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

• Published in: Nature genetics Vol. 50; no. 10; pp. 1366 - 1374
• Main Authors: Westra, Harm-Jan, Martínez-Bonet, Marta, Onengut-Gumuscu, Suna, Lee, Annette, Luo, Yang, Teslovich, Nikola, Worthington, Jane, Martin, Javier, Huizinga, Tom, Klareskog, Lars, Rantapaa-Dahlqvist, Solbritt, Chen, Wei-Min, Quinlan, Aaron, Todd, John A., Eyre, Steve, Nigrovic, Peter A., Gregersen, Peter K., Rich, Stephen S., Raychaudhuri, Soumya
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2018; Nature Publishing Group
• Subjects: 13/109; 13/44; 45/23; 45/43; 631/208/205; 692/699/249/1313/1418; 692/699/249/1313/498; Acids; Agriculture; Alleles; Animal Genetics and Genomics; Arthritis; Arthritis, Rheumatoid - epidemiology; Arthritis, Rheumatoid - genetics; Autoimmune diseases; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Case-Control Studies; CD28 antigen; CD28 Antigens - genetics; Chromosome Mapping; Consortia; CTLA-4 Antigen - genetics; CTLA-4 protein; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - epidemiology; Diabetes Mellitus, Type 1 - genetics; Disease; Disease control; Disease susceptibility; Gene Frequency; Gene Function; Genetic aspects; Genetic Loci; Genetic Predisposition to Disease; Genetic variation; Genome-Wide Association Study - statistics & numerical data; Genomes; Genotype & phenotype; Haplotypes; Health aspects; Human Genetics; Humans; Identification and classification; Interleukin 2 receptors; Jurkat Cells; Letter; Loci; Mutation; Polymorphism, Single Nucleotide; Probability; Protein-tyrosine-phosphatase; Proteins; Quantitative Trait Loci; Rheumatoid arthritis; Risk factors; RNA, Long Noncoding - genetics; Tumor Necrosis Factor alpha-Induced Protein 3 - genetics; Tyk2 protein; Type 1 diabetes; United States
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-018-0216-7

To define potentially causal variants for autoimmune disease, we fine-mapped 1 , 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. Fine-mapping and functional studies highlight potential causal risk variants for rheumatoid arthritis and type 1 diabetes, including missense variants at DNASE1L3, PTPN22, SH2B3, and TYK2, and noncoding variants at MEG3, CD28–CTLA4, and IL2RA.