Leveraging expression quantitative trait loci information in single-cell resolution to identify cell-specific genes...

Area of Science:

• Genetics
• Immunology
• Reproductive Medicine

Background:

• Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication with significant long-term health implications for mothers and offspring.
• Genome-wide association studies (GWAS) have identified genetic risk factors for GDM, but cell-type-specific genetic influences remain largely unknown due to bulk-tissue analysis limitations.

Purpose of the Study:

• To identify cell-type-specific genes associated with GDM by integrating GWAS data with single-cell expression quantitative trait loci (sc-eQTL) data.
• To characterize the genetic architecture of GDM at the single-cell level within immune cell populations.

Main Methods:

• Integrated FinnGen GWAS summary statistics with sc-eQTL data from 12 immune cell types (OneK1K cohort).
• Employed the OTTERS framework and ACAT-O omnibus testing for single-cell transcriptome-wide association studies (scTWAS).
• Performed functional enrichment analysis and bulk-level TWAS for comparison and validation.

Main Results:

• Identified 14 unique GDM-associated genes across immune cell types, with strongest signals in CD4+ T cells and monocytes.
• ERAP1, ERAP2, and RIOK2 showed significant associations across multiple cell types, implicating antigen processing and presentation pathways.
• Bulk TWAS identified only two nominally associated genes, underscoring the power of scTWAS in detecting cell-type-specific signals.

Conclusions:

• Single-cell TWAS successfully identified cell-type-specific GDM-associated genes missed by bulk tissue analyses.
• Dysregulated antigen presentation in peripheral immune cells is highlighted as a key factor in GDM pathogenesis.
• Monocytic LNPEP is prioritized as a causal candidate, while ERAP1, ERAP2, and RIOK2 associations may involve complex linkage disequilibrium or tissue-specific effects.