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

Gestational diabetes mellitus (GDM) is a common pregnancy complication with long-term metabolic consequences for both mother and offspring. While genome-wide association studies (GWAS) have identified risk loci, the cell-type-specific genetic architecture remains poorly characterized due to the limitations of bulk-tissue analyses.

We integrated GWAS summary statistics from FinnGen (12,332 cases, 131,109 controls) with single-cell expression quantitative trait loci (sc-eQTL) data from 12 immune cell types in the OneK1K cohort. Using the OTTERS framework and ACAT-O omnibus testing, we performed single-cell transcriptome-wide association studies (scTWAS) to identify GDM-associated genes. We performed bulk-level TWAS as a sensitivity analysis. To investigate the function of significant genes, we performed functional enrichment.

We detected 14 unique genes significantly associated with GDM across immune cell types (FDR < 0.05), with the strongest signals in CD4+ T cells and monocytes. Notably, ERAP1 and ERAP2 showed associations in 10 of 12 cell types (ACAT. P = 2.17 × 10-5), and RIOK2 emerged as a shared regulator. Gene Ontology analysis consistently highlighted "antigen processing and presentation via MHC class I" as the top enriched pathway (FDR < 10-5). In contrast, traditional bulk TWAS using GTEx whole blood identified only two genes with nominal associations.

Our sc-TWAS identifies cell-type-specific GDM-associated genes that are not detected in bulk tissue, highlighting dysregulated antigen presentation in peripheral immune cells. Colocalization prioritizes monocytic LNPEP as the primary causal candidate, while associations for ERAP1, ERAP2, and RIOK2 likely reflect complex LD or tissue-specific effects.