A genome-wide association study of adults with community-acquired pneumonia

Introduction Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of entry. Objective To identify genetic risk loci for CAP using a one-stage genome-wide association study (GWAS). Methods We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. Genotyping and imputation allowed testing the association of 7,6 million variants using logistic regressions. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association testing of the classic HLA alleles and amino acids was also conducted. Results We revealed six independent sentinel variants that were genome-wide significant ( p <5×10−8), three located on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophyilus influenzae . Associations were all non-significant for the classic HLA alleles. Conclusions We completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by: Instituto de Salud Carlos III (PI13/01456 and PI16/00759, PI17/00610, PI19/00141, PI20/00876, FI17/00177) and Ministerio de Ciencia e Innovacion (RTC-2017-6471-1; AEI/FEDER), co-financed by the European Regional Development Funds (ERDF), A way of making Europe from the EU; ITER agreements (OA17/008 and OA23/043); Grupo DISA (OA18/017), Fundacion Canaria Instituto de Investigacion Sanitaria de Canarias (PIFIISC19/43); Fundacion Mapfre-Guanarteme (OA19/072); SEPAR (Spanish Society of Pulmonology and Thoracic Surgery); Cabildo Insular de Tenerife (CGIEU0000219140); and Gobierno de Canarias & Social European Fund Canarias Avanza con Europa (TESIS2022010042 and TESIS2021010046). EH-B was supported by a grant from Universidad de Las Palmas de Gran Canaria. The Spain Biobank array genotyping service was carried out at CEGEN-PRB3-ISCIII; which is supported by PT17/0019, of the PE I+D+i 2013-2016, funded by Instituto de Salud Carlos III, and co-financed by ERDF. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Research Ethics Committees from Hospital Universitario de Gran Canaria Dr. Negrin (protocol number FIS PI 16/00759) and from Hospital Universitario Nuestra Sra. de Candelaria (protocol number PI-19/12) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors