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BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected over 26 million individuals in Italy, resulting in ∼200,000 COVID-19-related deaths. Unravelling host genetic factors underlying disease severity is key to understanding progression mechanisms. METHODS: We applied multi-omics approaches to investigate genetic susceptibility to COVID-19 severity in the Italian population. We combined an exome-wide case-control study of rare germline variants (215 severe/critically ill patients vs 1755 controls) with transcriptomic (differential gene expression and alternative splicing) analyses of 59 hospitalised patients to identify signatures associated with severe respiratory outcomes (ICU admission). FINDINGS: FC = 0.57, FDR = 0.028). Notably, we confirmed the genetic association with severity in independent cohorts (1873 cases vs 508,532 controls; meta-analysis p = 0.0050, OR = 3.44, 95% CI = 1.71-6.89). We propose that LPO haploinsufficiency may impair host capacity to neutralise ROS, contributing to COVID-19 progression. INTERPRETATION: In conclusion, our multi-omics analysis implicates oxidative stress and mitochondrial dysfunction as central to COVID-19 severity, identifying LPO as a candidate susceptibility gene. FUNDING: Banca Intesa San Paolo, EU Next-Generation EU-MUR-PNRR (INF-ACT, PE00000007), Dolce & Gabbana.
Cappadona et al. (Thu,) studied this question.