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. 2016 Jun 17;2(6):e1501678.
doi: 10.1126/sciadv.1501678. eCollection 2016 Jun.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Till F M Andlauer  1 , Dorothea Buck  2 , Gisela Antony  3 , Antonios Bayas  4 , Lukas Bechmann  5 , Achim Berthele  2 , Andrew Chan  6 , Christiane Gasperi  2 , Ralf Gold  7 , Christiane Graetz  8 , Jürgen Haas  9 , Michael Hecker  10 , Carmen Infante-Duarte  11 , Matthias Knop  12 , Tania Kümpfel  13 , Volker Limmroth  14 , Ralf A Linker  15 , Verena Loleit  2 , Felix Luessi  8 , Sven G Meuth  16 , Mark Mühlau  17 , Sandra Nischwitz  12 , Friedemann Paul  11 , Michael Pütz  18 , Tobias Ruck  16 , Anke Salmen  6 , Martin Stangel  19 , Jan-Patrick Stellmann  20 , Klarissa H Stürner  20 , Björn Tackenberg  18 , Florian Then Bergh  21 , Hayrettin Tumani  22 , Clemens Warnke  23 , Frank Weber  24 , Heinz Wiendl  16 , Brigitte Wildemann  9 , Uwe K Zettl  10 , Ulf Ziemann  25 , Frauke Zipp  8 , Janine Arloth  26 , Peter Weber  12 , Milena Radivojkov-Blagojevic  27 , Markus O Scheinhardt  28 , Theresa Dankowski  28 , Thomas Bettecken  12 , Peter Lichtner  29 , Darina Czamara  12 , Tania Carrillo-Roa  12 , Elisabeth B Binder  30 , Klaus Berger  31 , Lars Bertram  32 , Andre Franke  33 , Christian Gieger  34 , Stefan Herms  35 , Georg Homuth  36 , Marcus Ising  12 , Karl-Heinz Jöckel  37 , Tim Kacprowski  36 , Stefan Kloiber  12 , Matthias Laudes  38 , Wolfgang Lieb  39 , Christina M Lill  40 , Susanne Lucae  12 , Thomas Meitinger  29 , Susanne Moebus  37 , Martina Müller-Nurasyid  41 , Markus M Nöthen  42 , Astrid Petersmann  43 , Rajesh Rawal  34 , Ulf Schminke  44 , Konstantin Strauch  45 , Henry Völzke  46 , Melanie Waldenberger  34 , Jürgen Wellmann  31 , Eleonora Porcu  47 , Antonella Mulas  48 , Maristella Pitzalis  47 , Carlo Sidore  47 , Ilenia Zara  49 , Francesco Cucca  48 , Magdalena Zoledziewska  48 , Andreas Ziegler  50 , Bernhard Hemmer  17 , Bertram Müller-Myhsok  51
Affiliations

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Till F M Andlauer et al. Sci Adv. .

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.

Keywords: DLEU1; DNA methylation; ERG; L3MBTL3; MAZ; Multiple sclerosis; SHMT1; genome-wide association study.

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Figures

Fig. 1
Fig. 1. Genome-wide representation of MS associations in the pooled analysis of German data sets.
Manhattan plot showing strength of evidence for association (P value). Each variant is shown as a dot, with alternating shades of blue according to chromosome. Green dots represent established MS-associated variants and their proxies, as listed by Sawcer et al. (3) (except for rs2812197, which was not covered by that review). Top variants at the 15 non-MHC loci associated at the genome-wide significance threshold in our study are shown as diamonds. Novel variants showing genome-wide significance are plotted as red diamonds; their names are shown in bold font. Variants in high LD (r2 ≥ 0.7) with these novel variants are shown as red dots. Variants replicating in the Sardinian cohort are shown in red font. MA, minor allele. The OR is relative to the MA. Gene names for known loci are indicated as listed by Sawcer et al. (3). The plot is truncated at −log10p = 16 for better visibility; all truncated variants map to the MHC region. The lowest P value (rs3104373, *) was 1.3 × 10−234.
Fig. 2
Fig. 2. Comparison of results from the pooled analysis of Germans to associations found in an IMSGC study.
One hundred and four of the 108 variants showing genome-wide significant or suggestive associations with MS in the study published by the IMSGC in 2013 (4) were present in the pooled results of DE1 and DE2. All 104 variants showed the same direction of effect (P = 5 × 10−32, binomial sign test). Fifty-eight variants had lower ORs and 35 higher ORs compared to the published data set. P value–based categories labeled with different dots represent exclusive bins that add up to 104.
Fig. 3
Fig. 3. Fine-mapping analysis results of locus rs4925166.
(A) Regional plot for the rs4925166/SHMT1 locus. Color of dots indicates LD with the lead variant (rs4925166; pink). Gray dots represent signals with missing r2 values. cM, centimorgan. (B) Mediation analysis results in MPIP/GTP controls. Mediation effect: rs4925166→CpG cg26763362→SHMT1 expression. Direct effect: rs4925166→SHMT1 expression. Data have been calculated using the R package mediation (30), except for total effect (*), which was calculated by linear regression. Results were obtained using 1 million simulations. Effects and P values shown here differ from Table 5, as a lower number of samples contained both expression and methylation data than expression data alone. (C) Relationship between cg26763362 methylation, SHMT1 expression, and rs4925166 genotype in MPIP controls.
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