The Role of Genetics in Long COVID
By Buonsenso and the Kids (but based on your suggestions)
Long COVID, or post‑acute sequelae of COVID-19 (PASC), remains a medical challenge: persistent fatigue, brain fog, shortness of breath. Why do some children and adults get stuck with long-term symptoms while others don’t? Why there are family clusters? Genetics may hold part of the answer.
1. Landmark GWAS: The FOXP4 Locus
A large-scale genome-wide association study (GWAS), pooling data from 24 global cohorts including over 6,450 Long COVID cases, identified variants in the FOXP4 gene as significantly associated with Long COVID risk (PMC).
FOXP4, a transcription factor, is highly expressed in the lungs and immune cells.
A risk allele, particularly in homozygous form, increased Long COVID risk by ~5.6‑fold (PMC).
FOXP4 variants were also linked with fatigue, asthma, and use of β‑blockers and proton pump inhibitors (PMC).
These findings were independently replicated in Estonian and Mexican cohorts (PMC).
Confirmatory analyses in another 9,500 cases reinforced the FOXP4 signal, showing ~60% increased risk (News Medical).
Why FOXP4 matters:
It plays a role in lung regeneration, immune cell memory, and may link lung inflammation to systemic symptoms—key elements in Long COVID pathology.
2. Beyond FOXP4: Combinatorial Genomics
One study deployed a combinatorial genetic analysis (beyond single-SNP GWAS) and uncovered 73 genes associated with Long COVID in distinct phenotypes: severe vs. fatigue-dominant (Journal of Translational Medicine).
Genes linked to immune/inflammatory pathways (e.g., macrophage function) were enriched in severe cases.
Metabolic and mitochondrial genes (like MAPK/JNK pathway, circadian regulator CLOCK) emerged in fatigue-predominant cases (Journal of Translational Medicine).
Some of these genes overlapped with those identified in ME/CFS, reinforcing a shared genetic underpinning for post-viral fatigue syndromes (Journal of Translational Medicine).
A follow-up in a more diverse US cohort confirmed 77–83% of the original genetic signatures, validating the robustness of this combinatorial approach (Journal of Translational Medicine).
3. Other Genetic Clues
Variants in HLA-DRB1, part of immune response genes, were associated with Long COVID in a 23andMe study (23andMe Blog).
ABO blood group variants—already linked to COVID-19 severity—may influence Long COVID risk as well (23andMe Blog).
Genes associated with endothelial function, coagulation, and pulmonary vascular integrity may explain respiratory and thrombotic complications in some cases (PMC).
4. Practical Takeaways for Clinicians and Families
Long COVID susceptibility is polygenic and multifactorial.
While FOXP4 stands out, the full picture involves many genes modulating immunity, metabolism, vasculature, and neurobiology.Different phenotypes unfold via distinct pathways.
Fatigue-dominant cases may stem more from metabolic/mitochondrial dysregulation, while severe multisystem involvement hints at immune/inflammatory dysfunction.Overlap with ME/CFS genetics suggests shared mechanisms and potential for cross-disease therapy exploration.
Personalized medicine is on the horizon.
Genetic screening could help predict who may develop Long COVID, enabling early intervention. Drug repurposing—like TLR4 antagonists—targeted to genetic profiles may offer future solutions (Drug Target Review, PMC, Journal of Translational Medicine).
Limitations & Future Directions
Predictive power remains modest. Genetics is only one piece; environment, viral factors, vaccination status and lifestyle also influence outcomes.
More pediatric data needed. Most studies focus on adults, and we must validate findings in children.
Ethnic diversity matters. Initial studies focused on European ancestry; newer validations (e.g., All of Us cohort) help generalize findings (Journal of Translational Medicine).
Final Thoughts
Genetics is illuminating new paths in Long COVID—shedding light on why certain individuals, including children, suffer chronic symptoms while others recover. As we uncover genes like FOXP4, CLOCK, and HLA-DRB1, we inch closer to stratified care, targeted interventions, and ultimately hope for affected families.
The future of Long COVID medicine lies in integrating genomics with clinical phenotyping, symptom tracking, and environmental data. As “Buonsenso and the Kids,” we’re committed to exploring these frontiers responsibly—always with the well-being of children and families at heart.
References:
FOXP4 GWAS: Long COVID Host Genetics Initiative (News Medical)
Combinatorial genetic analysis: PrecisionLife GOLD cohort (Journal of Translational Medicine)
Validation in All of Us cohort
HLA-DRB1 & ABO variants: 23andMe genetic report (23andMe Blog)
Pulmonary genetics in Long COVID
Both my children are HLA B27 pos like their dad. They also have mannin binding lectin deficiency. They both had long covid but one recovered. It would be interesting to do deeper genetic tests.