Fine-Mapping Identifies Causal Variants for RA and T1D in DNASE1L3, Sirpg, MEG3, TNFAIP3 and CD28/CTLA4 Loc

Harm-Jan Westra¹, Marta Martinez-Bonet², Suna Onengut³, Annette Lee⁴, Yang Luo¹, Nikola Teslovich¹, Jane Worthington⁵, Javier Martín⁶, TWJ Huizinga⁷, Lars Klareskog⁸, Solbritt Rantapää Dahlqvist⁹, Wei-Min Chen³, Aaron Quinlan¹⁰, John Todd¹¹, Stephen Eyre⁵, Peter Nigrovic², Peter Gregersen⁴, Stephen Rich³ and Soumya Raychaudhuri¹², ¹Division of Genetics and Rheumatology, Department of Medicine, Harvard Medical School, Boston, MA, ²Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, ³Department of Public Health Sciences, University of Virginia, Charlottesville, VA, ⁴The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, ⁵Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom, ⁶Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, PTS-Granada, Granada, Spain, ⁷Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ⁸Dept. of Medicine, Rheumatology Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, ⁹University of Umeå, Umeå, Sweden, ¹⁰Department of Human Genetics, University of Utah, Salt Lake City, UT, ¹¹JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, ¹²Division of Medicine and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: autoimmune diseases, Genetic architecture, Genetics and rheumatoid arthritis (RA)

Session Information

Date: Tuesday, November 7, 2017

Session Title: Genetics, Genomics and Proteomics

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: While genome-wide association studies have identified risk loci for rheumatoid arthritis and other autoimmune diseases, in very few instances have causal variants driving risk been precisely defined.

Methods: We fine-mapped 76 autoimmune disease loci outside of the MHC, combining genotype data from rheumatoid arthritis (RA) and type 1 diabetes (T1D) case-control studies. After sequencing 799 1kb regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We applied Bayesian fine-mapping for these loci in RA (11,475 cases, 15,870 controls), T1D (9,334 cases and 11,111 controls) and combined datasets.

Results: 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 (Table, DNASE1L3, SIRPG, PTPN22, SH2B3 and TYK2) and likely causal non-coding variants in six loci (Table, MEG3, TNFAIP3, CD28/CTLA4, ANKRD55, IL2RA, REL/PUS10). In the DNASE1L3 locus, the previously reported missensse RA lead SNP rs35677470 (posterior=0.81) causes a R206C change in DNASE1L3, which abolishes its nuclease function. In SIRPG, we identified the rs6043409 missense variant, causing a V263A substitution (posterior=0.25). For the loci with non-coding causal candidates, we performed stringent filtering based on allelic function and enhancer activity. Using this approach, in the CD28/CTLA4 locus, we identified independent variants associated with RA and T1D: the rs117701653 SNP near CD28, associated with RA (posterior=0.82), and the rs3087243 SNP associated with both RA and T1D (posterior=0.91). Functional assays including EMSA and luciferase assay showed allele specific, cell type specific activity for rs117701653 but not rs3087243. Additionally, in the TNFAIP3 locus in RA, we identified allele specific and cell type specific enhancer activity for the rs35926684 indel (posterior=0.24), but not the previously reported lead variant rs6920220. Finally, in the MEG3 locus, we identified the rs34552516 indel (posterior=0.37) for T1D with allele specific and cell type specific enhancer activity.

Conclusion: This study demonstrates the potential for dense genotyping and imputation to pinpoint missense and non-coding causal alleles.

Disclosure: H. J. Westra, None; M. Martinez-Bonet, None; S. Onengut, None; A. Lee, None; Y. Luo, None; N. Teslovich, None; J. Worthington, None; J. Martín, None; T. Huizinga, Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough, UCB, Eli Lilly, 5,METEOR Board, 6,EU & Dutch Arthritis Foundation, 2,Abbott Laboratories, Biotest AG, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, Pfizer Inc, Roche, sanofi-aventis, Schering-Plough, 8,Abbott Laboratories, Roche, 9; L. Klareskog, None; S. Rantapää Dahlqvist, None; W. M. Chen, None; A. Quinlan, None; J. Todd, None; S. Eyre, None; P. Nigrovic, None; P. Gregersen, None; S. Rich, None; S. Raychaudhuri, Pfizer Inc, 2,Roche Pharmaceuticals, 2.

To cite this abstract in AMA style:

Westra HJ, Martinez-Bonet M, Onengut S, Lee A, Luo Y, Teslovich N, Worthington J, Martín J, Huizinga T, Klareskog L, Rantapää Dahlqvist S, Chen WM, Quinlan A, Todd J, Eyre S, Nigrovic P, Gregersen P, Rich S, Raychaudhuri S. Fine-Mapping Identifies Causal Variants for RA and T1D in DNASE1L3, Sirpg, MEG3, TNFAIP3 and CD28/CTLA4 Loc [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/fine-mapping-identifies-causal-variants-for-ra-and-t1d-in-dnase1l3-sirpg-meg3-tnfaip3-and-cd28ctla4-loc/. Accessed April 20, 2019.

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