RT Journal Article
SR Electronic
T1 Fine-mapping identifies causal variants for RA and T1D in DNASE1L3, SIRPG, MEG3, TNFAIP3 and CD28/CTLA4 loci
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 151423
DO 10.1101/151423
A1 Harm-Jan Westra
A1 Marta Martinez Bonet
A1 Suna Onengut
A1 Annette Lee
A1 Yang Luo
A1 Nick Teslovich
A1 Jane Worthington
A1 Javier Martin
A1 Tom Huizinga
A1 Lars Klareskog
A1 Solbritt Rantapaa-Dahlqvist
A1 Wei-Min Chen
A1 Aaron Quinlan
A1 John A. Todd
A1 Steve Eyre
A1 Peter A. Nigrovic
A1 Peter K. Gregersen
A1 Stephen S Rich
A1 Soumya Raychaudhuri
YR 2017
UL http://biorxiv.org/content/early/2017/06/19/151423.abstract
AB 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.