Article,
Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation
Contributors
Rothwell, S.
0000-0003-2123-9902
[1]
Rider, Lisa G
0000-0002-6912-2458
[3]
[4]
Lundberg, Ingrid
0000-0002-6068-9212
[5]
[6]
Gregersen, P.K.
0000-0003-1613-1518
[7]
Vencovsky, J.
0000-0002-0851-0713
[8]
[9]
Selva-O'Callaghan, Albert
0000-0003-2823-9761
[13]
Hanna, M.
0000-0003-0825-4075
[14]
[15]
Pachman, Lauren
0000-0001-8117-574X
[16]
[17]
[18]
Benveniste, O.
0000-0002-1167-5797
[21]
[22]
[23]
Doria, Alessandro
0000-0003-0548-4983
[28]
De Bleecker, J.
0000-0002-1328-1812
[29]
De Paepe, Boel
0000-0001-9403-4401
[29]
Wedderburn, L.
0000-0002-7495-1429
[14]
[15]
[33]
Chinoy, Hector
0000-0001-6492-1288
[1]
[34]
[35]
Lamb, Janine
0000-0002-7248-0539
(Corresponding author)
[1]
Affiliations
- [1] Univ Manchester, Fac Biol Med & Hlth, Ctr Genet & Genom Versus Arthrit, Ctr Musculoskeletal Res, Manchester, England [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [2] Baylor Coll Med, Houston, TX USA [NORA names: United States; America, North; OECD];
- [3] Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, NIH, Bethesda, MD USA [NORA names: United States; America, North; OECD];
- [4] Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, NIH, Bethesda, MD USA [NORA names: United States; America, North; OECD];
- [5] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Div Rheumatol, Solna, Stockholm, Sweden [NORA names: Sweden; Europe, EU; Nordic; OECD];
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Abstract
ObjectiveThe idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. MethodsWe analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. 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 serologic subgroups. ResultsThe HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, 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 for 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. ConclusionWe found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.
