TY - JOUR
T1 - DNase hypersensitive sites and association with multiple sclerosisxs
AU - Disanto, Giulio
AU - Sandve, Geir Kjetil
AU - Ricigliano, Vito A.G.
AU - Pakpoor, Julia
AU - Berlanga-Taylor, Antonio J.
AU - Handel, Adam E.
AU - Kuhle, Jens
AU - Holden, Lars
AU - Watson, Corey T.
AU - Giovannoni, Gavin
AU - Handunnetthi, Lahiru
AU - Ramagopalan, Sreeram V.
N1 - Funding Information:
This work was funded by: a research fellowship FISM-Fondazione Italiana Sclerosi Multipla-Cod.: (2010/B/5 to G.D.); the FUGE2 program of the Research Council of Norway to G.K.S.; the Medical Research Council (GRANT NUMBER G0801976). G.D. is a Domus B scholar at Merton College, Oxford. The study sponsors had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. All authors state that this research was carried out independently of the influence of funding bodies.
PY - 2014/2
Y1 - 2014/2
N2 - Genome-wide association studies (GWASs) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active.We used available data on MS-associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types.Genomic intervals were tested for overlap using the Genomic Hyper browser. The expression profile of the genes located nearby MS-associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment = 2.34, 2.19, 2.27, 2.05 and 1.95, respectively; P < 0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune-mediated traits were investigated. Several new candidate MS-associated genes located within regions of suggestive association were identified by GRAIL (CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play aprominent role in the etiology .Regions with confirmed and suggestive association have a similar immunological profile, indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the etiology of other immune-mediated diseases.
AB - Genome-wide association studies (GWASs) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active.We used available data on MS-associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types.Genomic intervals were tested for overlap using the Genomic Hyper browser. The expression profile of the genes located nearby MS-associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment = 2.34, 2.19, 2.27, 2.05 and 1.95, respectively; P < 0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune-mediated traits were investigated. Several new candidate MS-associated genes located within regions of suggestive association were identified by GRAIL (CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play aprominent role in the etiology .Regions with confirmed and suggestive association have a similar immunological profile, indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the etiology of other immune-mediated diseases.
UR - https://www.scopus.com/pages/publications/84892988063
U2 - 10.1093/hmg/ddt489
DO - 10.1093/hmg/ddt489
M3 - Article
C2 - 24092328
AN - SCOPUS:84892988063
SN - 0964-6906
VL - 23
SP - 942
EP - 948
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 4
ER -