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

An Goris; Ine Pauwels; Marte W Gustavsen; Brechtje van Son; Kelly Hilven; Steffan D Bos; Elisabeth Gulowsen Celius; Pål Berg-Hansen; Jan Aarseth; Kjell-Morten Myhr; Sandra D'Alfonso; Nadia Barizzone; Maurizio A Leone; Filippo Martinelli Boneschi; Melissa Sorosina; Giuseppe Liberatore; Ingrid Kockum; Tomas Olsson; Jan Hillert; Lars Alfredsson; Sahl Khalid Bedri; Bernhard Hemmer; Dorothea Buck; Achim Berthele; Benjamin Knier; Viola Biberacher; Vincent van Pesch; Christian Sindic; Annette Bang Oturai; Helle Bach Søndergaard; Finn Sellebjerg; Poul Erik H Jensen; Manuel Comabella; Xavier Montalban; Jennifer Pérez-Boza; Sunny Malhotra; Jeannette Lechner-Scott; Simon Broadley; Mark Slee; Bruce Taylor; Allan G Kermode; Pierre-Antoine Gourraud; Stephen J Sawcer; Bettina Kullle Andreassen; Bénédicte Dubois; Hanne F Harbo; International Multiple Sclerosis Genetics Consortium

doi:10.1093/brain/awu405

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

An Goris, Ine Pauwels, Marte W Gustavsen, Brechtje van Son, Kelly Hilven, Steffan D Bos, Elisabeth Gulowsen Celius, Pål Berg-Hansen, Jan Aarseth, Kjell-Morten Myhr, Sandra D'Alfonso, Nadia Barizzone, Maurizio A Leone, Filippo Martinelli Boneschi, Melissa Sorosina, Giuseppe Liberatore, Ingrid Kockum, Tomas Olsson, Jan Hillert, Lars AlfredssonSahl Khalid Bedri, Bernhard Hemmer, Dorothea Buck, Achim Berthele, Benjamin Knier, Viola Biberacher, Vincent van Pesch, Christian Sindic, Annette Bang Oturai, Helle Bach Søndergaard, Finn Sellebjerg, Poul Erik H Jensen, Manuel Comabella, Xavier Montalban, Jennifer Pérez-Boza, Sunny Malhotra, Jeannette Lechner-Scott, Simon Broadley, Mark Slee, Bruce Taylor, Allan G Kermode, Pierre-Antoine Gourraud, Stephen J Sawcer, Bettina Kullle Andreassen, Bénédicte Dubois, Hanne F Harbo, International Multiple Sclerosis Genetics Consortium

Department of Clinical Medicine

38 Citations (Scopus)

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.

Original language	English
Journal	Brain
Volume	138
Issue number	3
Pages (from-to)	632-43
Number of pages	12
ISSN	0006-8950
DOIs	https://doi.org/10.1093/brain/awu405
Publication status	Published - 1 Mar 2015

Keywords

Adolescent
Adult
Aged
Child
Child, Preschool
Europe
Female
Genetic Association Studies
Genetic Variation
Humans
Immunoglobulin G
Major Histocompatibility Complex
Male
Middle Aged
Multiple Sclerosis
Oligoclonal Bands
Polymorphism, Single Nucleotide
Severity of Illness Index
Smad4 Protein
Tumor Suppressor Proteins
Young Adult

Access to Document

10.1093/brain/awu405

awu405.pdfFinal published version, 441 KB

Cite this

Goris, A., Pauwels, I., Gustavsen, M. W., van Son, B., Hilven, K., Bos, S. D., Celius, E. G., Berg-Hansen, P., Aarseth, J., Myhr, K-M., D'Alfonso, S., Barizzone, N., Leone, M. A., Martinelli Boneschi, F., Sorosina, M., Liberatore, G., Kockum, I., Olsson, T., Hillert, J., ... International Multiple Sclerosis Genetics Consortium (2015). Genetic variants are major determinants of CSF antibody levels in multiple sclerosis. Brain, 138(3), 632-43. https://doi.org/10.1093/brain/awu405

Goris, A, Pauwels, I, Gustavsen, MW, van Son, B, Hilven, K, Bos, SD, Celius, EG, Berg-Hansen, P, Aarseth, J, Myhr, K-M, D'Alfonso, S, Barizzone, N, Leone, MA, Martinelli Boneschi, F, Sorosina, M, Liberatore, G, Kockum, I, Olsson, T, Hillert, J, Alfredsson, L, Bedri, SK, Hemmer, B, Buck, D, Berthele, A, Knier, B, Biberacher, V, van Pesch, V, Sindic, C, Bang Oturai, A, Søndergaard, HB, Sellebjerg, F, Jensen, PEH, Comabella, M, Montalban, X, Pérez-Boza, J, Malhotra, S, Lechner-Scott, J, Broadley, S, Slee, M, Taylor, B, Kermode, AG, Gourraud, P-A, Sawcer, SJ, Andreassen, BK, Dubois, B, Harbo, HF & International Multiple Sclerosis Genetics Consortium 2015, 'Genetic variants are major determinants of CSF antibody levels in multiple sclerosis', Brain, vol. 138, no. 3, pp. 632-43. https://doi.org/10.1093/brain/awu405

@article{a599599989ab4d929695ba667be2ffb9,

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.",

keywords = "Adolescent, Adult, Aged, Child, Child, Preschool, Europe, Female, Genetic Association Studies, Genetic Variation, Humans, Immunoglobulin G, Major Histocompatibility Complex, Male, Middle Aged, Multiple Sclerosis, Oligoclonal Bands, Polymorphism, Single Nucleotide, Severity of Illness Index, Smad4 Protein, Tumor Suppressor Proteins, Young Adult",

author = "An Goris and Ine Pauwels and Gustavsen, {Marte W} and {van Son}, Brechtje and Kelly Hilven and Bos, {Steffan D} and Celius, {Elisabeth Gulowsen} and P{\aa}l Berg-Hansen and Jan Aarseth and Kjell-Morten Myhr and Sandra D'Alfonso and Nadia Barizzone and Leone, {Maurizio A} and {Martinelli Boneschi}, Filippo and Melissa Sorosina and Giuseppe Liberatore and Ingrid Kockum and Tomas Olsson and Jan Hillert and Lars Alfredsson and Bedri, {Sahl Khalid} and Bernhard Hemmer and Dorothea Buck and Achim Berthele and Benjamin Knier and Viola Biberacher and {van Pesch}, Vincent and Christian Sindic and {Bang Oturai}, Annette and S{\o}ndergaard, {Helle Bach} and Finn Sellebjerg and Jensen, {Poul Erik H} and Manuel Comabella and Xavier Montalban and Jennifer P{\'e}rez-Boza and Sunny Malhotra and Jeannette Lechner-Scott and Simon Broadley and Mark Slee and Bruce Taylor and Kermode, {Allan G} and Pierre-Antoine Gourraud and Sawcer, {Stephen J} and Andreassen, {Bettina Kullle} and B{\'e}n{\'e}dicte Dubois and Harbo, {Hanne F} and {International Multiple Sclerosis Genetics Consortium}",

year = "2015",

month = mar,

day = "1",

doi = "10.1093/brain/awu405",

language = "English",

volume = "138",

pages = "632--43",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "3",

}

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

PY - 2015/3/1

Y1 - 2015/3/1

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

SN - 0006-8950

VL - 138

SP - 632

EP - 643

JO - Brain

JF - Brain

IS - 3

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this