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dc.contributor.authorGoris, An
dc.contributor.authorPauwels, Ine
dc.contributor.authorGustavsen, Marte W
dc.contributor.authorvan Son, Brechtje
dc.contributor.authorHilven, Kelly
dc.contributor.authorBos, Steffan D
dc.contributor.authorCelius, Elisabeth Gulowsen
dc.contributor.authorBerg-Hansen, Pal
dc.contributor.authorAarseth, Jan
dc.contributor.authorMyhr, Kjell-Morten
dc.contributor.authorD'Alfonso, Sandra
dc.contributor.authorBarizzone, Nadia
dc.contributor.authorLeone, Maurizio A
dc.contributor.authorBoneschi, Filippo Martinelli
dc.contributor.authorSorosina, Melissa
dc.contributor.authorLiberatore, Giuseppe
dc.contributor.authorKockum, Ingrid
dc.contributor.authorOlsson, Tomas
dc.contributor.authorHillert, Jan
dc.contributor.authorAlfredsson, Lars
dc.contributor.authorBedri, Sahl Khalid
dc.contributor.authorHemmer, Bernhard
dc.contributor.authorBuck, Dorothea
dc.contributor.authorBerthele, Achim
dc.contributor.authorKnier, Benjamin
dc.contributor.authorBiberacher, Viola
dc.contributor.authorvan Pesch, Vincent
dc.contributor.authorSindic, Christian
dc.contributor.authorOturai, Annette Bang
dc.contributor.authorSondergaard, Helle Bach
dc.contributor.authorSellebjerg, Finn
dc.contributor.authorJensen, Poul Erik H
dc.contributor.authorComabella, Manuel
dc.contributor.authorMontalban, Xavier
dc.contributor.authorPerez-Boza, Jennifer
dc.contributor.authorMalhotra, Sunny
dc.contributor.authorLechner-Scott, Jeannette
dc.contributor.authorBroadley, Simon
dc.contributor.authorSlee, Mark
dc.contributor.authorTaylor, Bruce
dc.contributor.authorKermode, Allan G
dc.contributor.authorGourraud, Pierre-Antoine
dc.contributor.authorSawcer, Stephen J
dc.contributor.authorAndreassen, Bettina Kullle
dc.contributor.authorDubois, Benedicte
dc.contributor.authorHarbo, Hanne F
dc.date.accessioned2018-10-22T01:46:53Z
dc.date.available2018-10-22T01:46:53Z
dc.date.issued2015
dc.identifier.issn0006-8950
dc.identifier.doi10.1093/brain/awu405
dc.identifier.urihttp://hdl.handle.net/10072/141948
dc.description.abstractImmunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index—the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10−16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10−7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10−37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10−22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10−6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherOxford University Press
dc.publisher.placeUnited Kingdom
dc.relation.ispartofpagefrom632
dc.relation.ispartofpageto643
dc.relation.ispartofissue3
dc.relation.ispartofjournalBrain
dc.relation.ispartofvolume138
dc.subject.fieldofresearchBiomedical and clinical sciences
dc.subject.fieldofresearchPsychology
dc.subject.fieldofresearchcode32
dc.subject.fieldofresearchcode52
dc.titleGenetic variants are major determinants of CSF antibody levels in multiple sclerosis
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dc.description.versionAccepted Manuscript (AM)
gro.rights.copyright© 2015 Oxford University Press. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Brain following peer review. The definitive publisher-authenticated version Genetic variants are major determinants of CSF antibody levels in multiple sclerosis, Brain, Volume 138, Issue 3, 2015, Pages 632–643 is available online at: https://doi.org/10.1093/brain/awu405.
gro.hasfulltextFull Text
gro.griffith.authorBroadley, Simon


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