Inflammatory and infectious upper respiratory diseases associate with 41 genomic loci and type 2 inflammation

Abstract

Inflammatory and infectious upper respiratory diseases (ICD-10: J30-J39), such as diseases of the sinonasal tract, pharynx and larynx, are growing health problems yet their genomic similarity is not known. We analyze genome-wide association to eight upper respiratory diseases (61,195 cases) among 260,405 FinnGen participants, meta-analyzing diseases in four groups based on an underlying genetic correlation structure. Aiming to understand which genetic loci contribute to susceptibility to upper respiratory diseases in general and its subtypes, we detect 41 independent genome-wide significant loci, distinguishing impact on sinonasal or pharyngeal diseases, or both. Fine-mapping implicated non-synonymous variants in nine genes, including three linked to immune-related diseases. Phenome-wide analysis implicated asthma and atopic dermatitis at sinonasal disease loci, and inflammatory bowel diseases and other immune-mediated disorders at pharyngeal disease loci. Upper respiratory diseases also genetically correlated with autoimmune diseases such as rheumatoid arthritis, autoimmune hypothyroidism, and psoriasis. Finally, we associated separate gene pathways in sinonasal and pharyngeal diseases that both contribute to type 2 immunological reaction. We show shared heritability among upper respiratory diseases that extends to several immune-mediated diseases with diverse mechanisms, such as type 2 high inflammation.

Genome-Wide Association Study Reveals Novel Associations of Annexin A13 to Secretory and GAS2L2 with Mucous Otitis Media

“…According to Clinvar [15,16] and Ensembl [43], the missense variant rs72553883 is mostly likely pathogenic. Other variants in TNFRSF13B (rs11649804, rs34557412) have previously been linked to tonsillectomy (rs34557412) and childhood ear infection [13,17,47]. In line with these ndings, we saw co-associations with sinusitis and chronic diseases of the tonsils and adenoids in the FinnGen study [17].…”

“…Other variants in TNFRSF13B (rs11649804, rs34557412) have previously been linked to tonsillectomy (rs34557412) and childhood ear infection [13,17,47]. In line with these ndings, we saw co-associations with sinusitis and chronic diseases of the tonsils and adenoids in the FinnGen study [17]. Functional characterization of the rs72553883 variant in mice and human B-cells reveal disrupted NF-KB signaling and signi cantly impaired B-cell function [29,30].…”

“…In the GWAS of mucous otitis media, we revealed three associated loci of genome-wide signi cance (p<1.7x10 -8 ), (Table 1, Figure 1, Supplementary Figure 3(b-d). ) The chromosome 17 locus harbored the same two missense variants that have already been reported above (Table 1) [13,14,17]. The chromosome 22 locus, near TBX1, included the same leading variant rs1978060-A/G (OR=1.15) that appears in the GWAS for the combined secretory and mucous otitis media phenotype (Figure 2, Forest plots).…”

“…The second locus in chromosome 17 included a missense lead variant rs3744374 (A (Ala) > (Gly)) in the GAS2L2 gene. Based on a recent study, rs3744374 is protective for chronic rhinosinusitis [17]. According to the Ensembl database and the variant effect predictors Polyphen and SIFT [35,43], both rs72553883 (CADD=8.96) and rs3744374 (CADD=22) are predicted to benign and well tolerated [45,46].…”

“…GAS2L2 regulates ciliary orientation and performance in cells found in the airway [30]. The variant rs3744374 has been recently linked with chronic rhinosinusitis and other sinonasal and pharyngeal diseases [17], although based on previous studies it is predicted to be benign [35,36]. There is a mouse model (C57BL/6N-Gas2l2tm1a(KOMP)Wtsi/Wtsi)with abnormal auditory tube and middle ear [24].…”