1. Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes
- Author
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Javier Martin, John A. Todd, Wei-Min Chen, Marta Martinez Bonet, Stephen S. Rich, Yang Luo, Aaron R. Quinlan, Lars Klareskog, Solbritt Rantapää-Dahlqvist, Annette Lee, Harm-Jan Westra, Peter A. Nigrovic, Soumya Raychaudhuri, Suna Onengut-Gumuscu, Jane Worthington, Nikola Teslovich, Steve Eyre, Tom W J Huizinga, and Peter K. Gregersen
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Lydia Becker Institute ,SUSCEPTIBILITY LOCI ,Quantitative Trait Loci ,Arthritis ,Genome-wide association study ,Biology ,Bioinformatics ,GENOTYPE IMPUTATION ,Polymorphism, Single Nucleotide ,Article ,Arthritis, Rheumatoid ,03 medical and health sciences ,Jurkat Cells ,CD28 Antigens ,Gene Frequency ,BURROWS-WHEELER TRANSFORM ,ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation ,Diabetes mellitus ,Genetics ,medicine ,Humans ,CTLA-4 Antigen ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,SYSTEMIC-LUPUS-ERYTHEMATOSUS ,CELL-TYPES ,Alleles ,Tumor Necrosis Factor alpha-Induced Protein 3 ,Autoimmune disease ,Type 1 diabetes ,Case-control study ,Chromosome Mapping ,COMPLEX TRAIT ,TYROSINE-PHOSPHATASE ,medicine.disease ,RISK LOCI ,030104 developmental biology ,Diabetes Mellitus, Type 1 ,Genetic Loci ,Rheumatoid arthritis ,Case-Control Studies ,Mutation ,Medical genetics ,RNA, Long Noncoding ,INFLAMMATORY-BOWEL-DISEASE ,Genome-Wide Association Study - Abstract
To define potentially causal variants for autoimmune disease, we fine-mapped1,2 76 rheumatoid arthritis (11,475 cases, 15,870 controls)3 and type 1 diabetes loci (9,334 cases, 11,111 controls)4. 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.
- Published
- 2017