GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis.
To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS), the Genome-Wide Association Studies noise reduction method (GWAS-NR) was applied to MS genotyping data. Regions of association were defined based on the significance of linkage disequilibrium blocks. Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins. Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery. The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte and leukocyte activation (P=6.1E-15, 1.2E-14 and 5.0E-14, respectively). Novel gene candidates include key regulators of NF-κB signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages. A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-κB-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells. This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility.
Hussman Foundation, Ellicott City, MD, USA.
J P
JP
Hussman
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.
A H
AH
Beecham
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.
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M
Schmidt
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.|Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA.
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ER
Martin
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.|Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA.
J L
JL
McCauley
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.|Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA.|Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL, USA.
J M
JM
Vance
Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
J L
JL
Haines
John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.|Dr John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA.|Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL, USA.
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MA
Pericak-Vance
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
D016328:NF-kappa B