Cascading epigenomic analysis for identifying disease genes from the regulatory landscape of GWAS variants.
Ontology highlight
ABSTRACT:
SUBMITTER: Ng B
PROVIDER: S-EPMC8648125 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We performed an analysis of 489 GWAS variants that are associated with RA disease or are markers of RA drug efficacy. These variants were analyzed for: 1) their spatial interactions in three-dimensions, as captured by proximity ligation; 2) chromatin markers of regulatory functions (DNAse Hypersensitivity Sites, transcription factor binding site motifs, luciferase allele-specific SNP enhancer activity); and 3) their ability to affect linked gene expression (i.e. act as an eQTL). SNPs rs3184504, rs653178, and rs11545078 show evidence of differential long distance spatial associations in HL-60/S4 cells in undifferentiated versus differentiated cell states. RA associated variants at the SH2B3 locus (rs3184504/rs653178)) have a spatially-reinforced eQTL with BAZ2A, ~60Mb away, which affects platelet formation. Similarly, a variant at the GGH locus, which is associated with methotrexate toxicity, forms an inter-chromosomal spatially-reinforced eQTL with MGEA5, which is overexpressed in peripheral blood mononuclear cells.
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