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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.

SUBMITTER: Andlauer TF

PROVIDER: S-EPMC4928990 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

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

Science advances 20160617 6

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, MA ...[more]

PMID: 27386562

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Project description:Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.

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Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

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Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

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