Meta-analyses uncover the genetic architecture of Idiopathic Inflammatory Myopathies

The Myositis Genetics Consortium (MYOGEN)

doi:10.1002/art.43088

Meta-analyses uncover the genetic architecture of Idiopathic Inflammatory Myopathies

The Myositis Genetics Consortium (MYOGEN)

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

1 Downloads (Pure)

Abstract

Objective: Idiopathic inflammatory myopathies (myositis, IIMs) are rare, systemic autoimmune diseases leading to muscle inflammation, muscle weakness, and extra-muscular manifestations. IIMs have a strong genetic component in disease development and progression. Previous genome-wide association studies (GWAS) have identified several loci associated with IIMs. In this study, we imputed the two prior genome-wide studies of IIMs against the largest genotype reference panel and performed meta-analyses on the largest myositis dataset to date, to identify novel risk loci and susceptibility genes associated with myositis and its clinical subtypes.

Methods: We performed association analyses on 14,903 individuals (3,206 cases and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel (TOPMed). Fine-mapping and expression quantitative trait locus co-localization analyses were conducted in myositis-relevant tissues, and associated variants were functionally annotated. The random walk with restart algorithm (RWR) was used to explore associated genetic networks.

Results: We identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 associated with total IIMs, NEMP2 in polymyositis, ACBC11 in dermatomyositis, and PSD3 in myositis with anti-histidyl-tRNA synthetase autoantibodies (anti-Jo1). We also characterized effects of HLA region variants and the role of C4A. Fine-mapping and co-localization analyses revealed tissue-specific potential causal variants in DCAKD from total IIMs and IRF4 in dermatomyositis and juvenile dermatomyositis. Additional top-ranked candidate genes were identified from RWR, including APP, CD74, CIITA, NR1H4, and TXNIP.

Conclusion: Our study uncovers novel genetic regions related to IIMs, enhancing our understanding of myositis and directing future research.

Original language	English
Journal	Arthritis and Rheumatology
Early online date	16 Dec 2024
DOIs	https://doi.org/10.1002/art.43088
Publication status	Published - 16 Dec 2024

Access to Document

10.1002/art.43088

Main_Paper_A_R_Revision_R1 v2Accepted author manuscript, 169 KBLicence: CC BY

NIHR Manchester Biomedical Research Centre
Bruce, I. (PI), Lord, G. (CoI), Lennon, R. (CoI), Black, G. (CoI), Wedge, D. (CoI), Morris, A. (CoI), Hussell, T. (CoI), Sharrocks, A. (CoI), Stivaros, S. (CoI), Buch, M. (CoI), Gough, J. (CoI), Kostarelos, K. (CoI), Thistlethwaite, F. (CoI), Kadler, K. (CoI), Barton, A. (CoI), Hyrich, K. (CoI), Mcbeth, J. (CoI), O'Neill, T. (CoI), Vestbo, J. (CoI), Simpson, A. (CoI), Singh, S. (CoI), Smith, J. (CoI), Felton, T. (CoI), Murray, C. (CoI), Griffiths, C. (CoI), Cullum, N. (CoI), Rhodes, L. (CoI), Warren, R. (CoI), Paus, R. (CoI), Dumville, J. (CoI), Viros Usandizaga, A. (CoI), Keavney, B. (CoI), Tomaszewski, M. (CoI), Allan, S. (CoI), Body, R. (CoI), Cartwright, E. (CoI), Heagerty, A. (CoI), Kalra, P. (CoI), Miller, C. (CoI), Rutter, M. (CoI), Smith, C. (CoI), Trafford, A. (CoI), Evans, D. (CoI), Crosbie, E. (CoI), Crosbie, P. (CoI), Harvie, M. (CoI), Howell, S. (CoI), Renehan, A. (CoI), Dive, C. (CoI), Blackhall, F. (CoI), Landers, D. (CoI), Krebs, M. (CoI), Cook, N. (CoI), Clarke, R. (CoI), Taylor, S. (CoI), Jorgensen, C. (CoI), Lorigan, P. (CoI), Jayson, G. (CoI), Valle, J. (CoI), Mccabe, M. (CoI), Armstrong, A. (CoI), Freitas, A. (CoI), Illidge, T. (CoI), Choudhury, A. (CoI), Hoskin, P. (CoI), West, C. (CoI), Van Herk, M. (CoI), Faivre-Finn, C. (CoI), Bristow, R. (CoI), Kirkby, K. (CoI), Birtle, A. (CoI), Mackay, R. (CoI), Radford, J. (CoI), Linton, K. (CoI), Higham, C. (CoI), Munro, K. (CoI), Plack, C. (CoI), Arden Armitage, C. (CoI), Bruce, I. (CoI), Moore, D. (CoI), Saunders, G. (CoI), Stone, M. (CoI), Haddock, G. (CoI), Lewis, S. (CoI), Elliott, R. (CoI), Green, J. (CoI), Lovell, K. (CoI), Morrison, A. (CoI), Shaw, J. (CoI), Bucci, S. (CoI), Ainsworth, J. (CoI), Webb, R. (CoI), Newman, W. (CoI), Banka, S. (CoI), Clayton-Smith, J. (CoI), Payne, K. (CoI), Moldovan, R. (CoI), Wynn, R. (CoI) & Jones, S. (CoI)
1/12/22 → 30/11/27
Project: Research

