Genome-wide imputation identifies novel associations and localises signals in idiopathic inflammatory myopathies

Simon Rothwell, Christopher I Amos, Frederick W Miller, Lisa G Rider, Ingrid E Lundberg, Peter K Gregersen, Jiri Vencovsky, Neil McHugh, Vidya Limaye, Albert Selva-O'Callaghan, Michael G Hanna, Pedro M Machado, Lauren M Pachman, Ann M Reed, Øyvind Molberg, Olivier Benveniste, Pernille Mathiesen, Timothy Radstake, Andrea Doria, Jan L De BleeckerBoel De Paepe, Britta Maurer, William E Ollier, Leonid Padyukov, Terrance P O'Hanlon, Annette Lee, Lucy R Wedderburn, Hector Chinoy, Janine A Lamb, Myositis Genetics Consortium


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. This article is protected by copyright. All rights reserved.

TidsskriftArthritis and Rheumatology
Sider (fra-til)epub
StatusE-pub ahead of print - 29 dec. 2022


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