Resolving mechanisms of immune-mediated disease in primary CD4 T cells
Bourges, C.; Groff, A. F.; Burren, O. S.; Gerhardinger, C.; Mattioli, K.; Hutchinson, A.; Hu, T.; Anand, T.; Epping, M. W.; Wallace, C.; Smith, K. G. C.; Rinn, J.; Lee, J. C.
Show abstract
Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by linkage disequilibrium. To determine whether causal variants could be identified via their functional effects, we adapted a massively-parallel reporter assay for use in primary CD4 T-cells, key effectors of many immune-mediated diseases. Using the results to guide further study, we provide a generalisable framework for resolving disease mechanisms from non-coding associations - illustrated by a locus linked to 6 immune-mediated diseases, where the lead functional variant causally disrupts a super-enhancer within an NF-{kappa}B-driven regulatory circuit, triggering unrestrained T-cell activation.
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