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.

doi:10.1101/2020.01.16.908988

bioRxiv · 10.1101/2020.01.16.908988

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.

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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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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.. 2020-01-17. Resolving mechanisms of immune-mediated disease in primary CD4 T cells. https://doi.org/10.1101/2020.01.16.908988

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