Global and Sex-Stratified Genome-Wide Association Study of Long COVID Based on Patient-Driven Symptom Recall, 2025, Polo-Alonso et al.

SNT Gatchaman

Senior Member (Voting Rights)
Staff member
Global and Sex-Stratified Genome-Wide Association Study of Long COVID Based on Patient-Driven Symptom Recall
Polo-Alonso, Sara; Hernáez, Álvaro; Dégano, Irene R; Martí-Lluch, Ruth; Pinsach-Abuin, Mel·lina; Elosua, Roberto; Subirana, Isaac; Puigmulé, Marta; Pérez, Alexandra; Cruz, Raquel; Almeida, Silvia Diz-de; Puigdecant, Eulàlia; Selga, Elisabet; Nogues, Xavier; Masclans, Joan Ramon; Güerri-Fernández, Roberto; Cubero-Gallego, Héctor; Tizon-Marcos, Helena; Vaquerizo, Beatriz; Brugada, Ramon; Ramos, Rafel; Camps-Vilaró, Anna; Marrugat, Jaume

We aimed to explore the global and sex-specific genetic variants associated with long COVID, as defined by patient-driven symptom recall. A 1-year cohort study of 2411 COVID-19 patients collected long COVID symptoms with an open-ended, non-directed questionnaire, and long COVID incidence was determined according to the World Health Organization definition.

Global and sex-stratified genome-wide association analyses were conducted by logistic regression models adjusted for age, sex (in the global analysis), and the first 10 principal components. We assessed sex-variant interactions and performed gene-based analyses, gene mapping, and gene-set enrichment analyses.

When comparing the 1392 long COVID cases with the non-cases, we identified 23 lead variants from suggestive signals: 13 from the global analysis, 5 from females, and 5 from males. Five variants showed a significant interaction with sex (two in females, three in males). We mapped 15 protein-coding genes related to diseases of the immune and nervous systems and tumoral processes. Notably, CD5 and VPS37C, linked to immune function, were significantly associated with long COVID in men.

Our results suggest that persistent immune dysregulation may be involved in the development of precisely defined long COVID.

Web | PDF | International Journal of Molecular Sciences | Open Access
 
Commenting on the previous FOXP4 finding in Genome-wide association study of long COVID (2025)
A key methodological difference is that Lammi et al. compared long COVID cases with controls drawn from the general population, which included both SARS-CoV-2–infected and non-infected individuals. Interestingly, when they restricted the analysis to controls with confirmed SARS-CoV-2 infection, the FOXP4 association did not reach statistical significance. Our study design, which compared long COVID cases exclusively against SARS-CoV-2–infected non-cases, follows this latter approach and may explain the absence of association at the FOXP4 locus in our results. This highlights how the choice of control group can influence the detection of genetic associations in long COVID research.

GeneCards —

LAMC3
TMEM109
PGA3
PGA5
VWCE
TMEM216
VPS37C
CD5
MYBPC2
EMC10
JOSD2
ASPDH
LRRC4B
PTOV1
FAM71E1
 
LRRC4B is Leucine Rich Repeat Containing 4B
Predicted to enable signaling receptor binding activity. Predicted to be involved in regulation of synapse assembly and synaptic membrane adhesion. Predicted to be located in cerebellar mossy fiber and presynaptic membrane. Predicted to be active in glutamatergic synapse and postsynaptic density membrane.

Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome (2025) —

9 of the 22 GWAS-1 associations were associated in R-1 with p-values < 0.05, a larger proportion than expected by chance. These nine included four DecodeME loci (RABGAP1L, FBXL4, OLFM4, CA10), plus LRRC7 – a gene associated by MAGMA gene-based testing
 
Back
Top Bottom