Cite this

@article{1548ce2fe57647d5b6e74fb05990755f,

title = "Meta-analyses uncover the genetic architecture of Idiopathic Inflammatory Myopathies",

abstract = "Objective: Idiopathic inflammatory myopathies (myositis, IIMs) are rare, systemic autoimmune diseases leading to muscle inflammation, muscle weakness, and extra-muscular manifestations. IIMs have a strong genetic component in disease development and progression. Previous genome-wide association studies (GWAS) have identified several loci associated with IIMs. In this study, we imputed the two prior genome-wide studies of IIMs against the largest genotype reference panel and performed meta-analyses on the largest myositis dataset to date, to identify novel risk loci and susceptibility genes associated with myositis and its clinical subtypes.Methods: We performed association analyses on 14,903 individuals (3,206 cases and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel (TOPMed). Fine-mapping and expression quantitative trait locus co-localization analyses were conducted in myositis-relevant tissues, and associated variants were functionally annotated. The random walk with restart algorithm (RWR) was used to explore associated genetic networks.Results: We identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 associated with total IIMs, NEMP2 in polymyositis, ACBC11 in dermatomyositis, and PSD3 in myositis with anti-histidyl-tRNA synthetase autoantibodies (anti-Jo1). We also characterized effects of HLA region variants and the role of C4A. Fine-mapping and co-localization analyses revealed tissue-specific potential causal variants in DCAKD from total IIMs and IRF4 in dermatomyositis and juvenile dermatomyositis. Additional top-ranked candidate genes were identified from RWR, including APP, CD74, CIITA, NR1H4, and TXNIP.Conclusion: Our study uncovers novel genetic regions related to IIMs, enhancing our understanding of myositis and directing future research.",

author = "{The Myositis Genetics Consortium (MYOGEN)} and Catherine Zhu and Younghun Han and Jinyoung Byun and Xiangjun Xiao and Simon Rothwell and Miller, {Frederick W} and Lundberg, {Ingrid E.} and Gregersen, {Peter K} and Jiri Vencovsky and Shaw, {Vikram R.} 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 Rider, {Lisa G} and {\O}yvind Molberg and Olivier Benveniste and Pernille Mathiesen and Radstake, {Timothy R D J} and Andrea Doria and {De Bleecker}, {Jan L} and {De Paepe}, Boel and Britta Maurer and Ollier, {William E.} and Leonid Padyukov and {Lucy R. Wedderburn} and Hector Chinoy and Janine Lamb and Amos, {Christopher I.}",

year = "2024",

month = dec,

day = "16",

doi = "10.1002/art.43088",

language = "English",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "John Wiley & Sons Ltd",

}

TY - JOUR

T1 - Meta-analyses uncover the genetic architecture of Idiopathic Inflammatory Myopathies

AU - The Myositis Genetics Consortium (MYOGEN)

AU - Zhu, Catherine

AU - Han, Younghun

AU - Byun, Jinyoung

AU - Xiao, Xiangjun

AU - Rothwell, Simon

AU - Miller, Frederick W

AU - Lundberg, Ingrid E.

