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

the Myositis Genetics Consortium

doi:10.1002/art.42434

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

the Myositis Genetics Consortium

Pediatrics

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Objective: The 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. Methods: We 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. Results: The 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. Conclusion: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.

Original language	English (US)
Pages (from-to)	1021-1027
Number of pages	7
Journal	Arthritis and Rheumatology
Volume	75
Issue number	6
DOIs	https://doi.org/10.1002/art.42434
State	Published - Jun 2023

Funding

Supported by the Intramural Research Program, National Institute of Environmental Health Sciences, NIH. Dr. Lundberg's work was supported by grants from the Swedish Research Council and Stockholm Regional Council (ALF). Dr. Vencovsky's work was supported by the Czech Ministry of Health–Conceptual Development of Research Organization (award 00023728) (Institute of Rheumatology). Drs. Hanna and Machado's work were supported by the NIHR University College London Hospitals Biomedical Research Centre. Drs. De Bleecker and De Paepe's work were supported by the European Reference Network for Rare Neuromuscular Diseases (ERN EURO‐NMD). Dr. Wedderburn's work was supported by Versus Arthritis (awards 21593 and 21552), the Wellcome trust (award 085860), Myositis UK, the Cure JM Foundation, the Remission Charity, and the NIHR Biomedical research Centre at GOSH. Dr. Chinoy's work was supported by the Medical Research Council UK (award MR/N003322/1), Myositis UK, and the NIHR Manchester Biomedical Research Centre Funding Scheme. Dr. Lamb's work was supported by the Medical Research Council UK (award MR/N003322/1) and Myositis UK.

ASJC Scopus subject areas

Immunology and Allergy
Rheumatology
Immunology

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10.1002/art.42434

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@article{3f3351992d7240ba8d7da9a94b2fdddb,

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

abstract = "Objective: The 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. Methods: We 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. Results: The 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. Conclusion: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.",

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

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Arthritis \& Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.",

year = "2023",

month = jun,

doi = "10.1002/art.42434",

language = "English (US)",

volume = "75",

pages = "1021--1027",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "John Wiley and Sons Ltd",

number = "6",

}

TY - JOUR

T1 - Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation

AU - the Myositis Genetics Consortium

AU - Rothwell, Simon

AU - Amos, Christopher I.

AU - Miller, Frederick W.

AU - Rider, Lisa G.

AU - Lundberg, Ingrid E.

AU - Gregersen, Peter K.

AU - Vencovsky, Jiri

AU - McHugh, Neil

AU - Limaye, Vidya

AU - Selva-O'Callaghan, Albert

AU - Hanna, Michael G.

AU - Machado, Pedro M.

AU - Pachman, Lauren M.

AU - Reed, Ann M.

AU - Molberg, Øyvind

AU - Benveniste, Olivier

AU - Mathiesen, Pernille

AU - Radstake, Timothy

AU - Doria, Andrea

AU - De Bleecker, Jan L.

AU - De Paepe, Boel

AU - Maurer, Britta

AU - Ollier, William E.

AU - Padyukov, Leonid

AU - O'Hanlon, Terrance P.

AU - Lee, Annette

AU - Wedderburn, Lucy R.

AU - Chinoy, Hector

AU - Lamb, Janine A.

PY - 2023/6

Y1 - 2023/6

N2 - Objective: The 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. Methods: We 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. Results: The 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. Conclusion: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.

AB - Objective: The 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. Methods: We 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. Results: The 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. Conclusion: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.

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U2 - 10.1002/art.42434

DO - 10.1002/art.42434

M3 - Article

C2 - 36580032

AN - SCOPUS:85151071966

SN - 2326-5191

VL - 75

SP - 1021

EP - 1027

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

IS - 6

ER -

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

Abstract

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