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Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation

Rothwell, Simon; Amos, Christopher I; Miller, Frederick W; Rider, Lisa G; Lundberg, Ingrid E; Gregersen, Peter K; Vencovsky, Jiri; ... Myositis Genetics Consortium, .; + view all (2023) Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation. Arthritis & Rheumatology 10.1002/art.42434. (In press). Green open access

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Abstract

OBJECTIVES: The idiopathic inflammatory myopathies (IIM) are heterogeneous diseases, thought to be initiated by immune activation in genetically predisposed individuals. In this study we imputed variants from the Immunochip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analysed 2,565 Caucasian IIM samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically-matched controls. We imputed 1,648,116 variants from the Immunochip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM, and clinical and serological subgroups. RESULTS: The human leukocyte antigen (HLA) locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, three in the whole IIM cohort (SDK2 and LINC00924 - both novel, and STAT4), with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM, for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSIONS: We report novel and strong associations in IIM and PM, and localise signals to single genes and immune cell types.

Type: Article
Title: Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/art.42434
Publisher version: https://doi.org/10.1002/art.42434
Language: English
Additional information: Copyright © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Myositis Genetics Consortium
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10162884
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