TY - JOUR

T1 - Genetic variants are major determinants of CSF antibody levels in multiple sclerosis

AU - Goris, An

AU - Pauwels, Ine

AU - Gustavsen, Marte W

AU - van Son, Brechtje

AU - Hilven, Kelly

AU - Bos, Steffan D

AU - Celius, Elisabeth Gulowsen

AU - Berg-Hansen, Pål

AU - Aarseth, Jan

AU - Myhr, Kjell-Morten

AU - D'Alfonso, Sandra

AU - Barizzone, Nadia

AU - Leone, Maurizio A

AU - Martinelli Boneschi, Filippo

AU - Sorosina, Melissa

AU - Liberatore, Giuseppe

AU - Kockum, Ingrid

AU - Olsson, Tomas

AU - Hillert, Jan

AU - Alfredsson, Lars

AU - Bedri, Sahl Khalid

AU - Hemmer, Bernhard

AU - Buck, Dorothea

AU - Berthele, Achim

AU - Knier, Benjamin

AU - Biberacher, Viola

AU - van Pesch, Vincent

AU - Sindic, Christian

AU - Bang Oturai, Annette

AU - Søndergaard, Helle Bach

AU - Sellebjerg, Finn

AU - Jensen, Poul Erik H

AU - Comabella, Manuel

AU - Montalban, Xavier

AU - Pérez-Boza, Jennifer

AU - Malhotra, Sunny

AU - Lechner-Scott, Jeannette

AU - Broadley, Simon

AU - Slee, Mark

AU - Taylor, Bruce

AU - Kermode, Allan G

AU - Gourraud, Pierre-Antoine

AU - Sawcer, Stephen J

AU - Andreassen, Bettina Kullle

AU - Dubois, Bénédicte

AU - Harbo, Hanne F

AU - International Multiple Sclerosis Genetics Consortium

N1 - © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2015/3

Y1 - 2015/3

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Child

KW - Child, Preschool

KW - Europe

KW - Female

KW - Genetic Association Studies

KW - Genetic Variation

KW - Humans

KW - Immunoglobulin G

KW - Major Histocompatibility Complex

KW - Male

KW - Middle Aged

KW - Multiple Sclerosis

KW - Oligoclonal Bands

KW - Polymorphism, Single Nucleotide

KW - Severity of Illness Index

KW - Smad4 Protein

KW - Tumor Suppressor Proteins

KW - Young Adult

U2 - 10.1093/brain/awu405

DO - 10.1093/brain/awu405

M3 - Journal article

C2 - 25616667

VL - 138

SP - 632

EP - 643

JO - Brain

JF - Brain

SN - 0006-8950

IS - 3

ER -