Species richness and functional attributes of fish assemblages across a large-scale salinity gradient in shallow coastal areas

Coastal ecosystems are biologically productive, and their diversity underlies various ecosystem services to humans. However, large-scale species richness (SR) and its regulating factors remain uncertain for many organism groups, owing not least to the fact that observed SR (SRobs) depends on sample size and inventory completeness (IC). We estimated changes in SR across a natural geographical gradient using statistical rarefaction and extrapolation methods, based on a large fish species incidence dataset compiled for shallow coastal areas (<30 m depth) from Swedish fish survey databases. The data covered a ca. 1300 km north-south distance and a 12-fold salinity gradient along sub-basins of the Baltic Sea plus the Skagerrak and, depending on the sub-basin, 4 to 47 years of samplings during 1975-2021. Total fish SRobs was 144, and the observed fish species were of 74 % marine and 26 % freshwater origin. In the 10 sub-basins with sufficient data for further analysis, IC ranged from 77 % to 98 %, implying that ca. 2 %-23 % of likely existing fish species had remained undetected. Sample coverage exceeded 98.5 %, suggesting that undetected species represented <1.5 % of incidences across the sub-basins, i.e. highly rare species. To compare sub-basins, we calculated standardized SR (SRstd) and estimated SR (SRest). Sub-basin-specific SRest varied between 35 +/- 7 (SE) and 109 +/- 6 fish species, being ca. 3 times higher in the most saline (salinity 29-32) compared to the least saline sub-basins (salinity < 3). Analysis of functional attributes showed that differences with decreasing salinity particularly reflected a decreasing SR of benthic and demersal fish, of piscivores and invertivores, and of marine migratory species. We conclude that, if climate change continues causing an upper-layer freshening of the Baltic Sea, this may influence the SR, community composition and functional characteristics of fish, which in turn may affect ecosystem processes such as benthic-pelagic coupling and connectivity between coastal and open-sea areas

Havsbaserad vindkraft i samexistens med fiske, vattenbruk och naturvård? : en inledande kunskapssammanställning

Havsbaserad vindkraft är en viktig komponent i omställningen till förnybar energi för att bemöta den globala klimatkrisen. För att bättre förstå förutsättningarna för utbyggnad av havsbaserad vindkraft behövs kunskap om möjligheter, hinder och åtgärder för samexistens mellan vindkraft och andra behov till havs. Den här rapporten presenterar resultat från en litteraturanalys för att belysa nuvarande kunskapsläge om samexistens mellan havsbaserad vindkraft och yrkesfiske, vattenbruk respektive naturvård. Angående samexistens med yrkesfiske är huvudsakliga möjligheter som diskuteras i litteraturen att utforma fiskeredskap och -metoder som är kompatibla med vindparker, och designa vindparker så att det kan finnas förutsättningar för att även utöva fiske. Huvudsakliga potentiella hinder som diskuteras i litteraturen är låg acceptans för havsbaserad vindkraft inom fiskesektorn som kan försvåra möjligheter till utvecklingsprojekt, och säkerhetsaspekter, som risk för olyckor, skada på vindparkens installationer, samt skada eller förlust av fiskeredskap, och även tillhörande osäkerheter kring försäkringsaspekter. Åtgärder som undersöks enligt litteraturen inkluderar dels förebyggande åtgärder, som noggrant samarbete med aktörer och intressegrupper vid platsval, lokala eller regionala samrådforum, och styrning på högre politisk nivå, dels strategiska åtgärder, som satsningar på utveckling av teknik som medför minskad risk för skada, utveckling av fiskeredskap som kan användas i vindparker och småskaliga pilotprojekt kring god praxis för fiskevänliga vindparker. Bland planeringsmässiga åtgärder betonas framförallt proaktiv havsplanering. Angående samexistens med vattenbruk diskuteras i litteraturen framförallt fördelar med att kombinera vattenbruk med vindparker, som kan leda till mer effektiv platsanvändning och ökade möjligheter för att etablera vattenbruk längre bort från kusten. Som hinder diskuteras främst att utvecklingen av sådan fleranvändning fortfarande är i ett tidigt skede och inte kommersiellt gångbar, så att det fortfarande behövs kunskapsutveckling i form av pilotstudier, teknikutveckling, risk- och konfliktanalyser, men även att lagstiftningen idag kan vara försvårande för samexistens. Centrala åtgärder som diskuteras i litteraturen är till exempel att stimulera forskning, innovation och utveckling, inkludera fleranvändning i havsplaneringen och utveckla ett gemensamt ramverk för aktörer inom fleranvändning inklusive ett tydligt regelverk för förvaltning, tillståndsprocesser och övervakning av verksamheterna. Angående samexistens med naturvård fokuserar rapporten på olika aspekter kring om, och i så fall hur, havsbaserad vindkraft kan vara förenlig med naturvårdens syften. Möjligheter för samexistens mellan vindparker och lagstadgade skyddade områden är svåra att fastställa på en generell nivå, då det beror på om vindparken medför en risk för det skyddade områdets målsättning eller inte. Förutsättningarna påverkas även hurdana förflyttningseffekter som skulle kunna uppstå inom fiske och andra marina användningar, och vilka miljöeffekter dessa kan leda till. Bland sätt på vilka havsbaserade vindparker skulle kunna gynna naturvården, på en mer generell nivå, belyser litteraturen till exempel att 1) artificiella reveffekter kan främja vissa arter, vilket skulle vara gynnsamt om det stärker hotade eller sårbara arter, eller arter som fyller en önskad funktion i ekosystemet, som filtrering eller bioreglering, och 2) indirekta skyddseffekter kan uppstå om fiske utesluts helt eller delvis i parken, och ge möjlighet till återhämtning för arter som dör i fisket, samt havsbottnar (om området tidigare har påverkats av bottentrålning). Litteraturen, och olika pågående pilotprojekt, belyser även möjligheter att integrera naturinkluderande designer i vindparkernas utformning, till exempel hur vindkraftverkens fundament och erosionsskydd skulle kunna utformas för att främja vissa, önskade arter. Bland potentiella hinder identifieras till exempel risken att en samlokalisering med skyddade områden skulle innebära ömsesidiga kompromisslösningar, så att nätverket av skyddade områden blir suboptimalt. Litteraturen diskuterar även en risk att reveffekter vid vindkraftverken kan motverka syftet med det skyddade området, till exempel att oönskade arter gynnas eller att den nya artificiella livsmiljön skadar naturligt förekommande livsmiljöer, samt osäkerheter kring hur fiskemönster kommer att utvecklas i området och dess närhet, inklusive förflyttningseffekter. Möjligheten att integrera naturbaserade lösningar, till exempel att utforma vindkraftverkens fundament så att de kan främja vissa arter, diskuteras allt mer. En farhåga som lyfts i detta sammanhang är att den forskningsbaserade utvecklingen går långsamt framåt, då det fortfarande finns osäkerheter kring ekologisk effektivitet, effektstorlek eller möjliga risker med sådana lösningar. Möjliga åtgärder som diskuteras i litteraturen för att stärka naturvården är till exempel att strategiskt använda havsplaneringen för att lokalisera områden för vindkraft på ett sätt som kan gynna sådana arter och livsmiljöer som behöver stärkas eller rehabiliteras från fysisk påverkan, samt att testa och vidareutveckla naturbaserade lösningar. En övergripande aspekt som lyfts i litteraturen är vikten av tillräcklig och kontinuerlig kommunikation, och av riktade insatser för att öka förutsättningarna för samexistens och acceptans. Exempel är att stärka möjligheter till engagemang från olika aktörer, konsultera en bredd av sektorer och intressegrupper, säkerställa information till allmänheten, samt att påbörja samråd tidigt i processen och på ett sätt så att det blir tydligt vilken typ av inflytande som är möjlig i vilket skede. Stimulering av forskning och innovation, transparenta och strukturerade processer för havsplanering, kunskapsutbyte mellan länder samt offentlig tillgång till data är andra centrala insatser som betonas

Cell Cycle Regulating Kinase Cdk4 as a Potential Target for Tumor Cell Treatment and Tumor Imaging

