• Something wrong with this record ?

Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses

C. Zhu, Y. Han, J. Byun, X. Xiao, S. Rothwell, FW. Miller, IE. Lundberg, PK. Gregersen, J. Vencovsky, VR. Shaw, N. McHugh, V. Limaye, A. Selva-O'Callaghan, MG. Hanna, PM. Machado, LM. Pachman, AM. Reed, LG. Rider, Ø. Molberg, O. Benveniste, T....

. 2025 ; 77 (6) : 750-764. [pub] 20250213

Language English Country United States

Document type Journal Article, Meta-Analysis

Persistent link   https://www.medvik.cz/link/bmc25015582

Grant support
00023728 the Czech Ministry of Health
Intramural Research Program NIEHS NIH HHS - United States
18474 Myositis UK
U19 CA203654 NCI NIH HHS - United States
Translational Precision Environmental Health Science (TPEHS)
the King Gustaf V 80 Year Foundation
MR/N003322/1 Medical Research Council - United Kingdom
The Cure JM Foundation
T32ES027801 Training Program fellowship
NIHR203308 NIHR Manchester Biomedical Research Centre
Region Stockholm Avtal om Läkarutbildning och Forskning (ALF project)
20380 Versus Arthritis - United Kingdom
2020-01378 The Swedish Research Council
the Swedish Rheumatism Association

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

Ann and Robert H Lurie Children's Hospital of Chicago and Northwestern University Feinberg School of Medicine Chicago Illinois

Baylor College of Medicine Houston Texas

Charles University Prague Czech Republic

Duke University Durham North Carolina

Ghent University Ghent Belgium

Karolinska Institutet and Karolinska University Hospital Stockholm Sweden

Manchester Metropolitan University Manchester United Kingdom

National Institute of Environmental Health Sciences NIH Bethesda Maryland

NIHR Biomedical Research Centre at Great Ormond Street Hospital Centre for Adolescent Rheumatology Versus Arthritis and University College London London United Kingdom

NIHR Manchester Biomedical Research Centre Manchester University NHS Foundation Trust and The University of Manchester Manchester United Kingdom and Salford Royal Hospital Northern Care Alliance NHS Foundation Trust and Manchester Academic Health Science Centre Salford United Kingdom

Oslo University Hospital Oslo Norway

Sorbonne Université AP HP Myology Research Center UMR974 Pitié Salpêtrière Hospital Paris France

