Single-Cell Immune Cis-eQTL Mendelian Randomization Prioritizes Cell-Type-Resolved Candidate Causal Genes for Endometriosis

Background: Endometriosis has a substantial immune component, but the cellular contexts of genetically regulated disease susceptibility remain incompletely resolved. Methods: We tested single-cell cis-eQTL instruments from 20 OneK1K peripheral-blood cell types against FinnGen R12 endometriosis (20,190 cases; 130,160 controls) using single-variant Mendelian randomization (MR), colocalization and sensitivity analyses. Benjamini–Yekutieli (BY) correction distinguished conservative findings from an exploratory Benjamini–Hochberg (BH) screen. Directional consistency, bulk-blood MR and lesion expression provided contextual comparisons. Results: Across 9157 unique gene–cell-type tests, 135 associations in 61 genes reached BH-FDR < 0.05. Colocalization at the default prior prioritized 10 genes (6 protein-coding) across 28 pairs. LOC102723878 and RUVBL1 were also BY-robust; IGF1R in natural killer (NK) cells was BH-supported but not BY-robust (PP4 = 0.89; OR 1.11 per SD higher expression). Its NK attribution reflects instrument availability and does not establish exclusivity. Colocalization was prior-sensitive. Directional concordance in a partly overlapping sample (8/8) was descriptive. Bulk-blood MR nominated 3/6 testable protein-coding genes. IGF1R lesion expression showed a nonsignificant upward trend (P = 0.101). Conclusion: The analysis prioritizes immune-context candidate genes for functional study. IGF1R remains an exploratory, mechanistically unresolved nomination. Genetic support and protein tractability do not establish therapeutic benefit or reproductive safety; experimental validation is required. Keywords: endometriosis, Mendelian randomization analysis, quantitative trait loci, single-cell gene expression, killer cells, natural, receptor, IGF type 1