The cyclin-dependent kinase (Cdk)-cyclin D/retinoblastoma (pRb)/E2F cascade, which controls the G1/S transition of cell cycle, has been found to be altered in many neoplasias. Inhibition of this pathway by using, for example, selective Cdk4 inhibitors has been suggested to be a promising approach for cancer therapy. We hypothesized that appropriately radiolabeled Cdk4 inhibitors are suitable probes for tumor imaging and may be helpful studying cell proliferation processes in vivo by positron emission tomography. Herein, we report the synthesis and biological, biochemical, and radiopharmacological characterizations of two 124I-labeled small molecule Cdk4 inhibitors (8-cyclopentyl-6-iodo-5-methyl-2-(4-piperazin-1-yl-phenylamino)-8H-pyrido[2,3-d]-pyrimidin-7-one (CKIA) and 8-cyclopentyl-6-iodo-5-methyl-2-(5-(piperazin-1-yl)-pyridin-2-yl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one (CKIB)). Our data demonstrate a defined and specific inhibition of tumor cell proliferation through CKIA and CKIB by inhibition of the Cdk4/pRb/E2F pathway emphasizing potential therapeutic benefit of CKIA and CKIB. Furthermore, radiopharmacological properties of [124I]CKIA and [124I]CKIB observed in human tumor cells are promising prerequisites for in vivo biodistribution and imaging studies

The Effect of Obstructive Sleep Apnea and Continuous Positive Airway Pressure Therapy on Skeletal Muscle Lipid Content in Obese and Nonobese Men.

Obstructive sleep apnea (OSA), independently of obesity (OBS), predisposes to insulin resistance (IR) for largely unknown reasons. Because OSA-related intermittent hypoxia triggers lipolysis, overnight increases in circulating free fatty acids (FFAs) including palmitic acid (PA) may lead to ectopic intramuscular lipid accumulation potentially contributing to IR. Using 3-T-1H-magnetic resonance spectroscopy, we therefore compared intramyocellular and extramyocellular lipid (IMCL and EMCL) in the vastus lateralis muscle at approximately 7 am between 26 male patients with moderate-to-severe OSA (17 obese, 9 nonobese) and 23 healthy male controls (12 obese, 11 nonobese). Fiber type composition was evaluated by muscle biopsies. Moreover, we measured fasted FFAs including PA, glycated hemoglobin A1c, thigh subcutaneous fat volume (ScFAT, 1.5-T magnetic resonance tomography), and maximal oxygen uptake (VO2max). Fourteen patients were reassessed after continuous positive airway pressure (CPAP) therapy. Total FFAs and PA were significantly (by 178% and 166%) higher in OSA patients vs controls and correlated with the apnea-hypopnea index (AHI) (r ≥ 0.45, P < .01). Moreover, IMCL and EMCL were 55% (P < .05) and 40% (P < .05) higher in OSA patients, that is, 114% and 103% in nonobese, 24.4% and 8.4% in obese participants (with higher control levels). Overall, PA, FFAs (minus PA), and ScFAT significantly contributed to IMCL (multiple r = 0.568, P = .002). CPAP significantly decreased EMCL (-26%) and, by trend only, IMCL, total FFAs, and PA. Muscle fiber composition was unaffected by OSA or CPAP. Increases in IMCL and EMCL are detectable at approximately 7 am in OSA patients and are partly attributable to overnight FFA excesses and high ScFAT or body mass index. CPAP decreases FFAs and IMCL by trend but significantly reduces EMCL

