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@ARTICLE{Abolhassani:284363,
      author       = {Abolhassani, Ayda and Alawathurage, T Madhusankha and
                      Schmidt, Axel and Brand, Fabian and Kilarski, Laura L and
                      Altmann, Heidi and Dahl, Edgar and Frank, Sandra and Göpel,
                      Siri and Hanses, Frank and Hellmuth, Johannes Christian and
                      Herr, Christian and Kaasch, Achim J and Kobbe, Robin and
                      Konik, Margarethe Justine and Pink, Isabell and Römmele,
                      Christoph and Rupp, Jan and Scheer, Christian S and
                      Schneider, Marc A and Stellbrink, Christoph and Stubbe, Hans
                      Christian and Tepasse, Phil-Robin and Teufel, Andreas and
                      Vadász, István and Vehreschild, Maria J G T and
                      Witzenrath, Martin and Anton, Gabriele and Bröhl, Isabel
                      and Herold, Susanne and Illig, Thomas and Jiru-Hillmann,
                      Steffi and Krawitz, Peter and Mitrov, Lazar and Philipsen,
                      Alexandra and Pütz, Sina M and Noethen, Markus M and
                      Nuernberg, Peter and Reese, Jens-Peter and Riess, Olaf and
                      Schreiber, Stefan and Schultze, Joachim and Steinbeis,
                      Fridolin and Vehreschild, J Janne and Wildberg, Christian
                      and Ludwig, Kerstin U and Schulte, Eva C},
      title        = {{G}enetic contribution to severe {COVID}-19 in adults under
                      60 years without major comorbidities in the {G}erman
                      {N}ational {P}andemic {C}ohort {N}etwork ({NAPKON}).},
      journal      = {Human genomics},
      volume       = {20},
      number       = {1},
      issn         = {1473-9542},
      address      = {London [u.a.]},
      publisher    = {Henry Stewart Publ.},
      reportid     = {DZNE-2026-00131},
      pages        = {23},
      year         = {2026},
      abstract     = {While 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.},
      keywords     = {Humans / COVID-19: genetics / COVID-19: epidemiology /
                      COVID-19: virology / Male / Female / Adult / Middle Aged /
                      Germany: epidemiology / Genome-Wide Association Study /
                      SARS-CoV-2 / Genetic Predisposition to Disease / Toll-Like
                      Receptor 7: genetics / Cohort Studies / Severity of Illness
                      Index / Comorbidity / Pandemics / Gene Frequency /
                      Interferon Type I: genetics / Multifactorial Inheritance /
                      Polymorphism, Single Nucleotide / Toll-Like Receptor 7 (NLM
                      Chemicals) / TLR7 protein, human (NLM Chemicals) /
                      Interferon Type I (NLM Chemicals)},
      cin          = {AG Schultze / PRECISE},
      ddc          = {570},
      cid          = {I:(DE-2719)1013038 / I:(DE-2719)1013031},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354) / 352
                      - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-354 / G:(DE-HGF)POF4-352},
      experiment   = {EXP:(DE-2719)PRECISE-20190321},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41578410},
      pmc          = {pmc:PMC12849158},
      doi          = {10.1186/s40246-025-00904-9},
      url          = {https://pub.dzne.de/record/284363},
}