Integrative Multi-Omics Analysis Reveals MHC Class II–Mediated Immune Dysregulation in Long COVID

Abstract

Background: Long COVID affects an estimated 65 million individuals globally and is characterised by persistent multisystemic symptoms including fatigue, cognitive dysfunction, and immune dysregulation. Despite its enormous public health burden, the genetic and transcriptomic mechanisms underlying Long COVID remain incompletely understood. Here, we applied an integrative multi-omics approach combining publicly available genome-wide association study (GWAS) summary statistics with peripheral blood mononuclear cell (PBMC) transcriptomics to identify convergent immune gene candidates. Methods: We performed quality control and analysis of Long COVID GWAS summary statistics from the Long COVID Host Genetics Initiative (HGI; 15,950 cases, 1,892,830 controls). PBMC transcriptomic data were obtained from GEO (GSE224615; 23 Long COVID cases vs 13 recovered controls, all 8 months post-infection). Differential expression analysis was conducted using author-provided DESeq2 results. Pathway enrichment was performed using clusterProfiler with Gene Ontology Biological Process (GO-BP) and KEGG databases. A literature-curated GWAS integration strategy was used to test whether genome-wide significant immune loci from published Long COVID GWAS showed concordant transcriptomic dysregulation. Results: GWAS QC retained 9,474,615 SNPs with a genomic inflation factor of λ=0.914, indicating no population stratification. Sixteen independent suggestive loci (P<1×10⁻⁵) were identified, distributed across 13 chromosomes. Transcriptomic analysis identified 72 differentially expressed genes (DEGs; nominal p<0.05, |log2FC|>1), including upregulation of erythroid genes (ALAS2, HBB, HBA1) and downregulation of immunoglobulin genes (IGHG2, IGHG4) and antigen presentation genes (HLA-V). GO-BP enrichment revealed 27 significant terms including complement activation, humoral immune response mediated by circulating immunoglobulin, and oxidant detoxification. Critically, integration with published GWAS immune loci identified HLA-DQA1 as a convergent candidate — nominally downregulated in Long COVID PBMCs (LFC=−0.39, p=0.049) — with a co-localised signal at HLA-DQB1 (LFC=−0.51, p=0.11). Conclusion: Our integrative analysis implicates MHC class II downregulation as a convergent mechanism linking genetic predisposition to transcriptomic immune dysregulation in Long COVID. HLA-DQA1 and HLA-DQB1 emerge as priority candidates for functional validation and potential therapeutic targeting. These findings provide a framework for hypothesis-driven multi-omics studies of post-acute sequelae.