Discovery of new myositis genetic associations through leveraging other immune-mediated diseases

Abstract

Genetic associations; Myositis; Immune-mediated diseases

Asociaciones genéticas; Miositis; Enfermedades inmunomediadas

Associacions genètiques; Miositis; Malalties inmunomediades

Genome-wide association studies (GWASs) have been successful at finding associations between genetic variants and human traits, including the immune-mediated diseases (IMDs). However, the requirement of large sample sizes for discovery poses a challenge for learning about less common diseases, where increasing volunteer numbers might not be feasible. An example of this is myositis (or idiopathic inflammatory myopathies [IIM]s), a group of rare, heterogeneous autoimmune diseases affecting skeletal muscle and other organs, severely impairing life quality. Here, we applied a feature engineering method to borrow information from larger IMD GWASs to find new genetic associations with IIM and its subgroups. Combining this approach with two clustering methods, we found 17 IMDs genetically close to IIM, including some common comorbid conditions, such as systemic sclerosis and Sjögren’s syndrome, as well as hypo- and hyperthyroidism. All IIM subtypes were genetically similar within this framework. Next, we colocalized IIM signals that overlapped IMD signals, and found seven potentially novel myositis associations mapped to immune-related genes, including BLK, IRF5/TNPO3, and ITK/HAVCR2, implicating a role for both B and T cells in IIM. This work proposes a new paradigm of genetic discovery in rarer diseases by leveraging information from more common IMD, and can be expanded to other conditions and traits beyond IMD.

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). Dr Machado's work was supported by the NIHR University College London Hospitals Biomedical Research Centre. Drs. Miller and Rider’s work was supported by the intramural research program of the National Institute of Environmental Health Sciences, National Institutes of Health (Project ZIA ES101074 ). Dr. Reed's work was funded by NIH (award K12HD105253 ). Dr. De Bleecker is a member of 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 by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre ( NIHR203308 ). Dr. Lamb's work was supported by the Medical Research Council UK (award MR/N003322/1 ) and Myositis UK. Dr. Wallace and Dr. Reales are funded by the Wellcome Trust ( WT220788 ). Dr. Wallace is funded by the Medical Research Council (MRC; MC UU 00002/4 ) and supported by the NIHR Cambridge BRC ( BRC-1215-20014 ). Dr. Amos is partially supported by a grant from the Juvenile Dermatomyositis Foundation. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. This research was funded in whole, or in part, by the Wellcome Trust WT220788. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We want to acknowledge the participants and investigators of the FinnGen study.