo, Rafa

AU - Astobiza, Ianire

AU - Blaschke, Paul

AU - Boyko, Alexei N.

AU - Buttmann, Mathias

AU - Chan, Andrew

AU - Dörner, Thomas

AU - Epplen, Joerg T.

AU - Favorova, Olga O.

AU - Fedetz, Maria

AU - Fernández, Oscar

AU - García-Martínez, Angel

AU - Gerdes, Lisa Ann

AU - Graetz, Christiane

AU - Hartung, Hans Peter

AU - Hoffjan, Sabine

AU - Izquierdo, Guillermo

AU - Korobko, Denis S.

AU - Kroner, Antje

AU - Kubisch, Christian

AU - Kümpfel, Tania

AU - Leyva, Laura

AU - Lohse, Peter

AU - Malkova, Nadezhda A.

AU - Montalban, Xavier

AU - Popova, Ekaterina V.

AU - Rieckmann, Peter

AU - Rozhdestvenskii, Alexei S.

AU - Schmied, Christiane

AU - Smagina, Inna V.

AU - Tsareva, Ekaterina Y.

AU - Winkelmann, Alexander

AU - Zettl, Uwe K.

AU - Binder, Harald

AU - Cournu-Rebeix, Isabelle

AU - Hintzen, Rogier

AU - Zimprich, Alexander

AU - Comabella, Manuel

AU - Fontaine, Bertrand

AU - Urcelay, Elena

AU - Vandenbroeck, Koen

AU - Filipenko, Maxim

AU - Matesanz, Fuencisla

AU - Zipp, Frauke

AU - Bertram, Lars

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect metaanalysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10-8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10-12), CD28 (rs6435203, p=1.35×10-9), LPP (rs4686953, p=3.35×10-8), ETS1 (rs3809006, p=7.74×10-9), DLEU1 (rs806349, p=8.14×10-12), LPIN3 (rs6072343, p=7.16×10-12) and IFNGR2 (rs9808753, p=4.40×10-10). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.

AB - Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect metaanalysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10-8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10-12), CD28 (rs6435203, p=1.35×10-9), LPP (rs4686953, p=3.35×10-8), ETS1 (rs3809006, p=7.74×10-9), DLEU1 (rs806349, p=8.14×10-12), LPIN3 (rs6072343, p=7.16×10-12) and IFNGR2 (rs9808753, p=4.40×10-10). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.

UR - https://www.scopus.com/pages/publications/84954285551

U2 - 10.1136/jmedgenet-2015-103442

DO - 10.1136/jmedgenet-2015-103442

M3 - Journal articles

C2 - 26475045

AN - SCOPUS:84954285551

SN - 0022-2593

VL - 52

SP - 848

EP - 855

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 12

ER -

Genome-wide significant association with seven novel multiple sclerosis risk loci

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