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

Courtney K Burrows,Carole Ober,Vincent J Lynch,Digna R Velez Edwards,Kristen Patterson,Mary D Stephenson,Catherine Herman,Katherine E Hartmann,Gülüm Kosova,Louis J Muglia

doi:10.1371/journal.pgen.1005858

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 (r2 >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.

Highlights

Natural variation in fertility traits is heritable in humans [1], yet identifying genes contributing to these traits remains challenging
Because HLA-F and that included genotype at rs2071473 (TAP2) are involved in immune processes, these results suggest their role in specific immune regulation in the endometrium during implantation
We performed expression quantitative trait locus (eQTL) mapping in the mid-secretory phase endometrium, corresponding to the luteal phase of the ovarian cycle, from 53 women with two or more early pregnancy losses, using 378,362 common (10%) single nucleotide polymorphisms (SNPs) that were within 200kb of one or more of the 10,191 genes detected as expressed in these tissues

Summary

Introduction

Natural variation in fertility traits is heritable in humans [1], yet identifying genes contributing to these traits remains challenging. A few GWAS of male fertility [2] or infertility [3, 4] traits have identified promising candidate genes, to date there have been no such studies in women To address these limitations, we have focused our genetic studies of fertility on members of a founder population, the Hutterites [1, 2, 5,6,7,8]. Whereas miscarriages of clinically recognized pregnancies among Hutterite couples is 15.6% [8], nearly identical to estimates of clinically recognized miscarriage rates in outbred populations [12], recurrent miscarriages in childless couples are rare (0 of 525 interviewed Hutterite women [1]) compared to 5% in the general population [13] Their communal lifestyle ensures that sociocultural factors influencing fertility are relatively uniform among Hutterite couples [1, 14]. We report here the discovery of independent associations between SNPs that are eQTLs for the HLA-F and TAP2 genes in mid-secretory phase endometrium and fecundability (the probability of achieving pregnancy), thereby implicating maternal HLA region genes for the first time in implantation processes

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Results

Discussion

Conclusion