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.

Cambridge Institute of Therapeutic Immunology and Infectious Disease University of Cambridge Cambridge UK; Department of Medicine University of Cambridge Cambridge UK

Cambridge Institute of Therapeutic Immunology and Infectious Disease University of Cambridge Cambridge UK; Department of Medicine University of Cambridge Cambridge UK; MRC Biostatistics Unit University of Cambridge Cambridge UK

Centre for Adolescent Rheumatology Versus Arthritis UCL Great Ormond Street Institute of Child Health University College London London UK; NIHR Biomedical Research Centre at Great Ormond Street Hospital London UK

Centre for Genetics and Genomics Versus Arthritis Centre for Musculoskeletal Research Faculty of Biology Medicine and Health University of Manchester Manchester UK

Children's Hospital of Chicago Northwestern University Feinberg School of Medicine Chicago IL USA

Department of Internal Medicine and Clinical Immunology Pitié Salpêtrière Hospital Paris France

Department of Medicine Baylor College of Medicine Houston TX USA

Department of Neurology Ghent University Ghent Belgium; Neuromuscular Reference Center Ghent University Hospital Ghent Belgium

Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology London UK; Centre for Rheumatology UCL Division of Medicine University College London London UK

Department of Pediatrics Duke University Durham NC USA

Department of Rheumatology and Clinical Immunology University Medical Center Utrecht the Netherlands

Department of Rheumatology and Immunology Inselspital Bern University Hospital University of Bern Bern Switzerland

Department of Rheumatology Oslo University Hospital Oslo Norway

Department of Rheumatology Salford Royal Hospital Northern Care Alliance NHS Foundation Trust Manchester Academic Health Science Centre Salford UK; Division of Musculoskeletal and Dermatological Sciences Faculty of Biology Medicine and Health The University of Manchester Manchester UK

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

Environmental Autoimmunity Group National Institute of Environmental Health Sciences NIH Bethesda MD USA

Epidemiology and Public Health Group Division of Population Health Health Services Research and Primary Care Faculty of Biology Medicine and Health University of Manchester Manchester UK

Institute of Rheumatology and Department of Rheumatology 1st Medical Faculty Charles University Prague Czech Republic

Internal Medicine Department Vall d'Hebron General Hospital Universitat Autonoma de Barcelona Barcelona Spain

Rheumatology Unit Department of Medicine University of Padova Padova Italy

Rheumatology Unit Royal Adelaide Hospital Adelaide South Australia Australia; Discipline of Medicine Adelaide University Adelaide South Australia Australia

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

See more in PubMed

Sollis E., Mosaku A., Abid A., Buniello A., Cerezo M., Gil L., Groza T., Güneş O., Hall P., Hayhurst J., et al. The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource. Nucleic Acids Res. 2023;51:D977–D985. PubMed PMC

Abdellaoui A., Yengo L., Verweij K.J.H., Visscher P.M. 15 years of GWAS discovery: Realizing the promise. Am. J. Hum. Genet. 2023;110:179–194. PubMed PMC

Feldon M., Farhadi P.N., Brunner H.I., Itert L., Goldberg B., Faiq A., Wilkerson J., Rose K.M., Rider L.G., Miller F.W., Giannini E.H. Predictors of Reduced Health-Related Quality of Life in Adult Patients With Idiopathic Inflammatory Myopathies. Arthritis Care Res. 2017;69:1743–1750. PubMed PMC

Leclair V., Regardt M., Wojcik S., Hudson M., Canadian Inflammatory Myopathy Study CIMS Study (CIMS), C. I. M. Health-Related Quality of Life (HRQoL) in Idiopathic Inflammatory Myopathy: A Systematic Review. PLoS One. 2016;11 PubMed PMC

Miller F.W., Lamb J.A., Schmidt J., Nagaraju K. Risk factors and disease mechanisms in myositis. Nat. Rev. Rheumatol. 2018;14:255–268. PubMed PMC

McHugh N.J., Tansley S.L. Autoantibodies in myositis. Nat. Rev. Rheumatol. 2018;14:290–302. PubMed

Miller F.W., Cooper R.G., Vencovský J., Rider L.G., Danko K., Wedderburn L.R., Lundberg I.E., Pachman L.M., Reed A.M., Ytterberg S.R., et al. Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders. Arthritis Rheum. 2013;65:3239–3247. PubMed PMC

Miller F.W., Chen W., O'Hanlon T.P., Cooper R.G., Vencovsky J., Rider L.G., Danko K., Wedderburn L.R., Lundberg I.E., Pachman L.M., et al. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes. Gene Immun. 2015;16:470–480. PubMed PMC

Rothwell S., Amos C.I., Miller F.W., Rider L.G., Lundberg I.E., Gregersen P.K., Vencovsky J., McHugh N., Limaye V., Selva-O'Callaghan A., et al. Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation. Arthritis Rheumatol. 2023;75:1021–1027. PubMed PMC

Rothwell S., Cooper R.G., Lundberg I.E., Miller F.W., Gregersen P.K., Bowes J., Vencovsky J., Danko K., Limaye V., Selva-O'Callaghan A., et al. Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups. Ann. Rheum. Dis. 2016;75:1558–1566. PubMed PMC

Chinoy H., Platt H., Lamb J.A., Betteridge Z., Gunawardena H., Fertig N., Varsani H., Davidson J., Oddis C.V., McHugh N.J., et al. The protein tyrosine phosphatase N22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients. Arthritis Rheum. 2008;58:3247–3254. PubMed PMC

Sugiura T., Kawaguchi Y., Goto K., Hayashi Y., Tsuburaya R., Furuya T., Gono T., Nishino I., Yamanaka H. Positive association between STAT4 polymorphisms and polymyositis/dermatomyositis in a Japanese population. Ann. Rheum. Dis. 2012;71:1646–1650. PubMed

Rothwell S., Cooper R.G., Lundberg I.E., Gregersen P.K., Hanna M.G., Machado P.M., Herbert M.K., Pruijn G.J.M., Lilleker J.B., Roberts M., et al. Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum. Arthritis Rheumatol. 2017;69:1090–1099. PubMed PMC

Bianchi M., Kozyrev S.V., Notarnicola A., Hultin Rosenberg L., Karlsson Å., Pucholt P., Rothwell S., Alexsson A., Sandling J.K., Andersson H., et al. Contribution of Rare Genetic Variation to Disease Susceptibility in a Large Scandinavian Myositis Cohort. Arthritis Rheumatol. 2022;74:342–352. PubMed

Che W.I., Westerlind H., Lundberg I.E., Hellgren K., Kuja-Halkola R., Holmqvist M.E. Familial autoimmunity in patients with idiopathic inflammatory myopathies. J. Intern. Med. 2023;293:200–211. PubMed PMC

Kuo C.-F., Grainge M.J., Valdes A.M., See L.C., Luo S.F., Yu K.H., Zhang W., Doherty M. Familial Aggregation of Systemic Lupus Erythematosus and Coaggregation of Autoimmune Diseases in Affected Families. JAMA Intern. Med. 2015;175:1518–1526. PubMed

Kuo C.-F., Luo S.F., Yu K.H., See L.C., Zhang W., Doherty M. Familial risk of systemic sclerosis and co-aggregation of autoimmune diseases in affected families. Arthritis Res. Ther. 2016;18:231. PubMed PMC

Cotsapas C., Voight B.F., Rossin E., Lage K., Neale B.M., Wallace C., Abecasis G.R., Barrett J.C., Behrens T., Cho J., et al. Pervasive sharing of genetic effects in autoimmune disease. PLoS Genet. 2011;7 PubMed PMC

Thomsen H., Li X., Sundquist K., Sundquist J., Försti A., Hemminki K. Familial associations for rheumatoid autoimmune diseases. Rheumatol. Adv. Pract. 2020;4 PubMed PMC

Burren O.S., Reales G., Wong L., Bowes J., Lee J.C., Barton A., Lyons P.A., Smith K.G.C., Thomson W., Kirk P.D.W., Wallace C. Genetic feature engineering enables characterisation of shared risk factors in immune-mediated diseases. Genome Med. 2020;12:106. PubMed PMC

Buniello A., MacArthur J.A.L., Cerezo M., Harris L.W., Hayhurst J., Malangone C., McMahon A., Morales J., Mountjoy E., Sollis E., et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 2019;47:D1005–D1012. PubMed PMC

Kurki M.I., Karjalainen J., Palta P., Sipilä T.P., Kristiansson K., Donner K.M., Reeve M.P., Laivuori H., Aavikko M., Kaunisto M.A., et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023;613:508–518. PubMed PMC

