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

Degenhardt, Frauke; Ellinghaus, David; Juzėnas, Simonas; Lerga-Jaso, Jon; Wendorff, Mareike; Maya‐Miles, Douglas; Uellendahl-Werth, Florian; ElAbd, Hesham; Rühlemann, Malte; Arora, Jatin; Özer, Onur; Lenning, Ole Bernt; Myhre, Ronny; Vadla, May Sissel; Wacker, Eike Matthias; Wienbrandt, Lars; Ortíz, Aaron Blandino; Salazar, Adolfo de; Chercoles, Adolfo Garrido; Palom, Adriana; Ruiz, Agustín; Garcia-Fernandez, Alba-Estela; Blanco‐Grau, Albert; Mantovani, Alberto; Zanella, Alberto; Holten, Aleksander Rygh; Mayer, Alena; Bandera, Alessandra; Cherubini, Alessandro; Protti, Alessandro; Aghemo, Alessio; Gerussi, Alessio; Ramı́rez, Alfredo; Braun, Alice; Nebel, Almut; Barreira, Ana; Lleò, Ana; Teles, Ana; Kildal, Anders Benjamin; Biondi, Andrea; Caballero-Garralda, Andrea; Ganna, Andrea; Gori, Andrea; Glück, Andreas; Lind, Andreas; Tanck, Anja; Hinney, Anke; Carreras, Anna; Fracanzani, Anna Ludovica; Peschuck, Anna; Cavallero, Annalisa; Dyrhol‐Riise, Anne Ma; Ruello, Antonella; Juliá, Antonio; Muscatello, Antonio; Artigas, Antonio; Voza, Antonio; Rando‐Segura, Ariadna; Solier, Aurora; Schmidt, Axel; Cortés, Beatriz; Mateos, Beatriz; Nafría-Jiménez, Beatriz; Schaefer, Benedikt; Jensen, Björn; Bellinghausen, Carla; Maj, Carlo; Ferrando, Carlos; Horra, Carmen de la; Quereda, Carmen; Skurk, Carsten; Thibeault, Charlotte; Scollo, Chiara; Herr, Christian; Spinner, Christoph D.; Gassner, Christoph; Lange, Christoph; Hu, Cinzia; Paccapelo, Cinzia; Lehmann, Clara; Angelini, Claudio; Cappadona, Claudio; Azuure, Clinton; Bianco, Cristiana; Cea, Cristina; Sancho, Cristina; Hoff, Dag Arne Lihaug; Galimberti, Daniela; Prati, Daniele; Haschka, David; Jiménez, David; Pestaña, David; Toapanta, David; Muñiz‐Díaz, Eduardo; Azzolini, Elena; Sandoval, Elena; Binatti, Eleonora; Scarpini, Elio; Helbig, Elisa T; Casalone, Elisabetta; Urrechaga, Eloísa; Paraboschi, Elvezia Maria; Pontali, Emanuele; Reverter, Enric; Calderón, E.; Navas, Enrique; Solligård, Erik; Contro, Ernesto; Arana‐Arri, Eunate; Aziz, Fátima; García, Federico; Sanchez, Felix; Ceriotti, Ferruccio; Boneschi, Filippo Martinelli; Peyvandi, Flora; Kurth, Florian; Blasi, Francesco; Malvestiti, Francesco; Medrano, F.J.; Mesonero, Francisco; Rodríguez‐Frías, Francisco; Hanses, Frank; Müller, Fredrik; Hemmrich-Stanisak, Georg; Bellani, Giacomo; Pezzoli, G.; Costantino, Giorgio; Albano, Giovanni; Cardamone, Giulia; Bellelli, Giuseppe; Foti, Giuseppe; Lamorte, Giuseppe; Matullo, Giuseppe; Baselli, Guido; Kurihara, Hayato; Neb, Holger; My, Ilaria; Kurth, Ingo; Hernández, Isabel; Pink, Isabell; Rojas, Itziar de; Galván-Femenía, Iván; Holter, Jan Cato; Afset, Jan Egil; Heyckendorf, Jan; Kässens, Jan Christian; Damås, Jan Kristian; Rybniker, Jan; Altmüller, Janine; Ampuero, Javier; Martı́n, Javier; Erdmann, J.; Bañales, Jesús M.; Badia, Joan R.; Dopazo, Joaquı́n; Schneider, J; Bergan, Jonas; Barretina, Jordi; Walter, Jörn; Quero, José Hernández; Goikoetxea, Josune; Delgado, Juan Vicente; Guerrero, Juan M.; Fazaal, Julia; Kraft, Julia; Schröder, Julia; Risnes, Kari; Banasik, Karina; Müller, Karl Erik; Gaede, Karoline I.; García-Etxebarria, Koldo; Tonby, Kristian; Heggelund, Lars; Izquierdo-Sánchez, Laura; Bettini, Laura Rachele; Sumoy, Lauro; Sander, Leif Erik; Lippert, Lena J; Terranova, Leonardo; Nkambule, Lindokuhle; Knopp, Lisa; Gustad, Lise Tuset; Garbarino, Lucia; Santoro, Luigi; Téllez, Luís; Roade, Luisa; Ostadreza, Mahnoosh; Intxausti, Maider; Kogevinas, Manolis; Riveiro‐Barciela, Mar; Berger, Marc Moritz; Schaefer, Marco; Niemi, Mari; Gutiérrez-Stampa, María A.; Carrabba, Maria; Basso, Maria Eloina Figuera; Valsecchi, Maria Grazia; Hernández-Tejero, María; Vehreschild, Maria J. G. T.; Manunta, Maria; Acosta‐Herrera, Marialbert; D’Angiò, Mariella; Baldini, Marina; Cazzaniga, Marina Elena; Grimsrud, Marit M.; Cornberg, Markus; Nöthen, Markus M.; Marquié, Marta; Castoldi, Massimo; Cordioli, Mattia; Cecconi, Maurizio; D’Amato, Mauro; Augustin, Max; Tomasi, Melissa; Boada, Merçé; Dreher, Michael; Seilmaier, Michael; Joannidis, Michael; Wittig, Michael; Mazzocco, Michela; Ciccarelli, Michele; Rodríguez-Gandía, Miguel Ángel; Bocciolone, Monica; Miozzo, Monica; Ayo, Natale Imaz; Blay, Natàlia; Chueca, Natalia; Montano, Nicola; Braun, Nicole; Ludwig, Nicole; Marx, Nikolaus; Martínez, N. M. de Oca; Cornely, Oliver A.; Witzke, Oliver; Palmieri, Orazio; Faverio, Paola; Preatoni, Paoletta; Bonfanti, Paolo; Omodei, Paolo; Tentorio, Paolo; Castro, Pedro; Rodrigues, Pedro M.; España, Pedro Pablo; Hoffmann, Per; Rosenstiel, Philip; Schommers, Philipp; Suwalski, Phillip; Pablo, Raúl de; Ferrer, Ricard; Bals, Robert; Gualtierotti, Roberta; Gallego‐Durán, Rocío; Nieto, Rosa; Carpani, Rossana; Morilla, Rubén; Badalamenti, Salvatore; Haider, Sammra; Ciesek, Sandra; May, Sandra; Bombace, Sara; Marsal, Sara; Pigazzini, Sara; Klein, Sebastian; Pelusi, Serena; Wilfling, Sibylle; Bòsari, Silvano; Volland, Sonja; Brunak, Søren; Raychaudhuri, Soumya; Schreiber, Stefan; Heilmann‐Heimbach, Stefanie; Aliberti, Stefano; Ripke, Stephan; Dudman, Susanne; Wesse, Tanja; Zheng, Tenghao; Bahmer, Thomas; Eggermann, Thomas; Illig, Thomas; Brenner, Thorsten; Pumarola, Tomás; Feldt, Torsten; Folseraas, Trine; Cejudo, T. González; Landmesser, Ulf; Protzer, Ulrike; Hehr, Ute; Rimoldi, Valeria; Monzani, Valter; Skogen, Vegard; Keitel, Verena; Kopfnagel, Verena; Friaza, Vicente; Andrade, Víctor; Moreno, Vı́ctor; Albrecht, Wolfgang; Peter, Wolfgang; Poller, Wolfgang; Farré, Xavier; Yi, Xiaoli; Wang, Xiaomin; Khodamoradi, Yascha; Karadeniz, Zehra; Latiano, Anna; Goerg, Siegfried; Bächer, Petra; Köehler, Philipp; Tran, Florian; Zoller, Heinz; Schulte, Eva C.; Heidecker, Bettina; Ludwig, Kerstin U.; Fernández, Javier; Romero–Gómez, Manuel; Albillos, Agustı́n; Invernizzi, Pietro; Buti, María; Duga, Stefano; Bujanda, Luís; Hov, Johannes R.; Lenz, Tobias; Asselta, Rosanna; Cid, Rafael de; Valenti, Luca; Karlsen, Tom H.; Cáceres, Mario; Franke, André

doi:10.1093/hmg/ddac158

Cited by 67 publications

(34 citation statements)

References 73 publications

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“…Male individuals are also at higher risk than female individuals. As for the main GWAS hits [ 58 , 59 ], we performed an analysis stratified for age and sex for the 15 type I IFN-related loci. The analysis stratified for sex revealed a much stronger association signal in male than in female individuals, as expected given the X-linked recessive mode of inheritance of TLR7 deficiency (Additional file 2 : Table S10).…”

Section: Resultsmentioning

confidence: 99%

“…In the analysis stratified for age, we assigned the cases to two age groups (under 60 years of age vs. 60 years and over), which we compared with all controls. We used an age cut-off of 60 years, which was close to the median age of the cases, in accordance with the analyses performed in [ 7 , 59 ]. The age stratified analysis revealed a strong impact of age, the genetic effect being restricted to younger cases (OR = 4.65 [2.4–9.0], P = 2.2 × 10 −9 , Additional file 2 : Table S10).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Matuozzo

Talouarn²,

Marchal³

et al. 2023

Genome Med

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Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Matuozzo

Talouarn²,

Marchal³

et al. 2023

Genome Med

View full text Add to dashboard Cite

show abstract

“…The male gender is a risk factor in critical COVID-19 and a link between genetic variants of the Y chromosome and severe COVID-19 has been reported [ 46 , 47 ]. However, a recent larger investigation, in which haplogroups on the Y chromosome were defined based on the analysis of SNP arrays, showed no significant association between COVID-19 and the Y-haplogroups [ 48 ]. Thus, the impact of Y-haplogroups on male immunity and its role in COVID-19 severity remains an open question and further studies are needed.…”

Section: Discussionmentioning

confidence: 99%

Loss of Y in leukocytes as a risk factor for critical COVID-19 in men

et al. 2022

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Background The COVID-19 pandemic, which has a prominent social and economic impact worldwide, shows a largely unexplained male bias for the severity and mortality of the disease. Loss of chromosome Y (LOY) is a risk factor candidate in COVID-19 due to its prior association with many chronic age-related diseases, and its impact on immune gene transcription. Methods Publicly available scRNA-seq data of PBMC samples derived from male patients critically ill with COVID-19 were reanalyzed, and LOY status was added to the annotated cells. We further studied LOY in whole blood for 211 COVID-19 patients treated at intensive care units (ICU) from the first and second waves of the pandemic. Of these, 139 patients were subject to cell sorting for LOY analysis in granulocytes, low-density neutrophils (LDNs), monocytes, and PBMCs. Results Reanalysis of available scRNA-seq data revealed LDNs and monocytes as the cell types most affected by LOY. Subsequently, DNA analysis indicated that 46%, 32%, and 29% of critically ill patients showed LOY above 5% cut-off in LDNs, granulocytes, and monocytes, respectively. Hence, the myeloid lineage that is crucial for the development of severe COVID-19 phenotype is affected by LOY. Moreover, LOY correlated with increasing WHO score (median difference 1.59%, 95% HDI 0.46% to 2.71%, p=0.025), death during ICU treatment (median difference 1.46%, 95% HDI 0.47% to 2.43%, p=0.0036), and history of vessel disease (median difference 2.16%, 95% HDI 0.74% to 3.7%, p=0.004), among other variables. In 16 recovered patients, sampled during ICU stay and 93–143 days later, LOY decreased significantly in whole blood and PBMCs. Furthermore, the number of LDNs at the recovery stage decreased dramatically (median difference 76.4 per 10,000 cell sorting events, 95% HDI 55.5 to 104, p=6e−11). Conclusions We present a link between LOY and an acute, life-threatening infectious disease. Furthermore, this study highlights LOY as the most prominent clonal mutation affecting the myeloid cell lineage during emergency myelopoiesis. The correlation between LOY level and COVID-19 severity might suggest that this mutation affects the functions of monocytes and neutrophils, which could have consequences for male innate immunity.

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“…This region includes a well-known pleiotropic inversion polymorphism that is positively selected in Europeans ( 102 ). Intriguingly, this locus has been associated with many traits related to lung function such as chronic obstructive pulmonary disease ( 103 ), response to inhaled corticosteroids in asthma ( 104 ) and, more recently, to severe forms of coronavirus infection (COVID-19) ( 41 ). AKAP13 , was later recognized as another IPF risk gene, therefore the profibrotic signaling pathway represents another potential target in IPF ( 93 ) ( Table 1 ).…”

Section: Genetics Of Ipfmentioning

confidence: 99%

Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine

et al. 2023

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Idiopathic pulmonary fibrosis (IPF) is a chronic, rare progressive lung disease, characterized by lung scarring and the irreversible loss of lung function. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been demonstrated to slow down disease progression, although IPF mortality remains a challenge and the patients die after a few years from diagnosis. Rare pathogenic variants in genes that are involved in the surfactant metabolism and telomere maintenance, among others, have a high penetrance and tend to co-segregate with the disease in families. Common recurrent variants in the population with modest effect sizes have been also associated with the disease risk and progression. Genome-wide association studies (GWAS) support at least 23 genetic risk loci, linking the disease pathogenesis with unexpected molecular pathways including cellular adhesion and signaling, wound healing, barrier function, airway clearance, and innate immunity and host defense, besides the surfactant metabolism and telomere biology. As the cost of high-throughput genomic technologies continuously decreases and new technologies and approaches arise, their widespread use by clinicians and researchers is efficiently contributing to a better understanding of the pathogenesis of progressive pulmonary fibrosis. Here we provide an overview of the genetic factors known to be involved in IPF pathogenesis and discuss how they will continue to further advance in this field. We also discuss how genomic technologies could help to further improve IPF diagnosis and prognosis as well as for assessing genetic risk in unaffected relatives. The development and validation of evidence-based guidelines for genetic-based screening of IPF will allow redefining and classifying this disease relying on molecular characteristics and contribute to the implementation of precision medicine approaches.

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

Cited by 67 publications

References 73 publications

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Loss of Y in leukocytes as a risk factor for critical COVID-19 in men

Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine

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