The Effect of Genetic Variation on the Placental Transcriptome in Humans

The knowledge of genetic variants shaping human placental transcriptome is limited and they are not cataloged in the Genotype-Tissue Expression project. So far, only one whole genome analysis of placental expression quantitative trait loci (eQTLs) has been published by Peng et al. (2017) with no external independent validation. We report the second study on the landscape of placental eQTLs. The study aimed to generate a high-confidence list of placental cis-eQTLs and to investigate their potential functional implications. Analysis of cis-eQTLs (±100 kbp from the gene) utilized 40 placental RNA sequencing and respective whole genome genotyping datasets. The identified 199 placental cis-eSNPs represented 88 independent eQTL signals (FDR < 5%). The most significant placental eQTLs (FDR < 10^-5) modulated the expression of ribosomal protein RPL9, transcription factor ZSCAN9 and aminopeptidase ERAP2. The analysis confirmed 50 eSNP-eGenes pairs reported by Peng et al. (2017) and thus, can be claimed as robust placental eQTL signals. The study identified also 13 novel placental eGenes. Among these, ZSCAN9 is modulated by several eSNPs (experimentally validated: rs1150707) that have been also shown to affect the methylation level of genes variably escaping X-chromosomal inactivation. The identified 63 placental eGenes exhibited mostly mixed or ubiquitous expression. Functional enrichment analysis highlighted 35 Gene Ontology categories with the top ranking pathways "ruffle membrane" (FDR = 1.81 × 10^-2) contributing to the formation of motile cell surface and "ATPase activity, coupled" (FDR = 2.88 × 10^-2), critical for the membrane transport. Placental eGenes were also significantly enriched in pathways implicated in development, signaling and immune function. However, this study was not able to confirm a significant overrepresentation of genome-wide association studies top hits among the placental eSNP and eGenes, reported by Peng et al. (2017). The identified eSNPs were further analyzed in association with newborn and pregnancy traits. In the discovery step, a suggestive association was detected between the eQTL of ALPG (rs11678251) and reduced placental, newborn's and infant's weight. Meta-analysis across REPROMETA, HAPPY PREGNANCY, ALSPAC cohorts (n = 6830) did not replicate these findings. In summary, the study emphasizes the role of genetic variation in driving the transcriptome profile of the human placenta and the importance to explore further its functional implications.