Pan-UKB team. 2020. https://pan.ukbb.broadinstitute.org

Nagai A., Hirata M., Kamatani Y., Muto K., Matsuda K., Kiyohara Y., Ninomiya T., Tamakoshi A., Yamagata Z., Mushiroda T., et al. Overview of the BioBank Japan Project: Study design and profile. J. Epidemiol. 2017;27:S2–S8. PubMed PMC

Loh P.-R., Tucker G., Bulik-Sullivan B.K., Vilhjálmsson B.J., Finucane H.K., Salem R.M., Chasman D.I., Ridker P.M., Neale B.M., Berger B., et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat. Genet. 2015;47:284–290. PubMed PMC

Bhattacharyya A.K. On a Measure of Divergence between Two Statistical Populations Defined by Their Probability Distributions. Bull. Calcutta Math. Soc. 1943;35:99–109.

Nicholls K., Kirk P.D.W., Wallace C. Bayesian Clustering with Uncertain Data. BioRxiv. 2022 doi: 10.1101/2022.12.07.519476. Preprint at. DOI

Fritsch A., Ickstadt K. Improved criteria for clustering based on the posterior similarity matrix. Bayesian Anal. 2009;4

Giambartolomei C., Vukcevic D., Schadt E.E., Franke L., Hingorani A.D., Wallace C., Plagnol V. Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics. PLoS Genet. 2014;10 PubMed PMC

Wallace C. Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses. PLoS Genet. 2020;16 PubMed PMC

Gomez-Rodriguez J., Kraus Z.J., Schwartzberg P.L. Tec family kinases Itk and Rlk/Txk in T lymphocytes: Cross-regulation of cytokine production and T cell fates. FEBS J. 2011;278:1980–1989. PubMed PMC

Weeks S., Harris R., Karimi M. Targeting ITK signaling for T cell-mediated diseases. iScience. 2021;24 PubMed PMC

Wolf Y., Anderson A.C., Kuchroo V.K. TIM3 comes of age as an inhibitory receptor. Nat. Rev. Immunol. 2020;20:173–185. PubMed PMC

Asimit J.L., Rainbow D.B., Fortune M.D., Grinberg N.F., Wicker L.S., Wallace C. Stochastic search and joint fine-mapping increases accuracy and identifies previously unreported associations in immune-mediated diseases. Nat. Commun. 2019;10:3216. PubMed PMC

Garg G., Tyler J.R., Yang J.H.M., Cutler A.J., Downes K., Pekalski M., Bell G.L., Nutland S., Peakman M., Todd J.A., et al. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J. Immunol. 1950. 2012;188:4644–4653. PubMed PMC

Mishra S., Liao W., Liu Y., Yang M., Ma C., Wu H., Zhao M., Zhang X., Qiu Y., Lu Q., Zhang N. TGF-β and Eomes control the homeostasis of CD8+ regulatory T cells. J. Exp. Med. 2021;218 PubMed PMC

Zhang X., Huo C., Liu Y., Su R., Zhao Y., Li Y. Mechanism and Disease Association With a Ubiquitin Conjugating E2 Enzyme: UBE2L3. Front. Immunol. 2022;13 PubMed PMC

Wang S., Adrianto I., Wiley G.B., Lessard C.J., Kelly J.A., Adler A.J., Glenn S.B., Williams A.H., Ziegler J.T., Comeau M.E., et al. A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. Gene Immun. 2012;13:380–387. PubMed PMC

Zuo X.-B., Sheng Y.J., Hu S.J., Gao J.P., Li Y., Tang H.Y., Tang X.F., Cheng H., Yin X.Y., Wen L.L., et al. Variants in TNFSF4, TNFAIP3, TNIP1, BLK, SLC15A4 and UBE2L3 interact to confer risk of systemic lupus erythematosus in Chinese population. Rheumatol. Int. 2014;34:459–464. PubMed

Agik S., Franek B.S., Kumar A.A., Kumabe M., Utset T.O., Mikolaitis R.A., Jolly M., Niewold T.B. The autoimmune disease risk allele of UBE2L3 in African American patients with systemic lupus erythematosus: a recessive effect upon subphenotypes. J. Rheumatol. 2012;39:73–78. PubMed PMC

Fransen K., Visschedijk M.C., van Sommeren S., Fu J.Y., Franke L., Festen E.A.M., Stokkers P.C.F., van Bodegraven A.A., Crusius J.B.A., Hommes D.W., et al. Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn’s disease. Hum. Mol. Genet. 2010;19:3482–3488. PubMed

