title: Combining genetic mapping with genome-wide expression in experimental autoimmune encephalomyelitis highlights a gene network enriched for T cell functions and candidate genes regulating autoimmunity.
abstract: The experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the central nervous system commonly used to study multiple sclerosis (MS). We combined clinical EAE phenotypes with genome-wide expression profiling in spleens from 150 backcross rats between susceptible DA and resistant PVG rat strains during the chronic EAE phase. This enabled correlation of transcripts with genotypes, other transcripts and clinical EAE phenotypes and implicated potential genetic causes and pathways in EAE. We detected 2285 expression quantitative trait loci (eQTLs). Sixty out of 599 cis-eQTLs overlapped well-known EAE QTLs and constitute positional candidate genes, including Ifit1 (Eae7), Atg7 (Eae20-22), Klrc3 (eEae22) and Mfsd4 (Eae17). A trans-eQTL that overlaps Eae23a regulated a large number of small RNAs and implicates a master regulator of transcription. We defined several disease-correlated networks enriched for pathways involved in cell-mediated immunity. They include C-type lectins, G protein coupled receptors, mitogen-activated protein kinases, transmembrane proteins, suppressors of transcription (Jundp2 and Nr1d1) and STAT transcription factors (Stat4) involved in interferon signaling. The most significant network was enriched for T cell functions, similar to genetic findings in MS, and revealed both established and novel gene interactions. Transcripts in the network have been associated with T cell proliferation and differentiation, the TCR signaling and regulation of regulatory T cells. A number of network genes and their family members have been associated with MS and/or other autoimmune diseases. Combining disease and genome-wide expression phenotypes provides a link between disease risk genes and distinct molecular pathways that are dysregulated during chronic autoimmune inflammation.
authors.affiliation: Department of Clinical Neuroscience, Neuroimmunology Unit, Center for Molecular Medicine L8:04, Karolinska Institutet, L8:04, 17176 Stockholm, Sweden.
authors.forename: Melanie
authors.initials: M
authors.lastname: Thessen Hedreul
authors.forename: Steffen
authors.initials: S
authors.lastname: Möller
authors.forename: Pernilla
authors.initials: P
authors.lastname: Stridh
authors.forename: Yask
authors.initials: Y
authors.lastname: Gupta
authors.forename: Alan
authors.initials: A
authors.lastname: Gillett
authors.forename: Amennai
authors.initials: A
authors.lastname: Daniel Beyeen
authors.forename: Johan
authors.initials: J
authors.lastname: Öckinger
authors.forename: Sevasti
authors.initials: S
authors.lastname: Flytzani
authors.forename: Margarita
authors.initials: M
authors.lastname: Diez
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D002874:Chromosome Mapping; D016000:Cluster Analysis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D004843:Epistasis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D007372:Interferons / Q000378:metabolism; D008297:Male; D010641:Phenotype; D040641:Quantitative Trait Loci; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D043562:Receptors, G-Protein-Coupled; D007372:Interferons
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