Fine-mapping identifies causal variants for RA and T1D in DNASE1L3, SIRPG, MEG3, TNFAIP3 and CD28/CTLA4 loci

Westra, H.-J.; Martinez Bonet, M.; Onengut, S.; Lee, A.; Luo, Y.; Teslovich, N.; Worthington, J.; Martin, J.; Huizinga, T.; Klareskog, L.; Rantapaa-Dahlqvist, S.; Chen, W.-M.; Quinlan, A.; Todd, J. A.; Eyre, S.; Nigrovic, P.; Gregersen, P.; Rich, S.; Raychaudhuri, S.

doi:10.1101/151423

bioRxiv · 10.1101/151423

Fine-mapping identifies causal variants for RA and T1D in DNASE1L3, SIRPG, MEG3, TNFAIP3 and CD28/CTLA4 loci

Westra, H.-J.·Martinez Bonet, M.·Onengut, S.·Lee, A.·Luo, Y.·Teslovich, N.·Worthington, J.·Martin, J.·Huizinga, T.·Klareskog, L.·Rantapaa-Dahlqvist, S.·Chen, W.-M.·Quinlan, A.·Todd, J. A.·Eyre, S.·Nigrovic, P.·Gregersen, P.·Rich, S.·Raychaudhuri, S.

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Abstract

We fine-mapped 76 rheumatoid arthritis (RA) and type 1 diabetes (T1D) loci outside of the MHC. After sequencing 799 1kb regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We fine-mapped1,2 these loci in RA (11,475 cases, 15,870 controls)3, T1D (9,334 cases and 11,111 controls) 4 and combined datasets. We reduced the number of potential causal variants to [≤]5 in 8 RA and 11 T1D loci. We identified causal missense variants in five loci (DNASE1L3, SIRPG, PTPN22, SH2B3 and TYK2) and likely causal non-coding variants in six loci (MEG3, TNFAIP3, CD28/CTLA4, ANKRD55, IL2RA, REL/PUS10). Functional analysis confirmed allele specific binding and differential enhancer activity for three variants: the CD28/CTLA4 rs117701653 SNP, the TNFAIP3 rs35926684 indel, and the MEG3 rs34552516 indel. This study demonstrates the potential for dense genotyping and imputation to pinpoint missense and non-coding causal alleles.

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Westra, H.-J., Martinez Bonet, M., Onengut, S., Lee, A., Luo, Y., Teslovich, N., Worthington, J., Martin, J., Huizinga, T., Klareskog, L., Rantapaa-Dahlqvist, S., Chen, W.-M., Quinlan, A., Todd, J. A., Eyre, S., Nigrovic, P., Gregersen, P., Rich, S., Raychaudhuri, S.. 2017-06-19. Fine-mapping identifies causal variants for RA and T1D in DNASE1L3, SIRPG, MEG3, TNFAIP3 and CD28/CTLA4 loci. https://doi.org/10.1101/151423

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