Preprint Integrative Multi-Omics Framework for Causal Gene Discovery in Long COVID, 2025, Le et al

Integrative Multi-Omics Framework for Causal Gene Discovery in Long COVID

Thuc Duy Le, Sindy Licette Pinero, Xiaomei Li, Lin Liu, Jiuyong Li, Sang Hong Lee, Marnie Winter, Thin Nguyen, Junpeng Zhang

Background
Long COVID, or Post–Acute Sequelae of COVID–19 (PASC), involves persistent, multisystemic symptoms in about 10–20% of COVID-19 patients. Although age, sex, ethnicity, and comorbidities are recognized as risk factors, identifying genetic contributors is essential for developing targeted therapies.

Methods
We developed a multi–omics framework using Transcriptome-Wide Mendelian Randomization (TWMR) and Control Theory (CT). This approach integrates Expression Quantitative Trait Loci (eQTL), Genome-Wide Association Studies (GWAS), RNA sequencing (RNA–seq), and Protein–Protein Interaction (PPI) networks to detect causal genes and regulatory nodes that drive critical expression changes in Long COVID.

Results
We identified 32 causal genes (19 previously reported and 13 novel), which act as regulatory drivers influencing disease risk, progression, and stability. Enrichment analyses highlighted pathways linked to the SARS–CoV–2 response, viral carcinogenesis, cell cycle regulation, and immune function. Analysis of other pathophysiological conditions revealed shared genetic factors across syndromic, metabolic, autoimmune, and connective tissue disorders. Using these genes, we identified three distinct symptom-based subtypes of Long COVID, offering insights for more precise diagnosis and potential therapeutic interventions. Additionally, we provided an open-source Shiny application to enable further data exploration.

Conclusion
Integrating TWMR and CT revealed genetic mechanisms and therapeutic targets for Long COVID, with novel genes informing pathogenesis and precision medicine strategies.

Link | PDF (MedRxiv) [Preprint]

 

This is very dense. But here are the 32 causal genes:

Previously associated with SARS-CoV-2 or long COVID:
androgen receptor (AR)
butyrophilin subfamily 3 member A1 (BTN3A1)
cyclin-dependent kinase inhibitor 1A (CDKN1A)
CREBBP
EIF5A
EP300
estrogen receptor 1 (ESR1)
atos homolog A (ATOSA)
FYN proto-oncogene (FYN)
GRB2
histone deacetylase 1 (HDAC1)
mitogen-activated protein kinase (MAPK1)
NADH:ubiquinone oxidoreductase subunit A6 (NDUFA6)
retinoblastoma transcriptional corepressor 1 (RB1)
SMAD family member 2 (SMAD2)
SMAD3
sarcoma proto-oncogene (SRC)
TP53
YWHAG

Novel genes in the context of SARS-CoV-2 or long COVID:
adenosine deaminase tRNA-specific (ADAT1)
B-cell lymphoma 2 interacting protein 1 (BNIP1)
bole-like 2 (BOLA2)
chromosome 19 open reading frame 18 (C19orf18)
inositol 1,4,5-trisphosphate receptor interacting domain containing 1 (ITPRID1)
CDC26
cytidine deaminase (CDA)
ceramide synthase 4 (CERS4)
casein kinase 2 alpha 1 (CSNK2A1)
GDP-mannose pyrophosphorylase B synthase (GMPPB)
MORN repeat containing 3 (MORN3)
MORN4
von Willebrand factor D and EGF domains gene (VWDE)

 

Does anything replicate here from the other genetic studies we've seen recently?

 

https://twitter.com/user/status/1889791402009121243

 

Could you explain in laymans terms how you identified those genes back in 2018? Just curious

 

I searched S4ME, Google Scholar, and PubMed for mentions of these genes in relation to "chronic fatigue syndrome" and found these. I didn't search very deeply, and might have missed some studies, particularly for the short gene names or the ones that could be other words (AR, SRC, CDA).

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing, 2024 (Frontiers in Immunology)

Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights... 2024 (Journal of Translational Medicine)

Bioinformatics and systems biology approach to identify the pathogenetic link of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2022 (Frontiers in Immunology)

Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients, 2021 (Scientific Reports)

Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases, 2019 (Diagnostics)

Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2023 (International Journal of Molecular Sciences)

Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise, 2024 (Journal of Extracellular Vesicles)

Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients, 2016 (Gene Regulation and System Biology)

Gene Profiling of Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, 2009 (Current Rheumatology Reports)

Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis, 2009 (Journal of Clinical Pathology)

Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses, 2022 (Frontiers in Neurology)

 

'Diseases associated with FYN include Wiskott-Aldrich Syndrome'

From the page about FYN.

A possible link with WASF3?

 

A very quick automated search yields a few more results:

CDKN1A crops up in Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome (Rajeevan et al, 2015); and CREBBP in Seven genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: a detailed analysis of gene networks and clinical phenotypes (Kerr et al, 2007). TP53 is of course mentioned in the Wang et al WAVE3/WASF3 paper as the patient in that case report had Li-Fraumeni syndrome.

Looking at other LC papers: SMAD3 comes up in several, including Mapping the Potential Genes and Associated Pathways Involved in Long COVID‐Associated Brain Fog Using Integrative Bioinformatics and Systems Biology Strategy (Chakraborty et al, 2024), Sex differences and immune correlates of Long COVID development, persistence, and resolution (Hamlin et al, 2024); and TP53 in Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients (Shahbaz et al, 2025).

 

The abstract does not actually tell us anything comprehensible about wha was done with what. I am pretty sceptical of this sort of scattershot picking out of molecules without very explicit description of practical issues that may introduce huge confounders.