title: Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.
abstract: Immunological 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.
authors.affiliation: 1 Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium an.goris@med.kuleuven.be.
authors.forename: An
authors.initials: A
authors.lastname: Goris
authors.affiliation: 1 Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Ine
authors.initials: I
authors.lastname: Pauwels
authors.affiliation: 2 Department of Neurology, Oslo University Hospital Ullevål, Oslo, Norway 3 Institute of Clinical Medicine, University of Oslo, Norway.
authors.forename: Marte W
authors.initials: MW
authors.lastname: Gustavsen
authors.affiliation: 4 Department of Neurology, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Brechtje
authors.initials: B
authors.lastname: van Son
authors.affiliation: 1 Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hilven
authors.affiliation: 2 Department of Neurology, Oslo University Hospital Ullevål, Oslo, Norway 3 Institute of Clinical Medicine, University of Oslo, Norway.
authors.forename: Steffan D
authors.initials: SD
authors.lastname: Bos
authors.affiliation: 2 Department of Neurology, Oslo University Hospital Ullevål, Oslo, Norway.
authors.forename: Elisabeth Gulowsen
authors.initials: EG
authors.lastname: Celius
authors.affiliation: 2 Department of Neurology, Oslo University Hospital Ullevål, Oslo, Norway 3 Institute of Clinical Medicine, University of Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Berg-Hansen
authors.affiliation: 5 Norwegian MS-Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Aarseth
authors.affiliation: 5 Norwegian MS-Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway 6 KG Jebsen Centre for MS-research, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Kjell-Morten
authors.initials: KM
authors.lastname: Myhr
authors.affiliation: 7 Department of Health Sciences, University of Eastern Piedmont, Novara, Italy 8 Interdisciplinary Research Centre of Autoimmune Diseases IRCAD, University of Eastern Piedmont, Novara, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
authors.affiliation: 7 Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Barizzone
authors.affiliation: 8 Interdisciplinary Research Centre of Autoimmune Diseases IRCAD, University of Eastern Piedmont, Novara, Italy 9 Neurology Unit, Scientific Institute, Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
authors.forename: Maurizio A
authors.initials: MA
authors.lastname: Leone
authors.affiliation: 11 Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy 11 Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli Boneschi
authors.affiliation: 11 Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: Sorosina
authors.affiliation: 10 Department of Neuro-rehabilitation, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy 11 Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Liberatore
authors.affiliation: 12 Neuroimmunology Unit, Department of Clinical Neuroscience, Centrum for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: 12 Neuroimmunology Unit, Department of Clinical Neuroscience, Centrum for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: 13 Multiple Sclerosis Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.affiliation: 14 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: 13 Multiple Sclerosis Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sahl Khalid
authors.initials: SK
authors.lastname: Bedri
authors.affiliation: 15 Department of Neurology, Technische Universität München, Munich, Germany 16 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.affiliation: 15 Department of Neurology, Technische Universität München, Munich, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Buck
authors.affiliation: 15 Department of Neurology, Technische Universität München, Munich, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Berthele
authors.affiliation: 15 Department of Neurology, Technische Universität München, Munich, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Knier
authors.affiliation: 15 Department of Neurology, Technische Universität München, Munich, Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Biberacher
authors.affiliation: 17 Institute of Neurosciences, Neurochemistry Unit, Université Catholique de Louvain-la-Neuve, Louvain-la-Neuve, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: van Pesch
authors.affiliation: 17 Institute of Neurosciences, Neurochemistry Unit, Université Catholique de Louvain-la-Neuve, Louvain-la-Neuve, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Sindic
authors.affiliation: 18 Danish Multiple Sclerosis Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Annette
authors.initials: A
authors.lastname: Bang Oturai
authors.affiliation: 18 Danish Multiple Sclerosis Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Helle Bach
authors.initials: HB
authors.lastname: Søndergaard
authors.affiliation: 18 Danish Multiple Sclerosis Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Finn
authors.initials: F
authors.lastname: Sellebjerg
authors.affiliation: 18 Danish Multiple Sclerosis Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Poul Erik H
authors.initials: PE
authors.lastname: Jensen
authors.affiliation: 19 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.affiliation: 19 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: 19 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pérez-Boza
authors.affiliation: 19 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Sunny
authors.initials: S
authors.lastname: Malhotra
authors.affiliation: 20 Hunter Medical Research Institute, University of Newcastle, Australia.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Lechner-Scott
authors.affiliation: 21 School of Medicine, Gold Coast Campus, Griffith University QLD 4222, Australia.
authors.forename: Simon
authors.initials: S
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authors.affiliation: 1 Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Mark
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authors.lastname: Slee
authors.affiliation: 23 Menzies Research Institute, University of Tasmania, Hobart, Australia.
authors.forename: Bruce
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authors.lastname: Taylor
authors.affiliation: 24 Institute of Immunology and Infectious Diseases, Murdoch University, Australia 25 Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australia.
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authors.initials: AG
authors.lastname: Kermode
authors.affiliation: 2 Department of Neurology, Oslo University Hospital Ullevål, Oslo, Norway.
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Gourraud
authors.affiliation: 27 Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawcer
authors.affiliation: 28 Department of Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Bettina Kullle
authors.initials: BK
authors.lastname: Andreassen
authors.affiliation: 1 Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium 4 Department of Neurology, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Dubois
authors.affiliation: 2 Department of Neurology, Oslo University Hospital Ullevål, Oslo, Norway 3 Institute of Clinical Medicine, University of Oslo, Norway.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005060:Europe; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000134:cerebrospinal fluid*; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid* / Q000235:genetics*; D043025:Oligoclonal Bands / Q000097:blood / Q000134:cerebrospinal fluid; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012720:Severity of Illness Index; D051901:Smad4 Protein / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: C430097:ELAC1 protein, human; D007074:Immunoglobulin G; D043025:Oligoclonal Bands; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D025521:Tumor Suppressor Proteins
keywords: CSF; genetics; immunoglobulin; multiple sclerosis; oligoclonal bands