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Prioritizing long COVID related single nucleotide polymorphisms by mining genome-wide association studies of COVID-19

Zhong-Shan Cheng1

  • 1Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, United States.

Frontiers in Systems Biology
|June 22, 2026
PubMed

Insights

Genetic analysis identified 62 potential risk loci for long COVID, but most showed weak associations. Further research is needed to understand the genetic basis of long COVID and its related traits.

Area of Science:

  • Genetics
  • Genomics
  • Infectious Diseases

Background:

  • Long COVID (post-acute sequelae of SARS-CoV-2 infection) is a complex condition with over 200 symptoms impacting multiple organ systems.
  • Genetic studies are challenged by symptom heterogeneity and small sample sizes, hindering the identification of risk factors.
  • Understanding the genetic underpinnings of Long COVID is crucial for public health and developing targeted interventions.

Purpose of the Study:

  • To identify candidate genetic risk loci associated with Long COVID using a hypothesis-generating approach.
  • To prioritize genetic variants by analyzing genome-wide association studies (GWAS) data for COVID-19 susceptibility, hospitalization, and Long COVID.
  • To explore the genetic overlap between acute COVID-19 and Long COVID.

Main Methods:

  • Utilized a proxy-based strategy analyzing GWAS summary statistics from the COVID-19 Host Genetics Initiative (Release 7).
  • Analyzed susceptibility, hospitalization, and Long COVID data to identify 62 candidate risk loci represented by independent variants.
  • Categorized variants based on associations with severe COVID-19, mild COVID-19, or both, and evaluated them in independent Long COVID datasets.
  • Performed integrative gene expression and phenome-wide analyses to identify genes linked to Long COVID-relevant traits.

Main Results:

  • Identified 62 candidate risk loci, categorized into severe COVID-19-specific, severe/mild COVID-19 associated, and mild COVID-19-specific variants.
  • Most candidate variants showed weak associations in Long COVID datasets, with only one genome-wide significant signal (rs12660421 in *FOXP1*).
  • Genes near candidate loci exhibited weaker associations with Long COVID compared to acute COVID-19 outcomes.
  • Broader phenome-wide analyses identified 52 genes associated with traits relevant to Long COVID.

Conclusions:

  • The study identified candidate genetic loci for Long COVID, but most require further investigation due to weak associations.
  • The *FOXP1* gene emerged as a potential significant locus for Long COVID.
  • Integrative analyses suggest a complex genetic architecture for Long COVID, with potential links to broader phenomic traits.
  • Further research is warranted to validate these candidate loci and elucidate the genetic basis of Long COVID.

Keywords:
COVID-19GWASSARS-CoV-2TWAShospitalizationlong COVIDsusceptibility

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