Wang Y., Zhu Y.f., Wang Q., Xu J., Yan N., Xu J., Shi L.f., He S.t., Zhang J.a. The haplotype of UBE2L3 gene is associated with Hashimoto’s thyroiditis in a Chinese Han population. BMC Endocr. Disord. 2016;16:18. PubMed PMC

Zhou Y., Li X., Wang G., Li X. Association of FAM167A-BLK rs2736340 Polymorphism with Susceptibility to Autoimmune Diseases: A Meta-Analysis. Immunol. Invest. 2016;45:336–348. PubMed

Simpfendorfer K.R., Armstead B.E., Shih A., Li W., Curran M., Manjarrez-Orduño N., Lee A.T., Diamond B., Gregersen P.K. Autoimmune disease-associated haplotypes of BLK exhibit lowered thresholds for B cell activation and expansion of Ig class-switched B cells. Arthritis Rheumatol. 2015;67:2866–2876. PubMed

López-Isac E., Acosta-Herrera M., Kerick M., Assassi S., Satpathy A.T., Granja J., Mumbach M.R., Beretta L., Simeón C.P., Carreira P., et al. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways. Nat. Commun. 2019;10:4955. PubMed PMC

Kottyan L.C., Zoller E.E., Bene J., Lu X., Kelly J.A., Rupert A.M., Lessard C.J., Vaughn S.E., Marion M., Weirauch M.T., et al. The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum. Mol. Genet. 2015;24:582–596. PubMed PMC

Arvaniti P., Le Dantec C., Charras A., Arleevskaya M.A., Hedrich C.M., Zachou K., Dalekos G.N., Renaudineau Y. Linking genetic variation with epigenetic profiles in Sjögren’s syndrome. Clin. Immunol. 2020;210 PubMed

Liu J.Z., Almarri M.A., Gaffney D.J., Mells G.F., Jostins L., Cordell H.J., Ducker S.J., Day D.B., Heneghan M.A., Neuberger J.M., et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat. Genet. 2012;44:1137–1141. PubMed PMC

Luo S., Li X.F., Yang Y.L., Song B., Wu S., Niu X.N., Wu Y.Y., Shi W., Huang C., Li J. PLCL1 regulates fibroblast-like synoviocytes inflammation via NLRP3 inflammasomes in rheumatoid arthritis. Adv. Rheumatol. 2022;62:25. PubMed

Ruan W., Liu R., Yang H., Ren J., Liu Y. Genetic Loci in Phospholipase C-Like 1 (PLCL1) are Protective Factors for Allergic Rhinitis in Han Population of Northern Shaanxi, China. J. Asthma Allergy. 2022;15:1321–1335. PubMed PMC

Paparo S.R. The MIG Chemokine in Inflammatory Myopathies. Clin. Ter. 2019;170:e55–e60. doi: 10.7417/CT.2019.2108. PubMed DOI

Gono T., Kaneko H., Kawaguchi Y., Hanaoka M., Kataoka S., Kuwana M., Takagi K., Ichida H., Katsumata Y., Ota Y., et al. Cytokine profiles in polymyositis and dermatomyositis complicated by rapidly progressive or chronic interstitial lung disease. Rheumatol. Oxf. Engl. 2014;53:2196–2203. PubMed

Richards T.J., Eggebeen A., Gibson K., Yousem S., Fuhrman C., Gochuico B.R., Fertig N., Oddis C.V., Kaminski N., Rosas I.O., Ascherman D.P. Characterization and peripheral blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease. Arthritis Rheum. 2009;60:2183–2192. PubMed PMC

Wienke J., Bellutti Enders F., Lim J., Mertens J.S., van den Hoogen L.L., Wijngaarde C.A., Yeo J.G., Meyer A., Otten H.G., Fritsch-Stork R.D.E., et al. Galectin-9 and CXCL10 as Biomarkers for Disease Activity in Juvenile Dermatomyositis: A Longitudinal Cohort Study and Multicohort Validation. Arthritis Rheumatol. 2019;71:1377–1390. PubMed PMC

