Novel genes and sex differences in COVID-19 severity

Sex differences; COVID-19Diferències de sexe; COVID-19Diferencias de sexo; COVID-19Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.Instituto de Salud Carlos III (COV20_00622 to A.C., COV20/00792 to M.B., COV20_00181 to C.A., COV20_1144 to M.A.J.S., PI20/00876 to C.F.); European Union (ERDF) ‘A way of making Europe’. Fundación Amancio Ortega, Banco de Santander (to A.C.), Estrella de Levante S.A. and Colabora Mujer Association (to E.G.-N.) and Obra Social La Caixa (to R.B.); Agencia Estatal de Investigación (RTC-2017-6471-1 to C.F.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.)

Chronic hepatitis D associated with worse patient-reported outcomes than chronic hepatitis B

Hepatitis vírica; Qualitat de vida relacionada amb la salut; Malaltia hepàtica crònicaHepatitis viral; Calidad de vida relacionada con la salud; Enfermedad crónica del hígadoViral hepatitis; Health-related quality of life; Chronic Liver DiseaseBackground & Aims Health-related quality of life (HRQoL) determined by patient-reported outcomes (PROs) is impaired in chronic hepatitis B (CHB) and C patients, but there are no data regarding patients with chronic hepatitis D (CHD). The aim of this study was to assess PRO scores in untreated patients with CHD and compare them with those obtained for patients with CHB. Methods Patients with CHD completed 3 PRO instruments (Chronic Liver Disease Questionnaire [CLDQ], Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-F], and Work Productivity and Activity Impairment [WPAI]), and the results were compared with those of patients mono-infected with CHB. Results In total, 125 patients were included: 43 with CHD and 82 with CHB. Overall, baseline PROs showed differences between both groups. Several assessments, such as the worry score from CLDQ (p = 0.0118), functional well-being from FACIT-F (p = 0.0281), and activity impairment from WPAI (p = 0.0029) showed a significant trend to worse scores in patients with CHD than with CHB. In addition, the linear regression model supports the finding that having CHD as opposed to having CHB was a predictor of a higher worry score (CLDQ) and a higher activity impairment (WPAI). Conclusions In this first assessment in CHD, PROs recorded in patients with CHD showed a significant impairment in some domains of HRQoL questionnaires in comparison with those with CHB. Studies in larger cohorts with lengthier follow-up are needed to fully assess patient-reported quality of life over the course of CHD. Lay summary Chronic hepatitis D (CHD) is a viral disease that causes rapid evolution to liver cirrhosis, amongst other severe complications, when compared to patients with chronic hepatitis B (CHB). Health-related quality of life in chronic hepatitis C and CHB has been reported widely, but no studies have been performed on patient-reported outcomes in patients with CHD. Results showed that CHD patients reported worse outcomes in psychological domains such as worry and emotional well-being, as well as in physical domains such as abdominal symptoms, physical well-being, and activity impairment in comparison with patients with CHB

Community Strategy for Hepatitis B, C, and D Screening and Linkage to Care in Mongolians Living in Spain

Mongolian community; Community program; Viral hepatitis screeningComunidad mongola; Programa comunitario; Cribado de hepatitis viralComunitat mongol; Programa comunitari; Cribatge de hepatitis viralMongolia has one of the highest viral hepatitis infection (B, C, and D) rates in the world. The aims of this study were to increase awareness of this disease and promote viral hepatitis screening in the Mongolian community living in Spain. Through a native community worker, Mongolian adults were invited to a community program consisting of an educational activity, an epidemiological questionnaire, and rapid point-of-care testing for hepatitis B and C. In those testing positive, blood extraction was performed to determine serological and virological parameters. In total, 280 Mongolians were invited to the program and 222 (79%) attended the event: 139 were women (63%), mean age was 42 years, and 78 (35%) had viral hepatitis risk factors. Testing found 13 (5.8%) anti-HCV-positive individuals, 1 with detectable HCV RNA (0.5%), 8 HBsAg-positive (3.6%), and 7 with detectable HBV DNA (3.1%). One additional individual had HBV/HCV co-infection with detectable HBV DNA and HCV RNA. Two subjects had hepatitis B/D co-infection (0.9%). The knowledge questionnaire showed a 1.64/8-point (20.5%) increase in correct answers after the educational activity. In summary, a viral hepatitis community program was feasible and widely accepted. It increased awareness of this condition in the Mongolian community in Spain and led to linkage to care in 22 participants, 50% of whom were unaware of their infection.This project was funded by GILEAD SCIENCES (GLD21/00139)

Cost-effectiveness analysis of an active search to retrieve HCV patients lost to follow-up (RELINK-C strategy) and the impact of COVID-19

Acord transformatiu CRUE-CSICAltres ajuts: Gilead Science

LINK-B: study protocol of a retrospective and prospective project for identification and linkage to care of people living with hepatitis B in a large health area of Barcelona

Hepatology; Telemedicine; VirologiaHepatologia; Telemedicina; VirologiaHepatología; Telemedicina; VirologíaIntroduction An estimated 290 million people are living with hepatitis B virus (HBV) worldwide; in Spain, the prevalence of hepatitis B virus surface antigen (HBsAg) is 0.4%. In our setting, many HBsAg-positive individuals are not linked to care, which implies a barrier to receiving treatment and controlling the infection. The main objective of this project is to evaluate the performance of a programme designed to achieve appropriate linkage to specialist care of HBsAg-positive individuals, newly tested or previously tested and lost to follow-up. Methods and analysis This is a retrospective and prospective study in which all HBsAg-positive cases recorded in the microbiology database will be identified. The retrospective phase will include cases detected between 2018 and 2020, and the prospective phase will run from January 2021 to June 2022. The project will be carried out in a tertiary university hospital covering the northern health area of Barcelona with a catchment population of 450 000 inhabitants and 16 affiliated primary care centres. The central laboratory detects approximately 1200 HBsAg-positive individuals every year; therefore, we expect to identify around 4000 patients over the duration of the project. The medical records of HBsAg-positive individuals will be consulted to identify and retrieve those who have not been appropriately linked to care. Candidates will be contacted to offer specialist disease assessment and follow-up. A website will be created to provide HBV-related information to primary care physicians, and a mobile phone application will be available to patients to improve the linkage circuits and ensure follow-up continuity. Ethics and dissemination The Vall d’Hebrón Hospital Ethics Committee (PR(AG)201/2021) and the Spanish Agency of Medicines and Medical Devices approved this study. The findings will be disseminated through peer-reviewed publications and conference presentations. This programme could increase the number of HBsAg-positive individuals properly linked to care and achieve better HBV monitoring, which will have a positive impact on WHO’s viral hepatitis elimination goals.This project is supported by Gilead Sciences through the competitive research 'HBV Treat' (protocol number IN-ES-320-6107)

Implementation of anti-HDV reflex testing among HBsAg-positive individuals increases testing for hepatitis D

Chronic hepatitis D; Anti-HDV screening; HDV diagnosisHepatitis crònica D; Cribatge anti-HDV; Diagnòstic de HDVHepatitis crónica D; Cribado anti-HDV; Diagnóstico de HDVBackground & Aims Although EASL guidelines recommend anti-HDV testing in all HBsAg-positive individuals, HDV infection remains an underdiagnosed condition. We describe the impact of an HDV screening program by reflex anti-HDV testing in all HBsAg-positive samples and compare the results before and after its implementation. Methods In total, 2,236 HBsAg-positive determinations were included from January 2018 to December 2021. Only the first sample from each participant was evaluated: 1,492 samples before reflex anti-HDV testing (2018–2020) and 744 samples after (2021). Demographic and clinical characteristics of anti-HDV-positive patients were collected. Results Before reflex testing, anti-HDV had been tested in 7.6% (114/1492) of HBsAg-positive individuals: 23% (91/390) attended in an academic hospital and only 2% (23/1,102) in primary care centres. After reflex testing was established, 93% (691/744) of HBsAg-positive cases were evaluated for anti-HDV: 91% (533/586) in the academic hospital and 100% (158/158) in primary care. The anti-HDV-positive prevalence was similar before and after reflex testing: 9.6% (11/114) and 8.1% (56/691), respectively. However, the absolute number of anti-HDV-positive patients increased. Most anti-HDV-positive patients were young, HBeAg-negative, Caucasian males. HDV-RNA was detectable in 35 (65%) of 54 tested, HBV-DNA was undetectable in 64%, and alanine aminotransferase levels were normal in 48%. Conclusions Anti-HDV reflex testing quintupled the absolute number of diagnoses of chronic hepatitis D infection. Before the reflex test, a large percentage of HBsAg-positive individuals had not undergone any anti-HDV determination. Implementation of reflex testing increases the diagnosis of patients with chronic hepatitis D.This study received support in part from the Instituto de Salud Carlos III (PI20/01692)

ACE Score Identifies HBeAg-negative Inactive Carriers at a Single-point Evaluation, Regardless of HBV Genotype

HBV DNA; Hepatitis B virus; Inactive carrierADN del VHB; Virus de la hepatitis B; Portador inactivoADN del VHB; Virus de l'hepatitis B; Portador inactiuBackground and Aims Hepatitis B virus (HBV) biomarkers have been used for a better categorization of patients, even though the lack of simple algorithms and the impact of genotypes limit their application. Our aim was to assess the usefulness of noninvasive markers for the identification of HBV inactive carriers (ICs) in a single-point evaluation and to design a predictive model for their identification. Methods This retrospective-prospective study included 343 consecutive HBeAg-negative individuals. Clinical, analytical, and virological data were collected, and a liver biopsy was performed if needed. Subjects were classified at the end of follow-up as ICs, chronic hepatitis B and gray zone.A predictive model was constructed, and validated by 1000-bootstrap samples. Results After 39 months of follow-up, 298 subjects were ICs, 36 were chronic hepatitis B CHB, and nine were gray zone. Eighty-nine (25.9%) individuals required a liver biopsy. Baseline HBV DNA hazard ratio (HR) 6.0, p<0.001), HBV core-related antigen (HBcrAg) (HR 6.5, p<0.001), and elastography (HR 4.6, p<0.001) were independently associated with the IC stage. The ACE score (HBV DNA, HBcrAg, elastography), obtained by bootstrapping, yielded an area under the receiver operating characteristics (AUROC) of 0.925 (95% CI: 0.880–0.970, p<0.001) for identification of ICs. The AUROC for genotype D was 0.95, 0.96 for A, 0.90 for E, and 0.88 for H/F. An ACE score of <1 had a positive predictive value of 99.5%, and a score ≤12 points had a diagnostic accuracy of 93.8%. Conclusions Low baseline HBV DNA, HBcrAg, and liver stiffness were independently associated with the IC phase. A score including those variables identified ICs at a single-point evaluation, and might be applied to implement less intensive follow-up strategies.This study received partial financial support from Instituto de Salud Carlos III (PI17/02233 and PI20/01692)

Inspecting the Ribozyme Region of Hepatitis Delta Virus Genotype 1: Conservation and Variability

Gene silencing; Quasispecies; RibozymeSilenciament gènic; Quasiespècie; RibozimaSilenciamiento de genes; Cuasiespecies; RibozimaThe hepatitis delta virus (HDV) genome has an autocatalytic region called the ribozyme, which is essential for viral replication. The aim of this study was to use next-generation sequencing (NGS) to analyze the ribozyme quasispecies (QS) in order to study its evolution and identify highly conserved regions potentially suitable for a gene-silencing strategy. HDV RNA was extracted from 2 longitudinal samples of chronic HDV patients and the ribozyme (nucleotide, nt 688–771) was analyzed using NGS. QS conservation, variability and genetic distance were analyzed. Mutations were identified by aligning sequences with their specific genotype consensus. The main relevant mutations were tested in vitro. The ribozyme was conserved overall, with a hyper-conserved region between nt 715–745. No difference in QS was observed over time. The most variable region was between nt 739–769. Thirteen mutations were observed, with three showing a higher frequency: T23C, T69C and C64 deletion. This last strongly reduced HDV replication by more than 1 log in vitro. HDV Ribozyme QS was generally highly conserved and was maintained during follow-up. The most conserved portion may be a valuable target for a gene-silencing strategy. The presence of the C64 deletion may strongly impair viral replication, as it is a potential mechanism of viral persistence.This research was funded by Institute of Health Carlos III, grant number PI20/01692 and co-financed by the European Regional Development Fund (ERDF), and by the European Regional Development Fund (ERDF)- Ministry of Economy, Industry and Competitiveness, grantRTI2018-101936-B-I00

Detailed stratified GWAS analysis for severe COVID-19 in four European populations

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ∼0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.publishedVersio

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

AG has received support by NordForsk Nordic Trial Alliance (NTA) grant, by Academy of Finland Fellow grant N. 323116 and the Academy of Finland for PREDICT consortium N. 340541. The Richards research group is supported by the Canadian Institutes of Health Research (CIHR) (365825 and 409511), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation (CFI), the NIH Foundation, Cancer Research UK, Genome Québec, the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS). TN is supported by a research fellowship of the Japan Society for the Promotion of Science for Young Scientists. GBL is supported by a CIHR scholarship and a joint FRQS and Québec Ministry of Health and Social Services scholarship. JBR is supported by an FRQS Clinical Research Scholarship. Support from Calcul Québec and Compute Canada is acknowledged. TwinsUK is funded by the Welcome Trust, the Medical Research Council, the European Union, the National Institute for Health Research-funded BioResource and the Clinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London. The Biobanque Québec COVID19 is funded by FRQS, Genome Québec and the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé. These funding agencies had no role in the design, implementation or interpretation of this study. The COVID19-Host(a)ge study received infrastructure support from the DFG Cluster of Excellence 2167 “Precision Medicine in Chronic Inflammation (PMI)” (DFG Grant: “EXC2167”). The COVID19-Host(a)ge study was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). Genotyping in COVID19-Host(a)ge was supported by a philantropic donation from Stein Erik Hagen. The COVID GWAs, Premed COVID-19 study (COVID19-Host(a)ge_3) was supported by "Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"and also by the Instituto de Salud Carlos III (CIBERehd and CIBERER). Funding comes from COVID-19-GWAS, COVID-PREMED initiatives. Both of them are supported by "Consejeria de Salud y Familias" of the Andalusian Government. DMM is currently funded by the the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018). The Columbia University Biobank was supported by Columbia University and the National Center for Advancing Translational Sciences, NIH, through Grant Number UL1TR001873. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Columbia University. The SPGRX study was supported by the Consejería de Economía, Conocimiento, Empresas y Universidad #CV20-10150. The GEN-COVID study was funded by: the MIUR grant “Dipartimenti di Eccellenza 2018-2020” to the Department of Medical Biotechnologies University of Siena, Italy; the “Intesa San Paolo 2020 charity fund” dedicated to the project NB/2020/0119; and philanthropic donations to the Department of Medical Biotechnologies, University of Siena for the COVID-19 host genetics research project (D.L n.18 of March 17, 2020). Part of this research project is also funded by Tuscany Region “Bando Ricerca COVID-19 Toscana” grant to the Azienda Ospedaliero Universitaria Senese (CUP I49C20000280002). Authors are grateful to: the CINECA consortium for providing computational resources; the Network for Italian Genomes (NIG) (http://www.nig.cineca.it) for its support; the COVID-19 Host Genetics Initiative (https://www.covid19hg.org/); the Genetic Biobank of Siena, member of BBMRI-IT, Telethon Network of Genetic Biobanks (project no. GTB18001), EuroBioBank, and RD-Connect, for managing specimens. Genetics against coronavirus (GENIUS), Humanitas University (COVID19-Host(a)ge_4) was supported by Ricerca Corrente (Italian Ministry of Health), intramural funding (Fondazione Humanitas per la Ricerca). The generous contribution of Banca Intesa San Paolo and of the Dolce&Gabbana Fashion Firm is gratefully acknowledged. Data acquisition and sample processing was supported by COVID-19 Biobank, Fondazione IRCCS Cà Granda Milano; LV group was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, the European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- “Liver Investigation: Testing Marker Utility in Steatohepatitis”, Programme “Photonics” under grant agreement “101016726” for the project “REVEAL: Neuronal microscopy for cell behavioural examination and manipulation”, Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361. DP was supported by Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV). Genetic modifiers for COVID-19 related illness (BeLCovid_1) was supported by the "Fonds Erasme". The Host genetics and immune response in SARS-Cov-2 infection (BelCovid_2) study was supported by grants from Fondation Léon Fredericq and from Fonds de la Recherche Scientifique (FNRS). The INMUNGEN-CoV2 study was funded by the Consejo Superior de Investigaciones Científicas. KUL is supported by the German Research Foundation (LU 1944/3-1) SweCovid is funded by the SciLifeLab/KAW national COVID-19 research program project grant to Michael Hultström (KAW 2020.0182) and the Swedish Research Council to Robert Frithiof (2014-02569 and 2014-07606). HZ is supported by Jeansson Stiftelser, Magnus Bergvalls Stiftelse. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping for the COMRI cohort was performed and funded by the Genotyping Laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki, Helsinki, Finland. These funding agencies had no role in the design, implementation or interpretation of this study.Background: There is considerable variability in COVID-19 outcomes amongst younger adults—and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. Findings: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2–1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3–1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality—and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management.Academy of Finland Fellow grant N. 323116Academy of Finland for PREDICT consortium N. 340541.Canadian Institutes of Health Research (CIHR) (365825 and 409511)Lady Davis Institute of the Jewish General HospitalCanadian Foundation for Innovation (CFI)NIH FoundationCancer Research UKGenome QuébecPublic Health Agency of CanadaMcGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS)Japan Society for the Promotion of Science for Young ScientistsCIHR scholarship and a joint FRQS and Québec Ministry of Health and Social Services scholarshipFRQS Clinical Research ScholarshipCalcul QuébecCompute CanadaWelcome TrustMedical Research CouncEuropean UnionNational Institute for Health Research-funded BioResourceClinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation TrustKing’s College LondonGenome QuébecPublic Health Agency of CanadaMcGill Interdisciplinary Initiative in Infection and ImmunityFonds de Recherche Québec Santé(DFG Grant: “EXC2167”)(CompLS grant 031L0165)Stein Erik Hagen"Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"Instituto de Salud Carlos III (CIBERehd and CIBERER)COVID-19-GWASCOVID-PREMED initiatives"Consejeria de Salud y Familias" of the Andalusian GovernmentAndalusian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018)Columbia UniversityNational Center for Advancing Translational SciencesNIH Grant Number UL1TR001873Consejería de Economía, Conocimiento, Empresas y Universidad #CV20-10150MIUR grant “Dipartimenti di Eccellenza 2018-2020”“Intesa San Paolo 2020 charity fund” dedicated to the project NB/2020/0119Tuscany Region “Bando Ricerca COVID-19 Toscana”CINECA consortiumNetwork for Italian Genomes (NIG)COVID-19 Host Genetics InitiativeGenetic Biobank of SienaEuroBioBankRD-ConnectRicerca Corrente (Italian Ministry of Health)Fondazione Humanitas per la RicercaBanca Intesa San PaoloDolce&Gabbana Fashion FirmCOVID-19 BiobankFondazione IRCCS Cà Granda MilanoMyFirst Grant AIRC n.16888Ricerca Finalizzata Ministero della Salute RF-2016-02364358Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoEuropean Union (EU) Programme Horizon 2020 (under grant agreement No. 777377)“Photonics” “101016726”Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV)"Fonds Erasme"Fondation Léon FredericqFonds de la Recherche Scientifique (FNRS)Consejo Superior de Investigaciones CientíficasGerman Research Foundation (LU 1944/3-1)SciLifeLab/KAW national COVID-19 research program project (KAW 2020.0182)Swedish Research Council (2014-02569 and 2014-07606)Jeansson Stiftelser, Magnus Bergvalls StiftelseTechnical University of Munich, Munich, GermanyGenotyping Laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki, Helsinki, Finlan