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

Harm-Jan Westra; Marta Martínez-Bonet; Suna Onengut-Gumuscu; Annette Lee; Yang Luo; Nikola Teslovich; Jane Worthington; Javier Martin; Tom Huizinga; Lars Klareskog; Solbritt Rantapaa-Dahlqvist; Wei-Min Chen; Aaron Quinlan; John A Todd; Steve Eyre; Peter A Nigrovic; Peter K Gregersen; Stephen S Rich; Soumya Raychaudhuri

doi:10.1038/s41588-018-0216-7

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

Nat Genet. 2018 Oct;50(10):1366-1374. doi: 10.1038/s41588-018-0216-7. Epub 2018 Sep 17.

Authors

Harm-Jan Westra^{1

2

3

4

5}, Marta Martínez-Bonet⁴, Suna Onengut-Gumuscu^{6

7}, Annette Lee⁸, Yang Luo^{1

2

3

4}, Nikola Teslovich^{1

2

3

4}, Jane Worthington^{9

10}, Javier Martin¹¹, Tom Huizinga¹², Lars Klareskog¹³, Solbritt Rantapaa-Dahlqvist¹⁴, Wei-Min Chen^{6

7}, Aaron Quinlan^{6

15

16}, John A Todd¹⁷, Steve Eyre^{9

10}, Peter A Nigrovic^{4

18}, Peter K Gregersen⁸, Stephen S Rich^{6

7}, Soumya Raychaudhuri^{19

20

21

22

23

24}

Affiliations

¹ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁴ Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁶ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁷ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁸ The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA.
⁹ Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
¹⁰ NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, UK.
¹¹ Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
¹² Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
¹³ Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
¹⁴ Department of Public Health and Clinical Medicine, Division of Rheumatology, Umeå University, Umeå, Sweden.
¹⁵ Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
¹⁶ Department of Biomedical Informatics, University of Utah, Salt Lake City, UT, USA.
¹⁷ JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁸ Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
¹⁹ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
²⁰ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
²¹ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. soumya@broadinstitute.org.
²² Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
²³ Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK. soumya@broadinstitute.org.
²⁴ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.

Abstract

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.

Publication types

Letter
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Arthritis, Rheumatoid / epidemiology
Arthritis, Rheumatoid / genetics*
CD28 Antigens / genetics
CTLA-4 Antigen / genetics
Case-Control Studies
Chromosome Mapping
Diabetes Mellitus, Type 1 / epidemiology
Diabetes Mellitus, Type 1 / genetics*
Gene Frequency
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study / statistics & numerical data
Humans
Jurkat Cells
Mutation
Polymorphism, Single Nucleotide*
Quantitative Trait Loci
RNA, Long Noncoding / genetics
Tumor Necrosis Factor alpha-Induced Protein 3 / genetics

Substances

CD28 Antigens
CTLA-4 Antigen
CTLA4 protein, human
MEG3 non-coding RNA, human
RNA, Long Noncoding
TNFAIP3 protein, human
Tumor Necrosis Factor alpha-Induced Protein 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding