Why Long COVID Remains a Medical Challenge
AN ESTIMATED 10–20% of people infected with SARS-CoV-2 go on to develop Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC). Symptoms can persist for months or years and affect multiple organ systems, ranging from fatigue and brain fog to cardiovascular, metabolic, and immune complications. Despite its scale, the biological mechanisms driving Long COVID remain poorly understood.
A new study has now applied an advanced multi-omics approach to uncover the genetic drivers of Long COVID, offering a framework for more targeted diagnosis and treatment.
Integrating Genetics, Gene Expression, and Network Biology
Researchers combined multiple analytical techniques, including Transcriptome-Wide Mendelian Randomisation (TWMR), genome-wide association studies (GWAS), RNA sequencing, expression quantitative trait loci (eQTLs), and protein–protein interaction networks. This integrative approach allowed the team to move beyond genetic association and identify genes that are likely to play a causal role in Long COVID.
Using this framework, the researchers prioritised 32 candidate genes, including 19 previously reported and 13 newly identified. These genes are involved in key biological processes such as immune regulation, viral response, cell cycle control, and pathways linked to viral carcinogenesis.
Three Biological Subtypes of Long COVID Identified
One of the most clinically important findings was the identification of three distinct Long COVID subtypes, each defined by different gene expression profiles. These subtypes appear to correspond to differing symptom patterns and underlying biology, helping to explain why Long COVID presents so heterogeneously between individuals.
The analysis also revealed shared genetic architecture between Long COVID and autoimmune, metabolic, connective tissue, and syndromic disorders, suggesting overlapping mechanisms that may drive chronic inflammation and multisystem dysfunction.
Implications for Long COVID Care
For infectious disease physicians, the study provides a biological framework for understanding Long COVID beyond symptom-based definitions. Identifying causal genes and network “control points” may enable biomarker development, risk stratification, and the repurposing of existing therapies targeting immune or metabolic pathways.
To support wider clinical and research use, the team has developed an open-access Shiny application, allowing users to explore genes, pathways, and subtypes interactively.
Reference
Pinero S et al. Integrative multi-omics framework for causal gene discovery in Long COVID. PLoS Comput Biol. 2025;21(12):e1013725.
