Inammatory and infectious upper respiratory diseases associate with 59 genomic loci that link to type 2 inammation genes Elmo Saarentaus University of Helsinki https://orcid.org/0000-0002-8475-7187 Juha Karjalainen The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA Joel Rämö Helsinki Institute of Life Science Tuomo Kiiskinen Institute for Molecular Medicine Finland https://orcid.org/0000-0002-6306-8227 Aki Havulinna Helsinki Institute of Life Science Juha Mehtonen Helsinki Institute of Life Science Heidi Hautakangas Helsinki Institute of Life Science Sanni Ruotsalainen Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki https://orcid.org/0000-0002-1631-4069 Sanna Salmi Helsinki Institute of Life Science Matti Pirinen University of Helsinki https://orcid.org/0000-0002-1664-1350 Mitja Kurki Helsinki Institute of Life Science Samuli Ripatti Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki Mark Daly Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki Tuula Palotie Helsinki Institute of Life Science Antti Mäkitie Helsinki Institute of Life Science Aarno Palotie ( aarno.palotie@mm. ) Helsinki Institute of Life Science Genetics Article Keywords: upper respiratory diseases, autoimmune disease, inammation genes Posted Date: July 12th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-654053/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License 1 Inflammatory and infectious upper respiratory diseases associate with 59 2 genomic loci that link to type 2 inflammation genes 3 Authors: Elmo C. Saarentaus1, Juha Karjalainen1,2,3, Joel T. Rämö1, Tuomo Kiiskinen1,4, Aki S. 4 Havulinna1,4, Juha Mehtonen1, Heidi Hautakangas1, Sanni Ruotsalainen1, FINNGEN, Sanna 5 Toppila-Salmi5, Matti Pirinen1,6,7, Mitja Kurki1,2,3, Samuli Ripatti1,2,3, Mark Daly1,2,3, Tuula 6 Palotie8,9, Antti Mäkitie10, Aarno Palotie1,2,11* 7 Affiliations: 8 1Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, Helsinki, 9 Finland. 10 2Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, 11 Massachusetts, USA. 12 3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 13 Massachusetts, USA. 14 4Finnish Institute for Health and Welfare, Helsinki, Finland. 15 5Skin and Allergy Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, 16 Finland 17 6Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland 18 7Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland 19 8Orthodontics, Department of Oral and Maxillofacial Diseases, Clinicum, Faculty of Medicine, 20 University of Helsinki, Helsinki, Finland; 21 9Oral and Maxillofacial Diseases, Helsinki University Hospital, Helsinki, Finland 22 10Department of Otorhinolaryngology – Head and Neck Surgery, University of Helsinki and 23 Helsinki University Hospital, Helsinki, Finland. 24 11Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology 25 and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. 26 *Corresponding author. Email: [email protected] 27 0 28 One Sentence Summary: Inflammatory upper respiratory diseases share genetic risk loci and 29 correlate genetically with each other and with diseases of the immune system 30 Abstract: 31 Inflammatory and infectious upper respiratory diseases (IURDs; ICD-10: J30-J39), such as 32 diseases of sinonasal tract, pharynx and larynx, are growing health problems yet their genomic 33 similarity is not known. We analyzed genome-wide association to eight IURDs (61,195 cases) 34 among 260,405 FinnGen participants, meta-analyzing diseases in four groups based on an 35 underlying genetic correlation structure. We aimed to understand which genetic loci contribute to 36 susceptibility to IURDs in general and its subtypes. We detected 59 independent genome-wide 37 significant (GWS) loci, distinguishing impact on sinonasal or pharyngeal diseases, or both. Fine- 38 mapping implicated non-synonymous variants in 16 genes, including 10 linked to immune- 39 related diseases. Phenome-wide analysis implicated asthma and atopic dermatitis at sinonasal 40 disease loci and inflammatory bowel diseases, and other immune-mediated disorders at 41 pharyngeal disease loci. IURDs also genetically correlated with autoimmune diseases such as 42 rheumatoid arthritis, autoimmune hypothyroidism, and psoriasis. Finally, we associated separate 43 gene pathways in sinonasal and pharyngeal diseases that both contribute to type 2 immunological 44 reaction. We show shared heritability among IURDs that extends to several immune-mediated 45 diseases with diverse mechanisms, such as type 2 high inflammation. 