Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0016632 (
Fox
)
1,461
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Background:
Prioritizing tag-SNPs carried on extended risk haplotypes at susceptibility loci for common disease is a challenge.
Methods:
We utilized trans-ancestral exclusion mapping to reduce risk haplotypes at
IKZF1
and
IKZF3
identified in multiple ancestries from SLE GWAS and ImmunoChip datasets. We characterized functional annotation data across each risk haplotype from publicly available datasets including ENCODE, RoadMap Consortium, PC Hi-C data from 3D genome browser, NESDR NTR conditional eQTL database, GeneCards Genehancers and TF (transcription factor) binding sites from Haploregv4.
Results:
We refined the 60 kb associated haplotype upstream of
IKZF1
to just 12 tag-SNPs tagging a 47.7 kb core risk haplotype. There was preferential enrichment of DNAse I hypersensitivity and H3K27ac modification across the 3' end of the risk haplotype, with four tag-SNPs sharing allele-specific TF binding sites with promoter variants, which are eQTLs for
IKZF1
in whole blood. At
IKZF3
, we refined a core risk haplotype of 101 kb (27 tag-SNPs) from an initial extended haplotype of 194 kb (282 tag-SNPs), which had widespread DNAse I hypersensitivity, H3K27ac modification and multiple allele-specific TF binding sites. Dimerization of
Fox
family TFs bound at the 3' and promoter of
IKZF3
may stabilize chromatin looping across the locus.
Conclusions:
We combined trans-ancestral exclusion mapping and epigenetic annotation to identify variants at both
IKZF1
and
IKZF3
with the highest likelihood of biological relevance. The approach will be of strong interest to other complex trait geneticists seeking to attribute biological relevance to risk alleles on extended risk haplotypes in their disease of interest.
...
PMID:Trans-Ancestral Fine-Mapping and Epigenetic Annotation as Tools to Delineate Functionally Relevant Risk Alleles at
IKZF1
and
IKZF3
in Systemic Lupus Erythematosus. 3318 26
