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.

Hum Mol Genet 2013 Dec 29;22(24):4952-66. Epub 2013 Jul 29.

Department of Clinical Neuroscience, Neuroimmunology Unit, Center for Molecular Medicine L8:04, Karolinska Institutet, L8:04, 17176 Stockholm, Sweden.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddt343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836475PMC
December 2013
26 Reads

Publication Analysis

Top Keywords

genome-wide expression
12
autoimmune encephalomyelitis
8
candidate genes
8
experimental autoimmune
8
clinical eae
8
cell functions
8
enriched cell
8
eae phenotypes
8
network enriched
8
eae
6
autoimmune
5
implicates master
4
enriched pathways
4
rnas implicates
4
pathways involved
4
networks enriched
4
disease-correlated networks
4
regulator transcription
4
master regulator
4
defined disease-correlated
4

References

(Supplied by CrossRef)

Pritchard et al.
Human Molecular Genetics 2002

Sawcer et al.
Nature; Physical Science (London) 2011

Human Molecular Genetics 2009

Storch et al.
Brain pathology (Zurich, Switzerland) 1998

Harnesk et al.
The Journal of Immunology 2008

Aitman et al.
Nature genetics 2008

Flint et al.
Nature reviews. Genetics 2005

Cheung et al.
Nature genetics 2003

Jansen et al.
Trends in genetics : TIG 2001

Science 2002

Schadt et al.
Nature; Physical Science (London) 2003

Similar Publications