Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Till F.M. Andlauer; Dorothea Buck; Gisela Antony; Antonios Bayas; Lukas Bechmann; Achim Berthele; Andrew Chan; Christiane Gasperi; Ralf Gold; Christiane Graetz; Jürgen Haas; Michael Hecker; Carmen Infante-Duarte; Matthias Knop; Tania Kümpfel; Volker Limmroth; Ralf A. Linker; Verena Loleit; Felix Luessi; Sven G. Meuth; Mark Mühlau; Sandra Nischwitz; Friedemann Paul; Michael Pütz; Tobias Ruck; Anke Salmen; Martin Stangel; Jan Patrick Stellmann; Klarissa H. Stürner; Björn Tackenberg; Florian Then Bergh; Hayrettin Tumani; Clemens Warnke; Frank Weber; Heinz Wiendl; Brigitte Wildemann; Uwe K. Zettl; Ulf Ziemann; Frauke Zipp; Janine Arloth; Peter Weber; Milena Radivojkov-Blagojevic; Markus O. Scheinhardt; Theresa Dankowski; Thomas Bettecken; Peter Lichtner; Darina Czamara; Tania Carrillo-Roa; Elisabeth B. Binder; Klaus Berger; Lars Bertram; Andre Franke; Christian Gieger; Stefan Herms; Georg Homuth; Marcus Ising; Karl Heinz Jöckel; Tim Kacprowski; Stefan Kloiber; Matthias Laudes; Wolfgang Lieb; Christina M. Lill; Susanne Lucae; Thomas Meitinger; Susanne Moebus; Martina Müller-Nurasyid; Markus M. Nöthen; Astrid Petersmann; Rajesh Rawal; Ulf Schminke; Konstantin Strauch; Henry Völzke; Melanie Waldenberger; Jürgen Wellmann; Eleonora Porcu; Antonella Mulas; Maristella Pitzalis; Carlo Sidore; Ilenia Zara; Francesco Cucca; Magdalena Zoledziewska; Andreas Ziegler; Bernhard Hemmer; Bertram Müller-Myhsok

doi:10.1126/sciadv.1501678

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Till F.M. Andlauer, Dorothea Buck, Gisela Antony, Antonios Bayas, Lukas Bechmann, Achim Berthele, Andrew Chan, Christiane Gasperi, Ralf Gold, Christiane Graetz, Jürgen Haas, Michael Hecker, Carmen Infante-Duarte, Matthias Knop, Tania Kümpfel, Volker Limmroth, Ralf A. Linker, Verena Loleit, Felix Luessi, Sven G. MeuthMark Mühlau, Sandra Nischwitz, Friedemann Paul, Michael Pütz, Tobias Ruck, Anke Salmen, Martin Stangel, Jan Patrick Stellmann, Klarissa H. Stürner, Björn Tackenberg, Florian Then Bergh, Hayrettin Tumani, Clemens Warnke, Frank Weber, Heinz Wiendl, Brigitte Wildemann, Uwe K. Zettl, Ulf Ziemann, Frauke Zipp, Janine Arloth, Peter Weber, Milena Radivojkov-Blagojevic, Markus O. Scheinhardt, Theresa Dankowski, Thomas Bettecken, Peter Lichtner, Darina Czamara, Tania Carrillo-Roa, Elisabeth B. Binder, Klaus Berger, Lars Bertram, Andre Franke, Christian Gieger, Stefan Herms, Georg Homuth, Marcus Ising, Karl Heinz Jöckel, Tim Kacprowski, Stefan Kloiber, Matthias Laudes, Wolfgang Lieb, Christina M. Lill, Susanne Lucae, Thomas Meitinger, Susanne Moebus, Martina Müller-Nurasyid, Markus M. Nöthen, Astrid Petersmann, Rajesh Rawal, Ulf Schminke, Konstantin Strauch, Henry Völzke, Melanie Waldenberger, Jürgen Wellmann, Eleonora Porcu, Antonella Mulas, Maristella Pitzalis, Carlo Sidore, Ilenia Zara, Francesco Cucca, Magdalena Zoledziewska, Andreas Ziegler, Bernhard Hemmer, Bertram Müller-Myhsok^*

