Expression Quantitative Trait Locus Mapping Studies in Mid-secretory Phase Endometrial Cells Identifies HLA-F and TAP2 as Fecundability-Associated Genes

Abstract

Fertility traits in humans are heritable, however, little is known about the genes that influence reproductive outcomes or the genetic variants that contribute to differences in these traits between individuals, particularly women. To address this gap in knowledge, we performed an unbiased genome-wide expression quantitative trait locus (eQTL) mapping study to identify common regulatory (expression) single nucleotide polymorphisms (eSNPs) in mid-secretory endometrium. We identified 423 cis-eQTLs for 132 genes that were significant at a false discovery rate (FDR) of 1%. After pruning for strong LD ( r ² >0.95), we tested for associations between eSNPs and fecundability (the ability to get pregnant), measured as the length of the interval to pregnancy, in 117 women. Two eSNPs were associated with fecundability at a FDR of 5%; both were in the HLA region and were eQTLs for the TAP2 gene ( P = 1.3x10 ^-4) and the HLA-F gene ( P = 4.0x10 ^-4), respectively. The effects of these SNPs on fecundability were replicated in an independent sample. The two eSNPs reside within or near regulatory elements in decidualized human endometrial stromal cells. Our study integrating eQTL mapping in a primary tissue with association studies of a related phenotype revealed novel genes and associated alleles with independent effects on fecundability, and identified a central role for two HLA region genes in human implantation success.

Author Summary

Little is known about the genetics of female fertility. In this study, we addressed this gap in knowledge by first searching for genetic variants that regulate gene expression in uterine endometrial cells, and then testing those functional variants for associations with the length of time to pregnancy in fertile women. Two functional genetic variants were associated with time to pregnancy in women after correcting for multiple testing. Those variants were each associated with the expression of genes in the HLA region, HLA-F and TAP2, which are have not previously been implicated female fertility. The association between HLA-F and TAP2 genotypes on the length of time to pregnancy was replicated in an independent cohort of women. Because HLA-F and TAP2 are involved in immune processes, these results suggest their role in specific immune regulation in the endometrium during implantation. Future studies will characterize these molecules in the implantation process and their potential as drug targets for treatment of conditions related to implantation failure.