Unravelling the genetic component of COVID-19 severity in the Italian population

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the development of a respiratory illness, first identified during late 2019 in China and called coronavirus disease 2019 (COVID-19). The virus was isolated and sequenced, identifying its positive-sense, single-stranded RNA genome of 29,903 nucleotides. Since then, the virus has rapidly spread to the rest of the worldwide population, primarily through respiratory droplets when an infected person coughs, sneezes, or talks, and on March 11, 2020, the World Health Organization (WHO) declared the pandemic. During the same period, Italy faced a peak in confirmed COVID-19 cases and became one of the epicenters of this pandemic. Italian hospitals and healthcare facilities, especially in the Lombardy region, were pushed to their limits, dealing with shortages of critical supplies and personnel. As of March, 16, 2020, Italy showed the highest estimated case fatality rate in the world. According to the WHO, since late 2019 Sars-CoV-2 has infected more than 772 million people and caused almost 7 million deaths worldwide (December 2023), while in Italy we observed more than 26 million infected people and 192,909 deaths. In this context, the GENIUS project (GENetics agaInst coronavirus) was born, with the aim to determine the genetic determinants responsible for the development of more severe COVID-19 symptoms in the Italian population. We analyzed the role of common genetic variants on candidate hemostatic genes and developed a polygenic risk score (PRS) capable to provide an individual-level proxy of genetic liability to COVID-19 severity in the Italian population. When performing a genome-wide association study, we identified 57 suggestive variants (p < 1 × 10-05) which replicated the most significant locus associated to COVID-19 severity and proposed two novel loci showing association signals specific for the Italian population. Analyzing rare germline variants, we identified a strong association (P < 1.82 × 10-03) between genes involved in oxidative stress and COVID-severity in the Italian population. While others have reported the role of mitochondrial ROS and oxidative stress in COVID-19 severity, to our knowledge this is the first time that the contribution of rare germline variants is added to this model. Our transcriptomics analyses sustained the pathogenesis models proposed in the literature, identifying two significantly distinct transcriptomic profiles for patients hospitalized or admitted to the intensive care unit (ICU). Studying the presence of splicing events in transcription factors and differentially expressed genes, we paved the way for the future analyses of the involvement of splicing events in the COVID-19 severity. In conclusion, we identified different genetic variants, ranging from common to rare, which can provide functional explanations for an increased risk of developing severe COVID-19 symptoms in individuals carrying these mutations. Our results are contextualized with the scientific literature and consistent with different proposed models of severe COVID-19 pathogenesis.