A multi-omic analysis to investigate the causal associations between circulating proteins and risk of spontaneous abortion and their potential implications.

Objective: Spontaneous abortion is a complex disorder with a significant genetic component. Identifying genetic variants influencing spontaneous abortion risk could unveil biological pathways and potential therapeutic targets.

Methods: We performed Mendelian randomization using cis- and trans-protein quantitative trait loci (pQTLs) as instrumental variables to assess causal effects of circulating proteins on spontaneous abortion. Proteins exhibiting differential expression between sexes were excluded. KEGG pathway enrichment was employed to investigate the pathways affected by susceptibility genes, while single-cell transcriptomic analysis was utilized to explore the susceptible cell types with elevated expression of these genes within the uterine endometrium.

Results: MMP9 and DC-SIGN were associated with increased spontaneous abortion risk (OR=1.11(1.03-1.19), P=3.70x10-3; OR=1.09(1.02-1.16), p=9.89x10-3), while HBAZ and NELL1 had protective effects (OR=0.96(0.94-0.99), p=5.20x10-3; OR=0.94(0.9-0.98), p=8.54x10-3). Additionally, TMM85 conferred higher spontaneous abortion risk (OR=1.06(1.02-1.1), p=4.72x10-3). Pathway analysis highlighted sphingolipid binding, chemorepellent activity, and tumor necrosis factor receptor activity. Single-cell transcriptomics revealed that MUL1, EMC4, NDC80, and SELL genes exhibit higher expression levels within uterus cells, and these susceptibility genes displayed elevated expression levels in leukocytes, mature NK T cells, and T cells in the uterus.

Conclusions: Our integrated multi-omics analysis identified genetic variants influencing spontaneous abortion risk and their downstream molecular mechanisms, providing insights into potential therapeutic targets. The implicated pathways and cell types may guide future investigations into the pathogenesis of spontaneous abortion.