Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Hum Mol Genet. 2022 Nov 28;31(23):3945-3966. doi: 10.1093/hmg/ddac158.
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.
由于 2019 年冠状病毒病（COVID-19）的临床表现高度多变，深入分析宿主遗传因素对严重 COVID-19 的影响对于加深我们对潜在疾病机制的理解非常重要。在这里，我们描述了一项针对意大利、西班牙、挪威和德国/奥地利的 3255 名呼吸衰竭的 COVID-19 患者和 12488 名人群对照的经过充分特征描述的队列的扩展全基因组关联荟萃分析，包括基于年龄、性别和疾病严重程度的分层分析，以及对染色体 Y 单倍型、人类白细胞抗原区域和 SARS-CoV-2 肽段的靶向分析。通过倒位导入，我们将报告的 17q21.31 处的关联追溯到一个约 0.9-Mb 的倒位多态性，该多态性产生了两个高度分化的单倍型，并详细描述了倒位的潜在影响。我们的数据，以及包括非白种人在内的 COVID-19 宿主遗传学倡议的第五次汇总统计数据，还确定了 19q13.33 处的一个新位点，包括 NAPSA，这是一个主要在肺泡细胞中表达的基因，负责肺部的气体交换。
