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000284363 037__ $$aDZNE-2026-00131
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000284363 1001_ $$aAbolhassani, Ayda$$b0
000284363 245__ $$aGenetic contribution to severe COVID-19 in adults under 60 years without major comorbidities in the German National Pandemic Cohort Network (NAPKON).
000284363 260__ $$aLondon [u.a.]$$bHenry Stewart Publ.$$c2026
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000284363 520__ $$aWhile genome-wide association studies (GWAS) have linked common genetic variants to COVID-19 susceptibility and severity, rare high-impact variants may also contribute to phenotypic heterogeneity. Inborn errors of type I interferon immunity (IFN-I-IEIs), including X-linked TLR7 deficiency, account for ~ 2% of critical COVID-19 cases. In this study, we investigated rare potentially deleterious variants in IFN-I-IEI and GWAS-prioritized genes in young, severely affected COVID-19 patients from the German National Pandemic Cohort Network (NAPKON). Genome sequencing was performed on 110 hospitalized COVID-19 patients, including 82 males and 28 females, all under 60 years of age and without relevant pre-existing medical conditions. Rare potentially deleterious variants in TLR7 and 25 additional IFN-I-IEI genes, as well as 23 GWAS risk genes for COVID-19 severity, were analyzed based on allele frequency, predicted functional impact, and inheritance pattern models and subsequently classified based on the American College of Medical Genetics and Genomics (ACMG) criteria. Polygenic Risk Scores (PRS) were additionally calculated as an exploratory and case-only analysis to assess the contribution of common variant-derived genetic predisposition for severe COVID-19. Consistent with prior findings from other studies in German cohorts, no candidate variants or large deletions were identified in TLR7. However, 7 variants of uncertain significance in IFN-I-IEI genes as well as 13 candidate variants of potential deleterious effect in GWAS risk genes were present in 19 individuals (17.3%). We observed nominally significant differences in PRS distributions, with younger individuals (< 40 years) having higher PRS (p = 0.045) compared to older individuals, and carriers of rare variants having lower PRS compared to non-carriers (p = 0.037). These patterns are consistent with an age-dependent contribution of polygenic risk to severe COVID-19 and a potentially lower polygenic burden among rare-variant carriers, although confirmation in larger well-controlled cohorts will be required. The candidate variants identified in IFN-I-IEI and GWAS risk genes represent targets for further functional studies to clarify their potential contribution to disease risk. These findings highlight the need for future integrative genomic approaches to better understand the joint contribution of common and rare variants to COVID-19 severity.
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000284363 650_7 $$2NLM Chemicals$$aToll-Like Receptor 7
000284363 650_7 $$2NLM Chemicals$$aTLR7 protein, human
000284363 650_7 $$2NLM Chemicals$$aInterferon Type I
000284363 650_2 $$2MeSH$$aHumans
000284363 650_2 $$2MeSH$$aCOVID-19: genetics
000284363 650_2 $$2MeSH$$aCOVID-19: epidemiology
000284363 650_2 $$2MeSH$$aCOVID-19: virology
000284363 650_2 $$2MeSH$$aMale
000284363 650_2 $$2MeSH$$aFemale
000284363 650_2 $$2MeSH$$aAdult
000284363 650_2 $$2MeSH$$aMiddle Aged
000284363 650_2 $$2MeSH$$aGermany: epidemiology
000284363 650_2 $$2MeSH$$aGenome-Wide Association Study
000284363 650_2 $$2MeSH$$aSARS-CoV-2
000284363 650_2 $$2MeSH$$aGenetic Predisposition to Disease
000284363 650_2 $$2MeSH$$aToll-Like Receptor 7: genetics
000284363 650_2 $$2MeSH$$aCohort Studies
000284363 650_2 $$2MeSH$$aSeverity of Illness Index
000284363 650_2 $$2MeSH$$aComorbidity
000284363 650_2 $$2MeSH$$aPandemics
000284363 650_2 $$2MeSH$$aGene Frequency
000284363 650_2 $$2MeSH$$aInterferon Type I: genetics
000284363 650_2 $$2MeSH$$aMultifactorial Inheritance
000284363 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide
000284363 693__ $$0EXP:(DE-2719)PRECISE-20190321$$5EXP:(DE-2719)PRECISE-20190321$$ePlatform for Single Cell Genomics and Epigenomics at DZNE  University of Bonn$$x0
000284363 7001_ $$aAlawathurage, T Madhusankha$$b1
000284363 7001_ $$aSchmidt, Axel$$b2
000284363 7001_ $$aBrand, Fabian$$b3
000284363 7001_ $$aKilarski, Laura L$$b4
000284363 7001_ $$aAltmann, Heidi$$b5
000284363 7001_ $$aDahl, Edgar$$b6
000284363 7001_ $$aFrank, Sandra$$b7
000284363 7001_ $$aGöpel, Siri$$b8
000284363 7001_ $$aHanses, Frank$$b9
000284363 7001_ $$aHellmuth, Johannes Christian$$b10
000284363 7001_ $$aHerr, Christian$$b11
000284363 7001_ $$aKaasch, Achim J$$b12
000284363 7001_ $$aKobbe, Robin$$b13
000284363 7001_ $$aKonik, Margarethe Justine$$b14
000284363 7001_ $$aPink, Isabell$$b15
000284363 7001_ $$aRömmele, Christoph$$b16
000284363 7001_ $$aRupp, Jan$$b17
000284363 7001_ $$aScheer, Christian S$$b18
000284363 7001_ $$aSchneider, Marc A$$b19
000284363 7001_ $$aStellbrink, Christoph$$b20
000284363 7001_ $$aStubbe, Hans Christian$$b21
000284363 7001_ $$aTepasse, Phil-Robin$$b22
000284363 7001_ $$aTeufel, Andreas$$b23
000284363 7001_ $$aVadász, István$$b24
000284363 7001_ $$aVehreschild, Maria J G T$$b25
000284363 7001_ $$aWitzenrath, Martin$$b26
000284363 7001_ $$aAnton, Gabriele$$b27
000284363 7001_ $$aBröhl, Isabel$$b28
000284363 7001_ $$aHerold, Susanne$$b29
000284363 7001_ $$aIllig, Thomas$$b30
000284363 7001_ $$aJiru-Hillmann, Steffi$$b31
000284363 7001_ $$aKrawitz, Peter$$b32
000284363 7001_ $$aMitrov, Lazar$$b33
000284363 7001_ $$aPhilipsen, Alexandra$$b34
000284363 7001_ $$aPütz, Sina M$$b35
000284363 7001_ $$0P:(DE-2719)9000400$$aNoethen, Markus M$$b36
000284363 7001_ $$aNuernberg, Peter$$b37
000284363 7001_ $$aReese, Jens-Peter$$b38
000284363 7001_ $$aRiess, Olaf$$b39
000284363 7001_ $$0P:(DE-HGF)0$$aSchreiber, Stefan$$b40
000284363 7001_ $$0P:(DE-2719)2811660$$aSchultze, Joachim$$b41$$udzne
000284363 7001_ $$aSteinbeis, Fridolin$$b42
000284363 7001_ $$aVehreschild, J Janne$$b43
000284363 7001_ $$aWildberg, Christian$$b44
000284363 7001_ $$aLudwig, Kerstin U$$b45
000284363 7001_ $$aSchulte, Eva C$$b46
000284363 773__ $$0PERI:(DE-600)2147618-4$$a10.1186/s40246-025-00904-9$$gVol. 20, no. 1, p. 23$$n1$$p23$$tHuman genomics$$v20$$x1473-9542$$y2026
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