Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

3rd Department of Internal Medicine Division of Immunology University of Debrecen Debrecen Hungary

Centre for Integrated Genomic Medical Research Manchester Academic Health Science Centre University of Manchester Manchester UK

Department of Community and Family Medicine Dartmouth College Hanover NH USA

Department of Pediatric Rheumatology Feinberg School of Medicine Northwestern University Chicago IL USA

Department of Rheumatology and Clinical Immunology Laboratory for Translational Immunology Utrecht University Medical Center; and Nijmegen Center for Molecular Life Sciences Nijmegen The Netherlands

Division of Medicine University College London London UK

Institute of Child Health University College London London UK

Institute of Rheumatology Charles University Prague Czech Republic

M D Anderson Cancer Center Houston TX USA

Mayo Clinic Rochester MN USA

MRC ARUK Institute for Ageing and Chronic Disease University of Liverpool UK

National Institute of Environmental Health Sciences National Institutes of Health Bethesda MD USA

Rheumatology Unit Department of Medicine Karolinska University Hospital Solna Karolinska Institutet Stockholm Sweden

Robert S Boas Center for Genomics and Human Genetics Feinstein Institute for Medical Research Manhasset NY USA

The National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit Centre for Musculoskeletal Research University of Manchester Manchester UK

Vall d'Hebron General Hospital Barcelona Spain

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Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses

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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

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Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum