Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

G. Gibson; Nikolaos A. Patsopoulos; Lisa F. Barcellos; Rogier Q. Hintzen; Catherine Schaefer; Cornelia M. van Duijn; Janelle A. Noble; Towfique Raj; Pierre-Antoine Gourraud; Barbara E. Stranger; Jorge Oksenberg; Tomas Olsson; Bruce V. Taylor; Stephen Sawcer; David A. Hafler; Mary Carrington; Philip L. De Jager; Paul I. W. de Bakker; A.G. Kermode

doi:10.1371/journal.pgen.1003926

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Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

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Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

G. Gibson, Nikolaos A. Patsopoulos, Lisa F. Barcellos, Rogier Q. Hintzen, Catherine Schaefer, Cornelia M. van Duijn, Janelle A. Noble, Towfique Raj, Pierre-Antoine Gourraud, Barbara E. Stranger, …

PLoS Genetics, Vol.9(11), e1003926

2013

DOI: https://doi.org/10.1371/journal.pgen.1003926

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Abstract

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

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Title: Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
Authors/Creators: G. Gibson (Author/Creator)
Nikolaos A. Patsopoulos (Author/Creator) - Massachusetts Institute of Technology
Lisa F. Barcellos (Author/Creator) - Kaiser Permanente
Rogier Q. Hintzen (Author/Creator) - Erasmus University Rotterdam
Catherine Schaefer (Author/Creator) - Kaiser Permanente
Cornelia M. van Duijn (Author/Creator) - Erasmus University Rotterdam
Janelle A. Noble (Author/Creator) - Children's Hospital Oakland Research Institute
Towfique Raj (Author/Creator) - Massachusetts Institute of Technology
Pierre-Antoine Gourraud (Author/Creator) - University of California, San Francisco
Barbara E. Stranger (Author/Creator) - University of Chicago
Jorge Oksenberg (Author/Creator) - University of California, San Francisco
Tomas Olsson (Author/Creator) - Karolinska Institutet
Bruce V. Taylor (Author/Creator) - University of Tasmania
Stephen Sawcer (Author/Creator) - University of Cambridge
David A. Hafler (Author/Creator) - Massachusetts Institute of Technology
Mary Carrington (Author/Creator) - Massachusetts Institute of Technology
Philip L. De Jager (Author/Creator) - Massachusetts Institute of Technology
Paul I. W. de Bakker (Author/Creator) - Massachusetts Institute of Technology
A.G. Kermode (Author/Creator)
Publication Details: PLoS Genetics, Vol.9(11), e1003926
Publisher: Public Library of Science
Identifiers: 991005540509407891
Copyright: 2013 The Authors
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.203 Neuromuscular Disorders; 1.203.147 Multiple Sclerosis
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics