Cell and state-specific eQTL analysis in human endometrial mesenchymal cells uncovers candidate susceptibility genes for reproductive diseases and traits

The functional consequence of genetic variants and how they contribute to disease remains elusive. Studying genetic variants in disease-relevant cells captures variations in effects in cell types and states. The endometrium is a heterogenic tissue with critical reproduction roles considered complex genetic traits. We assessed the association between genetic variants and gene expression in purified endometrial mesenchymal cells using both bulk and single-cell RNA-sequencing data from patients with endometria-driven reproductive disorders. We compared these to those identified in whole endometrium and to reproductive disease-associated genetic loci. We identified cis-eQTLs for 947 unique eGenes in isolated endometrial mesenchymal cells of which 50% had not previously been identified in whole endometrium. Single-cell RNA-sequencing data stratifying by differentiation state we found a further 25 and 26 unique eGenes in stem and mature mesenchymal cells respectively. Comparison with reproductive disease-associated variants identified overlaps with COG6 and AC012313.10 with age of menarche and HELB with age of menopause. Summary Mendelian Randomisation (SMR) identified potential causal effects of RPS2 on age of menarche and KANSLI on age at first birth, as well as a mesenchymal stem cell state-specific influence of GATD3A on uterine fibroid formation. Identifying functional consequences of genetic variants critical to disease can be enhanced with disease-relevant, purified cells. We provide evidence for critical roles for COG6 and HELB in age-related traits of reproduction and a causal role for GATD3A on uterine fibroid formation during early cell development supporting that genetic influences on early stem cell state and subsequent differentiation can contribute to disease pathology.