Genome-wide DNA methylation profiling in COVID-19 positive patients reveals alterations in pathways linked to neurological dysfunction, 2026, Zameer+

[SNT Gatchaman]

Genome-wide DNA methylation profiling in COVID-19 positive patients reveals alterations in pathways linked to neurological dysfunction

Spoiler: Authors

Zameer, Saima; Anis, Ehraz; Sha, Qiong; Escobar Galvis, Martha L; Khan, Sanam; Steiner, Jennifer A; Milčiūtė, Milda; Kerševičiūtė, Ieva; Gabrielaite, Migle; Gordevicius, Juozas; Pospisilik, Andrew; Saiyed, Nazia; Graham, Stewart F; Brundin, Patrik; Brundin, Lena

BACKGROUND
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA betacoronavirus, causing coronavirus disease-19 (COVID-19). Infection with SARS-CoV-2 can result in a broad spectrum of clinical outcomes, ranging from asymptomatic or mild to a severe, deadly illness. Emerging evidence suggests SARS-CoV-2 affects host gene regulation through epigenetic mechanisms, such as DNA methylation, potentially contributing to immune dysregulation and post-acute sequelae, including neurological and psychiatric disorders. However, the extent and functional relevance of these epigenetic changes remain uncertain.

METHODS AND RESULTS
We employed whole-genome methylation sequencing (WGMS) to profile DNA methylation in peripheral blood from SARS-CoV-2-positive patients across a spectrum of symptom severity, ranging from asymptomatic to severe (n = 101), in comparison to SARS-CoV-2-negative individuals (n = 105). We observed a widespread hypomethylation in the genomes of infected individuals, which was more pronounced in severe cases. Notably, we identified differentially methylated genes in patients with mild (19 genes), moderate (19 genes), and severe (35 genes) symptoms. These genes included those involved in canonical immune responses as well as known to be linked to neurodegenerative diseases. Subsequent pathway enrichment analysis further supported the significant association between the differentially methylated genes and those implicated in Alzheimers and Parkinsons disease, as well as neuropsychiatric conditions, suggesting potential epigenetic links between acute SARS-CoV-2 infection and long-term neurological outcomes. Our WGMS comprehensively mapped severity-stratified genome-wide DNA methylation changes in COVID-19 patients.

CONCLUSION
Our findings underscore the potential importance of epigenetic regulation in the acute responses to SARS-CoV-2 infection and highlight an overlap with epigenetic mechanisms relevant for neuropsychiatric disease processes.

Web | DOI | PDF | Clinical Epigenetics | Open Access

 

[SNT Gatchaman]

They're looking at differentially methylated genes in different severities of acute Covid, but the implication is that this could be relevant to long-term dysfunction (their discussion focuses on neurodegenerative conditions).

GeneCards —

Mild
CELF2 (also known as CUGBP2)
PTPRK
RAPGEF1
STK39

Moderate
MTUS2
LRRC3B
GLB1

Severe
ARHGEF40
VEGF4
ABCC1
TPCN1
TUBGCP3
SYN3
UMAD1

 

[SNT Gatchaman]

Cohort —

The SARS-CoV-2-positive cohort was divided into three groups based on hospital admission status and the maximum level of oxygen administered during admission: 1) Asymptomatic or Mild non-hospitalized patients with no oxygen required, 2) Moderate – hospitalized patients receiving nasal cannula at ≤6L of oxygen, and 3) Severe – hospitalized patients using nasal cannula >6L, or on O 2 devices such as ventilation masks, cold high-flow, heated high-flow, non-rebreather masks, Bi-PAP, or CPAP. These hospital-based controls included Beaumont Health staff or patients who tested negative

With QC they had 103 negatives, 40 mild, 36 moderate and 20 severe. (I haven't spotted the age, sex, BMI breakdown).

Analysis —

Given the genome-wide scope of this analysis (approximately 4.8 million genomic windows), the potential for false-positive findings must be carefully considered. We addressed this by applying Benjamini-Hochberg (BH) false discovery rate (FDR) correction across all tests

To identify overlapping features among these groups, we applied statistical threshold of FDR < 0.05.

 

[SNT Gatchaman]

Findings —

When stratified by disease severity, the number of hypomethylated windows was 25 in mild cases, 19 in moderate cases, and 42 in severe cases. Conversely, hypermethylated windows were limited, with 0, 4, and 5 identified in mild, moderate, and severe cases, respectively. These results suggest that hypomethylation increases with higher disease severity

Specifically, in mild cases: CELF2 (also known as CUGBP2), PTPRK, RAPGEF1, and STK39; in moderate cases: MTUS2, LRRC3B, and GLB1; and in severe cases: ARHGEF40, VEGF4, ABCC1, TPCN1, TUBGCP3, SYN3, and UMAD1 have been associated with risk for neurodegenerative disorders.

I'm highlighting two Rho GTPase activating genes (RAPGEF1 and ARHGEF40) as well as LRRC3B which may have relevance given the potential DecodeME highlighting (via MAGMA I think) of LRRC7 (see also summary here); and a previous small LC GWAS highlighting LRRC4B.

Most enriched pathways were driven by hypomethylated genes. In addition to the identified DMGs, differential methylation in SARS-CoV-2-positive patients significantly impacted pathways related to neurological processes, alongside the classical immune and inflammatory signaling.

Overlap between groups was limited, with 4.4%, 7.0%, and 8.8% of pathways shared between mild and moderate, mild and severe, and moderate and severe cases, respectively. Among the overlapping pathways, significant hypomethylation was observed in pathways related to axon and synapse assembly processes between mild and moderate cases. Similarly, pathways involved in neuroinflammation and glutamatergic signaling were enriched between mild and severe cases, while neurogenesis and postsynapse organization pathways were shared between moderate and severe cases.

Interestingly, among those 9.1% of commonly enriched pathways, axon guidance and neuron projection-related processes, including guidance, development, and morphogenesis, were consistently hypomethylated, while pathways associated with olfactory processes, including olfactory receptor expression, translocation, and signaling, were hypermethylated across all severity groups.