Kunskapsunderlag för ekosystembaserad havsförvaltning i Bottenhavet

Ekosystembaserad havsförvaltning anges som ett viktigt verktyg för att nå Sveriges miljömål. Denna rapport tar ett första steg i riktning mot ett vetenskapligt underlag för att stödja ekosystembaserad havsförvaltning i ett pilotområde i södra Bottenhavet. Ekosystemkomponenter (dvs. arter och livsmiljöer) som är viktiga för modellering av ekosystemet identifieras och deras status samt faktorer som påverkar dem redovisas. Även kunskapsluckor kopplade till påverkansfaktorer diskuteras, samt hur dessa påverkansfaktorer integreras med ekosystemkomponenterna, liksom vilka ekosystemtjänster som ekosystemkomponenterna bidrar till. Många av ekosystemkomponenterna har inte god miljöstatus, särskilt grunda bottnar som har ett högt exploateringstryck. Oroväckande nog saknas det övervakning av både grunda kustnära mjukbottnar och utsjöbankar, fastän dessa områden är av intresse för exploatering samtidigt som de har hög biodiversitet och är kopplade till många ekosystemtjänster. Dock finns det en del data tillgängligt i området som kan användas vid modellering för att ta fram kartor över ekosystemkomponenter och även ekosystemtjänster, som kan vara viktiga underlag för ekosystembaserad förvaltning i södra Bottenhavet. I flera fall är kunskapen om belastningar i södra Bottenhavet och hur de kopplar till statusen av ekosystemkomponenter relativt god, men det saknas information om kumulativa effekter av påverkansfaktorer. Många av de marina arter som finns längst in i Östersjön lever här vid sin nordliga utbredningsgräns, vilket kan innebära att de är extra känsliga för mänskliga belastningar och klimatförändring. Storskaligt fiske efter strömming i utsjön och dess effekter på strömmingsbestånden kan påverka ekosystemets funktion. Strömmingen är talrik och spelar en stor roll i södra Bottenhavets ekosystem. Eftersom strömming vandrar mellan utsjön och kusten kan den koppla samman näringsvävar i kust och utsjö. I Bottenhavets område kan man se tydliga intressekonflikter gällande resursförvaltning. Traditionella lokala näringar baserar sig mycket på fiske av strömming och laxfisk, men vikande fångster av den mer storvuxna strömming som fiskas för humankonsumtion, liksom av laxfisk, skapar problem för det kustnära yrkesfisket. Här finns en uppenbar konkurrenssituation både med det storskaliga pelagiska fisket i utsjön och med naturliga predatorer. Dessa konflikter är svåra att lösa med de förvaltningsmetoder som används idag. Södra Bottenhavets ekosystem skulle sannolikt gynnas av en mer helhetsbaserad förvaltning av fiskbestånden och livsmiljöer, utifrån samtliga faktorer som påverkar dem. I kustområdet gäller detta även, inte minst, de områden där gösens och sikens status är mycket svag, liksom viktiga områden för rekrytering av gädda. En sådan mer helhetsbaserad förvaltning innefattar en samplanering av fiskeregleringar, skyddade områden och åtgärder för att restaurera och skydda diverse livsmiljöer. Förbättring av livsmiljöer för fisk förväntas även gynna andra delar av den biologiska mångfalden och ekosystemtjänster, inklusive olika arters motståndskraft och förmåga att anpassa sig till pågående klimatförändringar

The mitochondrial import protein Mim1 promotes biogenesis of multispanning outer membrane proteins

The Mim1 complex imports α-helical mitochondrial outer membrane proteins with multiple transmembrane segments

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America

Background: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. Methods: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. Results: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. Conclusion: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.Radium Hospital Foundation (Oslo, Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, Helse Sør-Øst (Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, the French Association Recherche contre le Cancer (ARC) in the analysis, and interpretation of data, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (Gefluc) in the analysis, and interpretation of data, the Association Nationale de la Recherche et de la Technologie (ANRT, CIFRE PhD fellowship to H.T.) in the analysis, and interpretation of data and by the OpenHealth Institute in the analysis, and interpretation of data. Barretos Cancer Hospital received financial support by FINEP-CT-INFRA (02/2010)info:eu-repo/semantics/publishedVersio

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.S.E.H. and C.A.S. partially supported genotyping through a philanthropic donation. A.F. and D.E. were supported by a grant from the German Federal Ministry of Education and COVID-19 grant Research (BMBF; ID:01KI20197); A.F., D.E. and F.D. were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). D.E. 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). D.E., K.B. and S.B. acknowledge the Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). T.L.L., A.T. and O.Ö. were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. M.W. and H.E. are supported by the German Research Foundation (DFG) through the Research Training Group 1743, ‘Genes, Environment and Inflammation’. L.V. received funding from: Ricerca Finalizzata Ministero della Salute (RF-2016-02364358), Italian Ministry of Health ‘CV PREVITAL’—strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ‘REVEAL’; Fondazione IRCCS Ca’ Granda ‘Ricerca corrente’, Fondazione Sviluppo Ca’ Granda ‘Liver-BIBLE’ (PR-0391), Fondazione IRCCS Ca’ Granda ‘5permille’ ‘COVID-19 Biobank’ (RC100017A). A.B. was supported by a grant from Fondazione Cariplo to Fondazione Tettamanti: ‘Bio-banking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by an MIUR grant to the Department of Medical Sciences, under the program ‘Dipartimenti di Eccellenza 2018–2022’. This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP (The Institute for Health Science Research Germans Trias i Pujol) IGTP is part of the CERCA Program/Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIII-MINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). M.M. received research funding from grant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (European Regional Development Fund (FEDER)-Una manera de hacer Europa’). B.C. is supported by national grants PI18/01512. X.F. is supported by the VEIS project (001-P-001647) (co-funded by the European Regional Development Fund (ERDF), ‘A way to build Europe’). Additional data included in this study were obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, European Institute of Innovation & Technology (EIT), a body of the European Union, COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. A.J. and S.M. were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). A.J. was also supported by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the European Regional Development Fund (FEDER). The Basque Biobank, a hospital-related platform that also involves all Osakidetza health centres, the Basque government’s Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. M.C. received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). M.R.G., J.A.H., R.G.D. and D.M.M. are supported by the ‘Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III’ (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100) and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón’s team is supported by CIBER of Epidemiology and Public Health (CIBERESP), ‘Instituto de Salud Carlos III’. J.C.H. reports grants from Research Council of Norway grant no 312780 during the conduct of the study. E.S. reports grants from Research Council of Norway grant no. 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). P.K. Bergisch Gladbach, Germany and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF). O.A.C. is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—CECAD, EXC 2030–390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. K.U.L. is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. F.H. was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to A.R. from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme—Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to A.R. P.R. is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). F.T. is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). C.L. and J.H. are supported by the German Center for Infection Research (DZIF). T.B., M.M.B., O.W. und A.H. are supported by the Stiftung Universitätsmedizin Essen. M.A.-H. was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. E.C.S. is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).Peer reviewe

