Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes.

TitleFine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes.
Publication TypeJournal Article
Year of Publication2018
AuthorsWestra, H-J, Martínez-Bonet, M, Onengut-Gumuscu, S, Lee, A, Luo, Y, Teslovich, N, Worthington, J, Martin, J, Huizinga, T, Klareskog, L, Rantapaa-Dahlqvist, S, Chen, W-M, Quinlan, A, Todd, JA, Eyre, S, Nigrovic, PA, Gregersen, PK, Rich, SS, Raychaudhuri, S
JournalNat Genet
Date Published2018 10
KeywordsAlleles, Arthritis, Rheumatoid, Case-Control Studies, CD28 Antigens, Chromosome Mapping, CTLA-4 Antigen, Diabetes Mellitus, Type 1, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Jurkat Cells, Mutation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, RNA, Long Noncoding, Tumor Necrosis Factor alpha-Induced Protein 3

To define potentially causal variants for autoimmune disease, we fine-mapped 76 rheumatoid arthritis (11,475 cases, 15,870 controls) and type 1 diabetes loci (9,334 cases, 11,111 controls). After sequencing 799 1-kilobase regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We defined credible sets of ≤5 causal variants at 5 rheumatoid arthritis and 10 type 1 diabetes loci. We identified potentially causal missense variants at DNASE1L3, PTPN22, SH2B3, and TYK2, and noncoding variants at MEG3, CD28-CTLA4, and IL2RA. We also identified potential candidate causal variants at SIRPG and TNFAIP3. Using functional assays, we confirmed allele-specific protein binding and differential enhancer activity for three variants: the CD28-CTLA4 rs117701653 SNP, MEG3 rs34552516 indel, and TNFAIP3 rs35926684 indel.

Alternate JournalNat. Genet.
PubMed ID30224649
PubMed Central IDPMC6364548
Grant ListR01 AR063759 / AR / NIAMS NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States
UH2 AR067677 / AR / NIAMS NIH HHS / United States