Genome-Wide Association Meta-Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci - PubMed (original) (raw)

Meta-Analysis

. 2017 Nov;69(11):2222-2232.

doi: 10.1002/art.40216. Epub 2017 Oct 12.

Miranda C Marion 2, Marc Sudman 3, Mary E Comeau 2, Mara L Becker 4, John F Bohnsack 5, Tasha E Fingerlin 6, Thomas A Griffin 7, J Peter Haas 8, Daniel J Lovell 1, Lisa A Maier 6, Peter A Nigrovic 9, Sampath Prahalad 10, Marilynn Punaro 11, Carlos D Rosé 12, Carol A Wallace 13, Carol A Wise 14, Halima Moncrieffe 1, Timothy D Howard 15, Carl D Langefeld 15, Susan D Thompson 1

Affiliations

Meta-Analysis

Genome-Wide Association Meta-Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci

Laura A McIntosh et al. Arthritis Rheumatol. 2017 Nov.

Abstract

Objective: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)-negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes.

Methods: Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single-nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis.

Results: Meta-analysis showed evidence of association (P < 1 × 10-6 ) at 9 regions: PRR9_LOR (P = 5.12 × 10-8 ), ILDR1_CD86 (P = 6.73 × 10-8 ), WDFY4 (P = 1.79 × 10-7 ), PTH1R (P = 1.87 × 10-7 ), RNF215 (P = 3.09 × 10-7 ), AHI1_LINC00271 (P = 3.48 × 10-7 ), JAK1 (P = 4.18 × 10-7 ), LINC00951 (P = 5.80 × 10-7 ), and HBP1 (P = 7.29 × 10-7 ). Of these, PRR9_LOR, ILDR1_CD86, RNF215, LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22.

Conclusion: This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA.

© 2017, American College of Rheumatology.

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Figures

Figure 1

Figure 1

Manhattan plot of genome-wide genetic association statistics for oligoarticular and rheumatoid factor–negative polyarticular juvenile idiopathic arthritis (JIA) risk loci. The upper gray line indicates the genome-wide significance (P < 5 × 10−8) threshold. The lower gray line indicates the suggestive association (P < 1 × 10−6) threshold. Loci reaching this threshold and individual single-nucleotide polymorphisms mapping to these loci are shown in dark blue. Loci in gray have been reported for association by Hinks et al (see ref. 3). The loci are named using the genes bounding the regions of association and do not necessarily reflect a functional link with a specific gene.

Figure 2

Figure 2

IPA showing interactions between products of genes located in the juvenile idiopathic arthritis–associated regions from the current study and previous Immunochip studies. Solid lines represent direct interactions, where 2 molecules make direct physical contact with each other. Dashed lines represent indirect interactions. Only experimentally validated interactions are shown. GWAS = genome-wide association study.

References

    1. Petty R, Cassidy J. Chronic arthritis in childhood. Philadelphia: Elsevier; 2011.
    1. Saurenmann RK, Rose JB, Tyrrell P, Feldman BM, Laxer RM, Schneider R, et al. Epidemiology of juvenile idiopathic arthritis in a multiethnic cohort: ethnicity as a risk factor. Arthritis Rheum. 2007;56:1974–84. -PubMed
    1. Hinks A, Cobb J, Marion MC, Prahalad S, Sudman M, Bowes J, et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet. 2013;45:664–9. -PMC -PubMed
    1. Thompson SD, Marion MC, Sudman M, Ryan M, Tsoras M, Howard TD, et al. Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13. Arthritis Rheum. 2012;64:2781–91. -PMC -PubMed
    1. Thompson SD, Sudman M, Ramos PS, Marion MC, Ryan M, Tsoras M, et al. The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1. Arthritis Rheum. 2010;62:3265–76. -PMC -PubMed

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