The Feinstein Institute Manhasset New York

The University of Manchester Manchester United Kingdom

Universitat Autonoma de Barcelona Barcelona Spain

University College London London United Kingdom

University Hospital Bern Switzerland

University Medical Center Utrecht Utrecht The Netherlands

University of Adelaide Adelaide South Australia Australia

University of Bath Bath United Kingdom

University of Padova Padova Italy

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc25015582
003      
CZ-PrNML
005      
20250731091109.0
007      
ta
008      
250708s2025 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1002/art.43088 $2 doi
035    __
$a (PubMed)39679859
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Zhu, Catherine $u Baylor College of Medicine, Houston, Texas $1 https://orcid.org/000000024939515X
245    10
$a Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses / $c C. Zhu, Y. Han, J. Byun, X. Xiao, S. Rothwell, FW. Miller, IE. Lundberg, PK. Gregersen, J. Vencovsky, VR. Shaw, N. McHugh, V. Limaye, A. Selva-O'Callaghan, MG. Hanna, PM. Machado, LM. Pachman, AM. Reed, LG. Rider, Ø. Molberg, O. Benveniste, T. Radstake, A. Doria, JL. De Bleecker, B. De Paepe, B. Maurer, WE. Ollier, L. Padyukov, LR. Wedderburn, H. Chinoy, JA. Lamb, CI. Amos, Myositis Genetics Consortium
520    9_
$a OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.
650    _2
$a lidé $7 D006801
650    12
$a myozitida $x genetika $7 D009220
650    _2
$a celogenomová asociační studie $7 D055106
650    _2
$a genetická predispozice k nemoci $7 D020022
650    _2
$a jednonukleotidový polymorfismus $7 D020641
650    _2
$a lokus kvantitativního znaku $7 D040641
655    _2
$a časopisecké články $7 D016428
655    _2
$a metaanalýza $7 D017418
700    1_
$a Han, Younghun $u Baylor College of Medicine, Houston, Texas $1 https://orcid.org/0000000150488479
700    1_
$a Byun, Jinyoung $u Baylor College of Medicine, Houston, Texas $1 https://orcid.org/0000000185791435
700    1_
$a Xiao, Xiangjun $u Baylor College of Medicine, Houston, Texas
700    1_
$a Rothwell, Simon $u The University of Manchester, Manchester, United Kingdom $1 https://orcid.org/0000000321239902
700    1_
$a Miller, Frederick W $u National Institute of Environmental Health Sciences, NIH, Bethesda, Maryland $1 https://orcid.org/0000000328319593
700    1_
$a Lundberg, Ingrid E $u Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden $1 https://orcid.org/0000000260689212
700    1_
$a Gregersen, Peter K $u The Feinstein Institute, Manhasset, New York $1 https://orcid.org/0000000316131518
700    1_
$a Vencovsky, Jiri $u Charles University, Prague, Czech Republic $1 https://orcid.org/0000000208510713 $7 jo20000080529
700    1_
$a Shaw, Vikram R $u Baylor College of Medicine, Houston, Texas $1 https://orcid.org/0000000211725686
700    1_
$a McHugh, Neil $u University of Bath, Bath, United Kingdom
700    1_
$a Limaye, Vidya $u University of Adelaide, Adelaide, South Australia, Australia
700    1_
$a Selva-O'Callaghan, Albert $u Universitat Autonoma de Barcelona, Barcelona, Spain $1 https://orcid.org/0000000328239761
700    1_
$a Hanna, Michael G $u University College London, London, United Kingdom $1 https://orcid.org/0000000308254075
700    1_
$a Machado, Pedro M $u University College London, London, United Kingdom $1 https://orcid.org/0000000284117972
700    1_
$a Pachman, Lauren M $u Ann & Robert H. Lurie Children's Hospital of Chicago and Northwestern University Feinberg School of Medicine, Chicago, Illinois
700    1_
$a Reed, Ann M $u Duke University, Durham, North Carolina $1 https://orcid.org/0000000245217647
700    1_
$a Rider, Lisa G $u National Institute of Environmental Health Sciences, NIH, Bethesda, Maryland $1 https://orcid.org/0000000269122458
700    1_
$a Molberg, Øyvind $u Oslo University Hospital, Oslo, Norway
700    1_
$a Benveniste, Olivier $u Sorbonne Université, AP-HP, Myology Research Center UMR974, Pitié-Salpêtrière Hospital, Paris, France $1 https://orcid.org/0000000211675797
700    1_
$a Radstake, Timothy $u University Medical Center Utrecht, Utrecht, The Netherlands
700    1_
$a Doria, Andrea $u University of Padova, Padova, Italy $1 https://orcid.org/0000000305484983
700    1_
$a De Bleecker, Jan L $u Ghent University, Ghent, Belgium $1 https://orcid.org/0000000213281812
700    1_
$a De Paepe, Boel $u Ghent University, Ghent, Belgium $1 https://orcid.org/0000000194034401
700    1_
$a Maurer, Britta $u University Hospital, Bern, Switzerland $1 https://orcid.org/0000000193858097
700    1_
$a Ollier, William E $u Manchester Metropolitan University, Manchester, United Kingdom $1 https://orcid.org/0000000165026584
700    1_
$a Padyukov, Leonid $u Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden $1 https://orcid.org/0000000329505670
700    1_
$a Wedderburn, Lucy R $u NIHR Biomedical Research Centre at Great Ormond Street Hospital, Centre for Adolescent Rheumatology Versus Arthritis, and University College London, London, United Kingdom $1 https://orcid.org/0000000274951429
700    1_
$a Chinoy, Hector $u NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust and The University of Manchester, Manchester, United Kingdom, and Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust and Manchester Academic Health Science Centre, Salford, United Kingdom $1 https://orcid.org/0000000164921288
700    1_
$a Lamb, Janine A $u The University of Manchester, Manchester, United Kingdom $1 https://orcid.org/0000000272480539
700    1_
$a Amos, Christopher I $u Baylor College of Medicine, Houston, Texas $1 https://orcid.org/0000000285407023
710    2_
$a Myositis Genetics Consortium
773    0_
$w MED00188151 $t Arthritis & rheumatology $x 2326-5205 $g Roč. 77, č. 6 (2025), s. 750-764
856    41
$u https://pubmed.ncbi.nlm.nih.gov/39679859 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20250708 $b ABA008
991    __
$a 20250731091104 $b ABA008
999    __
$a ok $b bmc $g 2366437 $s 1252707
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2025 $b 77 $c 6 $d 750-764 $e 20250213 $i 2326-5205 $m Arthritis & rheumatology $n Arthritis Rheumatol $x MED00188151
GRA    __
$a 00023728 $p the Czech Ministry of Health
GRA    __
$a Intramural Research Program $p NIEHS NIH HHS $2 United States
GRA    __
$a 18474 $p Myositis UK
GRA    __
$a U19 CA203654 $p NCI NIH HHS $2 United States
GRA    __
$p Translational Precision Environmental Health Science (TPEHS)
GRA    __
$p the King Gustaf V 80 Year Foundation
GRA    __
$a MR/N003322/1 $p Medical Research Council $2 United Kingdom
GRA    __
$p The Cure JM Foundation
GRA    __
$a T32ES027801 $p Training Program fellowship
GRA    __
$a NIHR203308 $p NIHR Manchester Biomedical Research Centre
GRA    __
$p Region Stockholm Avtal om Läkarutbildning och Forskning (ALF project)
GRA    __
$a 20380 $p Versus Arthritis $2 United Kingdom
GRA    __
$a 2020-01378 $p The Swedish Research Council
GRA    __
$p the Swedish Rheumatism Association
LZP    __
$a Pubmed-20250708

Find record

Citation metrics

Archiving options