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

By Harm-Jan Westra, Marta Martinez Bonet, Suna Onengut, Annette Lee, Yang Luo, Nick Teslovich, Jane Worthington, Javier Martin, Tom Huizinga, Lars Klareskog, Solbritt Rantapaa-Dahlqvist, Wei-Min Chen, Aaron R Quinlan, John A Todd, Stephen Eyre, Peter A. Nigrovic, Peter Gregersen, Stephen S Rich, Soumya Raychaudhuri

Posted 19 Jun 2017
bioRxiv DOI: 10.1101/151423 (published DOI: 10.1038/s41588-018-0216-7)

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-mapped these loci in RA (11,475 cases, 15,870 controls), T1D (9,334 cases and 11,111 controls) 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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