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.

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).

Rare variant analysis revealed significant associations with genes implicated in oxidative stress and mitochondrial dysfunction, including MTERF1 (FDR = 7.69 × 10−5), TDP1 (FDR = 3.23 × 10−7), and LPO (FDR = 1.58 × 10−2). Pathway analyses confirmed enrichment in “reactive oxygen species”, “oxidative phosphorylation”, and “inflammatory response” pathways. Transcriptomics showed a proinflammatory profile in hospitalised patients (N = 24) and a prothrombotic signature in ICU-admitted individuals (N = 35), reflecting disease progression. Genomic and transcriptomic data integration highlighted LPO, encoding the antimicrobial enzyme lactoperoxidase, as the only gene both significantly enriched for damaging variants and upregulated in ICU-admitted cases (log2FC = 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.

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.

Banca Intesa San Paolo, EU Next-Generation EU-MUR-PNRR (INF-ACT, PE00000007), Dolce & Gabbana.

COVID-19

Multi-omics

Oxidative stress

Lactoperoxidase

Thrombosis

Immune response

© 2026 The Authors. Published by Elsevier B.V.