AU - Gregersen, Peter K

AU - Vencovsky, Jiri

AU - Shaw, Vikram R.

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 - Rider, Lisa G

AU - Molberg, Øyvind

AU - Benveniste, Olivier

AU - Mathiesen, Pernille

AU - Radstake, Timothy R D J

AU - Doria, Andrea

AU - De Bleecker, Jan L

AU - De Paepe, Boel

AU - Maurer, Britta

AU - Ollier, William E.

AU - Padyukov, Leonid

AU - Lucy R. Wedderburn,

AU - Chinoy, Hector

AU - Lamb, Janine

AU - Amos, Christopher I.

PY - 2024/12/16

Y1 - 2024/12/16

N2 - Objective: Idiopathic inflammatory myopathies (myositis, IIMs) are rare, systemic autoimmune diseases leading to muscle inflammation, muscle weakness, and extra-muscular manifestations. IIMs have a strong genetic component in disease development and progression. Previous genome-wide association studies (GWAS) have identified several loci associated with IIMs. In this study, we imputed the two prior genome-wide studies of IIMs against the largest genotype reference panel and performed meta-analyses on the largest myositis dataset to date, to identify novel risk loci and susceptibility genes associated with myositis and its clinical subtypes.Methods: We performed association analyses on 14,903 individuals (3,206 cases and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel (TOPMed). Fine-mapping and expression quantitative trait locus co-localization analyses were conducted in myositis-relevant tissues, and associated variants were functionally annotated. The random walk with restart algorithm (RWR) was used to explore associated genetic networks.Results: We identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 associated with total IIMs, NEMP2 in polymyositis, ACBC11 in dermatomyositis, and PSD3 in myositis with anti-histidyl-tRNA synthetase autoantibodies (anti-Jo1). We also characterized effects of HLA region variants and the role of C4A. Fine-mapping and co-localization analyses revealed tissue-specific potential causal variants in DCAKD from total IIMs and IRF4 in dermatomyositis and juvenile dermatomyositis. Additional top-ranked candidate genes were identified from RWR, including APP, CD74, CIITA, NR1H4, and TXNIP.Conclusion: Our study uncovers novel genetic regions related to IIMs, enhancing our understanding of myositis and directing future research.

AB - Objective: Idiopathic inflammatory myopathies (myositis, IIMs) are rare, systemic autoimmune diseases leading to muscle inflammation, muscle weakness, and extra-muscular manifestations. IIMs have a strong genetic component in disease development and progression. Previous genome-wide association studies (GWAS) have identified several loci associated with IIMs. In this study, we imputed the two prior genome-wide studies of IIMs against the largest genotype reference panel and performed meta-analyses on the largest myositis dataset to date, to identify novel risk loci and susceptibility genes associated with myositis and its clinical subtypes.Methods: We performed association analyses on 14,903 individuals (3,206 cases and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel (TOPMed). Fine-mapping and expression quantitative trait locus co-localization analyses were conducted in myositis-relevant tissues, and associated variants were functionally annotated. The random walk with restart algorithm (RWR) was used to explore associated genetic networks.Results: We identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 associated with total IIMs, NEMP2 in polymyositis, ACBC11 in dermatomyositis, and PSD3 in myositis with anti-histidyl-tRNA synthetase autoantibodies (anti-Jo1). We also characterized effects of HLA region variants and the role of C4A. Fine-mapping and co-localization analyses revealed tissue-specific potential causal variants in DCAKD from total IIMs and IRF4 in dermatomyositis and juvenile dermatomyositis. Additional top-ranked candidate genes were identified from RWR, including APP, CD74, CIITA, NR1H4, and TXNIP.Conclusion: Our study uncovers novel genetic regions related to IIMs, enhancing our understanding of myositis and directing future research.

U2 - 10.1002/art.43088

DO - 10.1002/art.43088

M3 - Article

SN - 2326-5191

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

ER -

Meta-analyses uncover the genetic architecture of Idiopathic Inflammatory Myopathies

Abstract

Access to Document

Fingerprint

Projects

NIHR Manchester Biomedical Research Centre

Cite this