1 46 Main Text: 47 INTRODUCTION 48 Inflammatory and infectious upper respiratory diseases (IURD) affect the sinonasal tract, 49 pharynx, and larynx, and include diseases such as chronic tonsillitis, allergic rhinitis, and chronic 50 rhinosinusitis. They lead to increased morbidity1,2 and costs3, and to the highest public health 51 burden in the world4 by serving as the main route of infection to the body, and by their 52 connection to non-communicable diseases, such as asthma5-7, autoimmune diseases8,9, 53 cardiovascular diseases10 and obesity11. Genetic predisposition12-15 together with environmental 54 megatrends such as the COVID-19 pandemic16-18, Western lifestyle19, urbanization20,21, global 55 warming22 and dysbiosis23,24 influence the burden of IURDs. IURDs often co-exist25-28, and they 56 have shown overlapping mechanisms5,6,29,30. Understanding the genetic (dis)similarities behind 57 IURDs can remarkably improve preventive actions and therapies, and reduce the burden of 58 IURDs and related diseases2,31. 59 IURDs are characterized by an etiology related to recurrent infections and dysbiosis20,21,24 60 leading to chronic and treatment-resistant diseases32 with acute and even life-threatening 61 exacerbations. IURDs involve inflammation in the nasal cavity, such as vasomotor and allergic 62 rhinitis (VAR), both characterized by hyperresponsiveness to stimuli33; non-specific chronic 63 rhinitis, nasopharyngitis and pharyngitis (CRNP) and nasal septal deviation (NSD); and in the 64 adjoining paranasal sinuses, such as chronic rhinosinusitis (CRS) with or without nasal polyps 65 (NP)6. Allergic rhinitis (AR) is a part of an allergic disease entity involving allergic asthma, 66 atopic dermatitis, allergic conjunctivitis and food allergy27,34,35. IURDs also encompass other 2 67 diseases of the pharynx such as chronic laryngitis and laryngotracheitis (CLT), chronic diseases 68 of tonsils and adenoids (CDTA), and peritonsillar abscess (PA). Previous genetic studies of 69 IURDs and related immune responses have largely focused on rare variants36 and the HLA 70 region37,38. IURD-related GWAS have been reported of CRS and NP39, tonsillectomy and 71 childhood ear infections40,41, cold sores, mononucleosis, strep throat, pneumonia and 72 myringotomy40, hay fever39-42, and of infective diseases caused by specific airway-related 73 microbes such as pneumococcus43 and staphylococcus aureus44. However, no prior research has 74 analyzed shared genetic contributions of IURDs. 75 The FinnGen study is a large biobank study including both genetic and lifelong health record 76 data from all participants, thus allowing the investigation of potentially shared and distinct 77 genetic landscape associated to IURDs. This provides an opportunity both for GWASs as well as 78 for cross-disease analyses to better understand potential shared genetic contributors. We aimed to 79 study genetic predispositions to recurrent, chronic and complicated IURDs. We hypothesized 80 that, on one hand, shared genetic variants contribute to IURD susceptibility in general, and some 81 variants contribute more to distinct IURD phenotypes. To test this hypothesis, we analyzed 82 genome-wide association of IURD cases in the FinnGen study (release 6/Aug 2020), a nation- 83 wide collection of genotyped samples from Finnish individuals. Our study sample included 84 260,405 individuals of all ages, where we focused on cases of specialist-diagnosed IURDs (n = 85 61,197), including their more specific diagnosis. We tested the genetic associations across 86 IURDs to highlight shared and distinct genetic contributions among IURDs. Finally, we 87 compared the genome-wide association of IURDs and phenotypes to other anatomically related 3 88 and systemic immunological disorders (such as chronic periodontitis) linked with the same 89 genetic loci. 4 90 RESULTS 91 Genome-wide association of inflammatory and infectious upper respiratory diseases 92 We performed genome-wide association of all IURD cases (n = 61,197, ranging from 2,623 to 93 29,135 per phenotype) in FinnGen. We genotyped and imputed 16,355,289 single-nucleotide 94 genetic variants in 260,405 Finnish individuals of all ages. We used a logistic mixed model with 95 the SAIGE software45 (see Methods) to detect genome-wide association between 61,197 cases of 96 IURDs (Table 1, Supplementary Figure 1) and 199,208 controls, and set as covariates age, 97 genetic sex, principal components (PCs) 1–10, and genotyping batch. This resulted in 698 98 genome-wide significant (GWS, p<5e-8) SNPs in 20 loci (Table 2). Fine-mapping using the 99 SuSiE software46 on the 19 non-HLA loci identified 21 independent credible