^*Corresponding author for this work

9 Citations (Scopus)

Abstract

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

Original language	English
Article number	e1501678
Journal	Science Advances
Volume	2
Issue number	6
DOIs	https://doi.org/10.1126/sciadv.1501678
Publication status	Published - 01.06.2016

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Andlauer, T. F. M., Buck, D., Antony, G., Bayas, A., Bechmann, L., Berthele, A., Chan, A., Gasperi, C., Gold, R., Graetz, C., Haas, J., Hecker, M., Infante-Duarte, C., Knop, M., Kümpfel, T., Limmroth, V., Linker, R. A., Loleit, V., Luessi, F., ... Müller-Myhsok, B. (2016). Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation. Science Advances, 2(6), Article e1501678. https://doi.org/10.1126/sciadv.1501678

@article{9429d27866154d309f28184f070b87da,

title = "Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation",

abstract = "We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.",

author = "Andlauer, {Till F.M.} and Dorothea Buck and Gisela Antony and Antonios Bayas and Lukas Bechmann and Achim Berthele and Andrew Chan and Christiane Gasperi and Ralf Gold and Christiane Graetz and J{\"u}rgen Haas and Michael Hecker and Carmen Infante-Duarte and Matthias Knop and Tania K{\"u}mpfel and Volker Limmroth and Linker, {Ralf A.} and Verena Loleit and Felix Luessi and Meuth, {Sven G.} and Mark M{\"u}hlau and Sandra Nischwitz and Friedemann Paul and Michael P{\"u}tz and Tobias Ruck and Anke Salmen and Martin Stangel and Stellmann, {Jan Patrick} and St{\"u}rner, {Klarissa H.} and Bj{\"o}rn Tackenberg and Bergh, {Florian Then} and Hayrettin Tumani and Clemens Warnke and Frank Weber and Heinz Wiendl and Brigitte Wildemann and Zettl, {Uwe K.} and Ulf Ziemann and Frauke Zipp and Janine Arloth and Peter Weber and Milena Radivojkov-Blagojevic and Scheinhardt, {Markus O.} and Theresa Dankowski and Thomas Bettecken and Peter Lichtner and Darina Czamara and Tania Carrillo-Roa and Binder, {Elisabeth B.} and Klaus Berger and Lars Bertram and Andre Franke and Christian Gieger and Stefan Herms and Georg Homuth and Marcus Ising and J{\"o}ckel, {Karl Heinz} and Tim Kacprowski and Stefan Kloiber and Matthias Laudes and Wolfgang Lieb and Lill, {Christina M.} and Susanne Lucae and Thomas Meitinger and Susanne Moebus and Martina M{\"u}ller-Nurasyid and N{\"o}then, {Markus M.} and Astrid Petersmann and Rajesh Rawal and Ulf Schminke and Konstantin Strauch and Henry V{\"o}lzke and Melanie Waldenberger and J{\"u}rgen Wellmann and Eleonora Porcu and Antonella Mulas and Maristella Pitzalis and Carlo Sidore and Ilenia Zara and Francesco Cucca and Magdalena Zoledziewska and Andreas Ziegler and Bernhard Hemmer and Bertram M{\"u}ller-Myhsok",

year = "2016",

month = jun,

day = "1",

doi = "10.1126/sciadv.1501678",

language = "English",

volume = "2",

journal = "Science Advances",

issn = "2375-2548",

number = "6",

}

Andlauer, TFM, Buck, D, Antony, G, Bayas, A, Bechmann, L, Berthele, A, Chan, A, Gasperi, C, Gold, R, Graetz, C, Haas, J, Hecker, M, Infante-Duarte, C, Knop, M, Kümpfel, T, Limmroth, V, Linker, RA, Loleit, V, Luessi, F, Meuth, SG, Mühlau, M, Nischwitz, S, Paul, F, Pütz, M, Ruck, T, Salmen, A, Stangel, M, Stellmann, JP, Stürner, KH, Tackenberg, B, Bergh, FT, Tumani, H, Warnke, C, Weber, F, Wiendl, H, Wildemann, B, Zettl, UK, Ziemann, U, Zipp, F, Arloth, J, Weber, P, Radivojkov-Blagojevic, M, Scheinhardt, MO, Dankowski, T, Bettecken, T, Lichtner, P, Czamara, D, Carrillo-Roa, T, Binder, EB, Berger, K, Bertram, L, Franke, A, Gieger, C, Herms, S, Homuth, G, Ising, M, Jöckel, KH, Kacprowski, T, Kloiber, S, Laudes, M, Lieb, W, Lill, CM, Lucae, S, Meitinger, T, Moebus, S, Müller-Nurasyid, M, Nöthen, MM, Petersmann, A, Rawal, R, Schminke, U, Strauch, K, Völzke, H, Waldenberger, M, Wellmann, J, Porcu, E, Mulas, A, Pitzalis, M, Sidore, C, Zara, I, Cucca, F, Zoledziewska, M, Ziegler, A, Hemmer, B & Müller-Myhsok, B 2016, 'Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation', Science Advances, vol. 2, no. 6, e1501678. https://doi.org/10.1126/sciadv.1501678