Wienke J., Pachman L.M., Morgan G.A., Yeo J.G., Amoruso M.C., Hans V., Kamphuis S.S.M., Hoppenreijs E.P.A.H., Armbrust W., van den Berg J.M., et al. Endothelial and Inflammation Biomarker Profiles at Diagnosis Reflecting Clinical Heterogeneity and Serving as a Prognostic Tool for Treatment Response in Two Independent Cohorts of Patients With Juvenile Dermatomyositis. Arthritis Rheumatol. 2020;72:1214–1226. PubMed PMC

De Paepe B., Bracke K.R., De Bleecker J.L. Retrospective Study Shows That Serum Levels of Chemokine CXCL10 and Cytokine GDF15 Support a Diagnosis of Sporadic Inclusion Body Myositis and Immune-Mediated Necrotizing Myopathy. Brain Sci. 2023;13:1369. PubMed PMC

De Paepe B., Creus K.K., De Bleecker J.L. Role of cytokines and chemokines in idiopathic inflammatory myopathies. Curr. Opin. Rheumatol. 2009;21:610–616. PubMed

Gans M.D., Gavrilova T. Understanding the immunology of asthma: Pathophysiology, biomarkers, and treatments for asthma endotypes. Paediatr. Respir. Rev. 2020;36:118–127. PubMed

Fermon C., Authier F.-J., Gallay L. Idiopathic eosinophilic myositis: a systematic literature review. Neuromuscul. Disord. 2022;32:116–124. PubMed

Aguila L.A., Lopes M.R.U., Pretti F.Z., Sampaio-Barros P.D., Carlos de Souza F.H., Borba E.F., Shinjo S.K. Clinical and laboratory features of overlap syndromes of idiopathic inflammatory myopathies associated with systemic lupus erythematosus, systemic sclerosis, or rheumatoid arthritis. Clin. Rheumatol. 2014;33:1093–1098. PubMed

Fredi M., Cavazzana I., Franceschini F. The clinico-serological spectrum of overlap myositis. Curr. Opin. Rheumatol. 2018;30:637–643. PubMed

Jennette J.C., Falk R.J. Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat. Rev. Rheumatol. 2014;10:463–473. PubMed

Dutcher J.S., Bui A., Ibe T.A., Umadat G., Harper E.P., Middlebrooks E.H., Mohseni M.M., Phillips M.B. ANCA-associated vasculitis and severe proximal muscle weakness. SAVE Proc. 2021;34:384–386. PubMed PMC

Bhan C., Twydell P. Statin Associated Necrotizing Autoimmune Myositis and p-ANCA Vasculitis: A Rare Case Report (P16-13.002) Neurology. 2022;98

Zeb S., Sagdeo A., Amarasena R. Rare case of overlap of myositis and myasthenia gravis. Clin. Med. 2022;22:47. PubMed PMC

Fang F., Sveinsson O., Thormar G., Granqvist M., Askling J., Lundberg I.E., Ye W., Hammarström L., Pirskanen R., Piehl F. The autoimmune spectrum of myasthenia gravis: a Swedish population-based study. J. Intern. Med. 2015;277:594–604. PubMed

Salvatore D., Simonides W.S., Dentice M., Zavacki A.M., Larsen P.R. Thyroid hormones and skeletal muscle--new insights and potential implications. Nat. Rev. Endocrinol. 2014;10:206–214. PubMed PMC

Cakir M., Samanci N., Balci N., Balci M.K. Musculoskeletal manifestations in patients with thyroid disease. Clin. Endocrinol. 2003;59:162–167. PubMed

Ji Y.-K., Kim S.-H. Myopathy Associated with Treatment of Graves’ Disease. Medicina. 2021;57:1016. PubMed PMC

Sindoni A., Rodolico C., Pappalardo M.A., Portaro S., Benvenga S. Hypothyroid myopathy: A peculiar clinical presentation of thyroid failure. Review of the literature. Rev. Endocr. Metab. Disord. 2016;17:499–519. PubMed

Selva-O’Callaghan A., Redondo-Benito A., Trallero-Araguás E., Martínez-Gómez X., Palou E., Vilardell-Tarres M. Clinical Significance of Thyroid Disease in Patients With Inflammatory Myopathy. Medicine (Baltim.) 2007;86:293–298. PubMed

Cooper N.J., Wallace C., Burren O., Cutler A., Walker N., Todd J.A. Type 1 diabetes genome-wide association analysis with imputation identifies five new risk regions. bioRxiv. 2017 doi: 10.1101/120022. Preprint at. DOI