Abstract：
BACKGROUND:The identification of causal genes from genome-wide association studies (GWAS) is the next important step for the translation of genetic findings into biologically meaningful mechanisms of disease and potential therapeutic targets. Using novel chromatin interaction detection techniques and allele specific assays in T and B cell lines, we provide compelling evidence that redefines causal genes at the 6q23 locus, one of the most important loci that confers autoimmunity risk. RESULTS:Although the function of disease-associated non-coding single nucleotide polymorphisms (SNPs) at 6q23 is unknown, the association is generally assigned to TNFAIP3, the closest gene. However, the DNA fragment containing the associated SNPs interacts through chromatin looping not only with TNFAIP3, but also with IL20RA, located 680 kb upstream. The risk allele of the most likely causal SNP, rs6927172, is correlated with both a higher frequency of interactions and increased expression of IL20RA, along with a stronger binding of both the NFκB transcription factor and chromatin marks characteristic of active enhancers in T-cells. CONCLUSIONS:Our results highlight the importance of gene assignment for translating GWAS findings into biologically meaningful mechanisms of disease and potential therapeutic targets; indeed, monoclonal antibody therapy targeting IL-20 is effective in the treatment of rheumatoid arthritis and psoriasis, both with strong GWAS associations to this region.
journal_name
Genome Bioljournal_title
Genome biologyauthors
McGovern A,Schoenfelder S,Martin P,Massey J,Duffus K,Plant D,Yarwood A,Pratt AG,Anderson AE,Isaacs JD,Diboll J,Thalayasingam N,Ospelt C,Barton A,Worthington J,Fraser P,Eyre S,Orozco Gdoi
10.1186/s13059-016-1078-xsubject
Has Abstractpub_date
2016-11-01 00:00:00pages
212issue
1eissn
1474-7596issn
1474-760Xpii
10.1186/s13059-016-1078-xjournal_volume
17pub_type
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