TY - JOUR

T1 - Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

AU - Andlauer, Till F.M.

AU - Buck, Dorothea

AU - Antony, Gisela

AU - Bayas, Antonios

AU - Bechmann, Lukas

AU - Berthele, Achim

AU - Chan, Andrew

AU - Gasperi, Christiane

AU - Gold, Ralf

AU - Graetz, Christiane

AU - Haas, Jürgen

AU - Hecker, Michael

AU - Infante-Duarte, Carmen

AU - Knop, Matthias

AU - Kümpfel, Tania

AU - Limmroth, Volker

AU - Linker, Ralf A.

AU - Loleit, Verena

AU - Luessi, Felix

AU - Meuth, Sven G.

AU - Mühlau, Mark

AU - Nischwitz, Sandra

AU - Paul, Friedemann

AU - Pütz, Michael

AU - Ruck, Tobias

AU - Salmen, Anke

AU - Stangel, Martin

AU - Stellmann, Jan Patrick

AU - Stürner, Klarissa H.

AU - Tackenberg, Björn

AU - Bergh, Florian Then

AU - Tumani, Hayrettin

AU - Warnke, Clemens

AU - Weber, Frank

AU - Wiendl, Heinz

AU - Wildemann, Brigitte

AU - Zettl, Uwe K.

AU - Ziemann, Ulf

AU - Zipp, Frauke

AU - Arloth, Janine

AU - Weber, Peter

AU - Radivojkov-Blagojevic, Milena

AU - Scheinhardt, Markus O.

AU - Dankowski, Theresa

AU - Bettecken, Thomas

AU - Lichtner, Peter

AU - Czamara, Darina

AU - Carrillo-Roa, Tania

AU - Binder, Elisabeth B.

AU - Berger, Klaus

AU - Bertram, Lars

AU - Franke, Andre

AU - Gieger, Christian

AU - Herms, Stefan

AU - Homuth, Georg

AU - Ising, Marcus

AU - Jöckel, Karl Heinz

AU - Kacprowski, Tim

AU - Kloiber, Stefan

AU - Laudes, Matthias

AU - Lieb, Wolfgang

AU - Lill, Christina M.

AU - Lucae, Susanne

AU - Meitinger, Thomas

AU - Moebus, Susanne

AU - Müller-Nurasyid, Martina

AU - Nöthen, Markus M.

AU - Petersmann, Astrid

AU - Rawal, Rajesh

AU - Schminke, Ulf

AU - Strauch, Konstantin

AU - Völzke, Henry

AU - Waldenberger, Melanie

AU - Wellmann, Jürgen

AU - Porcu, Eleonora

AU - Mulas, Antonella

AU - Pitzalis, Maristella

AU - Sidore, Carlo

AU - Zara, Ilenia

AU - Cucca, Francesco

AU - Zoledziewska, Magdalena

AU - Ziegler, Andreas

AU - Hemmer, Bernhard

AU - Müller-Myhsok, Bertram

PY - 2016/6/1

Y1 - 2016/6/1

N2 - We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

AB - We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=85009238794&partnerID=8YFLogxK

U2 - 10.1126/sciadv.1501678

DO - 10.1126/sciadv.1501678

M3 - Journal articles

C2 - 27386562

AN - SCOPUS:85009238794

SN - 2375-2548

VL - 2

JO - Science Advances

JF - Science Advances

IS - 6

M1 - e1501678

ER -

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

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