Single-cell expression quantitative trait loci-based Mendelian randomization identifies MAN1A2 in naive CD4+ T cells
Xuan-Yi Zhou1, Fang-Yu Liu1, Yan Zhang1
1Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, China.
Background:
Osteoarthritis (OA) is a leading cause of chronic pain and disability worldwide, with growing evidence implicating immune dysregulation in its pathogenesis. However, the specific peripheral immune cell populations contributing causally to OA risk remain poorly characterized.
Methods:
We performed a multi-stage two-sample Mendelian randomization (MR) study integrating single-cell cis-expression quantitative trait loci (cis-eQTLs) for 14 peripheral immune cell types from the OneK1K cohort with two independent OA GWAS datasets - the Million Veteran Program for discovery and the UK Biobank for replication and ICD-10-based subtype analyses. Causal inference was strengthened through Bayesian colocalization, Steiger directionality testing, and phenome-wide pleiotropy screening. Gene-level safety profiling and functional annotation were also performed.
Results:
Among the eGene-outcome pairs tested, 13 reached false discovery rate significance in discovery. Two were replicated with concordant effect direction: MAN1A2 in CD4+ naïve and central memory T cells and SLC44A4 in NK cells. Bayesian colocalization supported a shared causal variant for MAN1A2 (PP.H4 = 0.96) and SLC44A4 (PP.H4 = 0.81). However, SLC44A4 was excluded due to extensive HLA-related pleiotropy within the major histocompatibility complex region. MAN1A2 showed concordant risk-increasing effects across all five OA subtypes, reaching significance for hip OA, polyarthrosis, and other unspecified arthrosis. Gene-level phenome-wide testing showed that genetic perturbation of MAN1A2 is not associated with detectable adverse phenotypes in population-based exome data, and functional analysis positioned MAN1A2 within N-glycan processing and endoplasmic reticulum quality control pathways.
Conclusion:
Cell-type-specific MR identifies MAN1A2 expression in CD4+ naïve T cells as a candidate therapeutic target for osteoarthritis for which genetic perturbation is not associated with detectable adverse phenotypes in population-based exome data.