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 GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 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 (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ∼0.9-Mb inversion polymorphism 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, 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.Andre Franke and David Ellinghaus were supported by a grant from the German Federal Ministry of Education and Research (01KI20197), Andre Franke, David Ellinghaus and Frauke Degenhardt were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). David Ellinghaus 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). David Ellinghaus, Karina Banasik and Søren Brunak acknowledge the Novo Nordisk Foundation (grant NNF14CC0001 and NNF17OC0027594). Tobias L. Lenz, Ana Teles and Onur Özer were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. Mareike Wendorff and Hesham ElAbd are supported by the German Research Foundation (DFG) through the Research Training Group 1743, "Genes, Environment and Inflammation". This project was supported by a Covid-19 grant from the German Federal Ministry of Education and Research (BMBF; ID: 01KI20197). Luca Valenti received funding from: Ricerca Finalizzata Ministero della Salute RF2016-02364358, Italian Ministry of Health ""CV PREVITAL – strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ""REVEAL""; Fondazione IRCCS Ca' Granda ""Ricerca corrente"", Fondazione Sviluppo Ca' Granda ""Liver-BIBLE"" (PR-0391), Fondazione IRCCS Ca' Granda ""5permille"" ""COVID-19 Biobank"" (RC100017A). Andrea Biondi was supported by the grant from Fondazione Cariplo to Fondazione Tettamanti: "Biobanking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by a MIUR grant to the Department of Medical Sciences, under the program "Dipartimenti di Eccellenza 2018–2022". This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP. IGTP is part of the CERCA Program / Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIIIMINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). Marta Marquié received research funding from ant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIIISubdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa").Beatriz Cortes is supported by national grants PI18/01512. Xavier Farre is supported by VEIS project (001-P-001647) (cofunded by European Regional Development Fund (ERDF), “A way to build Europe”). Additional data included in this study was obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, EIT COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. Antonio Julià and Sara Marsal were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). Antonio Julià was also supported the by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the FEDER. The Basque Biobank is a hospitalrelated platform that also involves all Osakidetza health centres, the Basque government's Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. Mario Cáceres received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). Manuel Romero Gómez, Javier Ampuero Herrojo, Rocío Gallego Durán and Douglas Maya Miles are supported by the “Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III” (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100), and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón's team is supported by CIBER of Epidemiology and Public Health (CIBERESP), "Instituto de Salud Carlos III". Jan Cato Holter reports grants from Research Council of Norway grant no 312780 during the conduct of the study. Dr. Solligård: reports grants from Research Council of Norway grant no 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). Philipp Koehler has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF).Oliver A. Cornely is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping was performed by the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. Kerstin U. Ludwig is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. Frank Hanses was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to Alfredo Ramirez from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme – Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Philip Rosenstiel is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). Florian Tran is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). Christoph Lange and Jan Heyckendorf are supported by the German Center for Infection Research (DZIF). Thorsen Brenner, Marc M Berger, Oliver Witzke und Anke Hinney are supported by the Stiftung Universitätsmedizin Essen. Marialbert Acosta-Herrera was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. Eva C Schulte is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).N