GWAS Identifies FOXP4 Locus as a Key Player in Long COVID

Long COVID, as per the World Health Organization's definition, refers to individuals who remain symptomatic for at least 2 months after a new crown infection, occurring 3 months after the initial infection, and cannot be attributed to other underlying conditions. The prevalence of this condition has been widely studied, with estimates ranging from 10% to 70%, displaying significant heterogeneity in its manifestation, an unknown cause, diverse pathogenesis, and symptoms that evolve over time.

Recently, the Karolinska Institutet in Stockholm carried out a groundbreaking genome-wide association study (GWAS) focused on long COVID using HGI data. This extensive study analyzed information from 24 research projects conducted in 16 different countries, involving 6,450 patients diagnosed with long COVID and 1,093,995 control subjects. As a result of this study, they identified the first genome-wide significant association related to long COVID at the FOXP4 locus. Notably, FOXP4 was found to be associated not only with the severity of new crown pneumonia but also with lung function and cancer, implying that lung dysfunction and the severity of new crown pneumonia play broader roles in the pathophysiology of long COVID.

FOXP4 Locus Are Associated with Long COVID

The link between the FOXP4 locus and long COVID has been established. Fatigue, shortness of breath, and cognitive issues such as memory and concentration problems are the prevalent symptoms of this condition. A comprehensive GWAS meta-analysis revealed a significant genetic association with long COVID in the chromosomal region 6, located upstream of the FOXP4 gene. Specifically, the presence of the rs9361706-C allele was found to be associated with a 1.63-fold higher risk of developing long COVID.

A comprehensive GWAS meta-analysis revealed a significant genetic association with long COVID. (Lammi et al., 2023)

FOXP4 exhibits high expression levels within the lung and shows a correlation with the severity of COVID-19

In the context of LONG COVID-associated variants within a 100 kb region, the rs12660421-A allele of European descent was found to be linked to the LONG COVID risk allele, rs9367106-C. This association was further connected to increased expression of FOXP4 in both the lungs and hypothalamus. Notably, FOXP4 was most abundantly expressed in type 2 alveolar cells, suggesting their involvement in immune regulation within the lungs. Additionally, FOXP4 showed nearly equally high expression in granulocytes, which also play a role in regulating innate immune responses.

Long COVID appears to be a heterogeneous disease, influenced by both individual genetic variations and environmental risk factors contributing to disease susceptibility. (Lammi et al., 2023)

The complexity of FOXP4's association with long COVID goes beyond simply explaining it by the severity of acute COVID-19.

Previous research indicated that the severity of COVID-19 might act as a risk factor for

long COVID. To explore the link between COVID-19 hospitalization and long COVID, researchers conducted a two-sample MR analysis. However, the results revealed that long COVID and COVID-19 hospitalization were outcomes of the same underlying infection, making it challenging to establish COVID-19 hospitalization as a causal exposure. Notably, FOXP4 exhibited a stronger association with long COVID than expected, indicating that its correlation with susceptibility or severity alone could not fully explain its role in long COVID.

Summary

This study presents compelling genetic evidence supporting the crucial involvement of lung pathophysiology in the development of long COVID. Furthermore, it identifies genetic variants within the FOXP4 locus as significant risk factors for long COVID. These findings align with previous epidemiological and clinical reports of long COVID, emphasizing its polygenic nature. As with other postviral conditions, long COVID appears to be a heterogeneous disease, influenced by both individual genetic variations and environmental risk factors contributing to disease susceptibility.

Reference:

1. Lammi, Vilma, et al. "Genome-wide Association Study of Long COVID." medRxiv (2023): 2023-06.