Pan-Genomic Regulation of Gene Expression in Normal and Pathological Human Placentas
Clara Apicella,
Camino S. M. Ruano,
Basky Thilaganathan,
Asma Khalil,
Veronica Giorgione,
Géraldine Gascoin,
Louis Marcellin,
Cassandra Gaspar,
Sébastien Jacques,
Colin E. Murdoch,
Francisco Miralles,
Céline Méhats,
Daniel Vaiman
Affiliations
Clara Apicella
Team ‘From Gametes to Birth’, Institut Cochin, U1016 INSERM, UMR 8104 CNRS, Paris-Descartes University, 75014 Paris, France
Camino S. M. Ruano
Team ‘From Gametes to Birth’, Institut Cochin, U1016 INSERM, UMR 8104 CNRS, Paris-Descartes University, 75014 Paris, France
Basky Thilaganathan
Fetal Medicine Unit, St George’s University Hospitals NHS Foundation Trust, London SW17 0RE, UK
Asma Khalil
Fetal Medicine Unit, St George’s University Hospitals NHS Foundation Trust, London SW17 0RE, UK
Veronica Giorgione
Fetal Medicine Unit, St George’s University Hospitals NHS Foundation Trust, London SW17 0RE, UK
Géraldine Gascoin
Department of Neonatology, Angers University Hospital, F-49000 Angers, France
Louis Marcellin
Department of Gynaecology, Obstetrics and Reproductive Medicine, Centre Hospitalier Universitaire (CHU) Cochin Faculté de Médecine, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris Centre (HUPC), Université de Paris, 138 Boulevard de Port-Royal, 75014 Paris, France
Cassandra Gaspar
Sorbonne Université, Inserm, UMS Production et Analyse des données en Sciences de la vie et en Santé, PASS, Plateforme Post-génomique de la Pitié-Salpêtrière, 75013 Paris, France
Sébastien Jacques
Team ‘From Gametes to Birth’, Institut Cochin, U1016 INSERM, UMR 8104 CNRS, Paris-Descartes University, 75014 Paris, France
Colin E. Murdoch
Systems Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK
Francisco Miralles
Team ‘From Gametes to Birth’, Institut Cochin, U1016 INSERM, UMR 8104 CNRS, Paris-Descartes University, 75014 Paris, France
Céline Méhats
Team ‘From Gametes to Birth’, Institut Cochin, U1016 INSERM, UMR 8104 CNRS, Paris-Descartes University, 75014 Paris, France
Daniel Vaiman
Team ‘From Gametes to Birth’, Institut Cochin, U1016 INSERM, UMR 8104 CNRS, Paris-Descartes University, 75014 Paris, France
In this study, we attempted to find genetic variants affecting gene expression (eQTL = expression Quantitative Trait Loci) in the human placenta in normal and pathological situations. The analysis of gene expression in placental diseases (Pre-eclampsia and Intra-Uterine Growth Restriction) is hindered by the fact that diseased placental tissue samples are generally taken at earlier gestations compared to control samples. The difference in gestational age is considered a major confounding factor in the transcriptome regulation of the placenta. To alleviate this significant problem, we propose here a novel approach to pinpoint disease-specific cis-eQTLs. By statistical correction for gestational age at sampling as well as other confounding/surrogate variables systematically searched and identified, we found 43 e-genes for which proximal SNPs influence expression level. Then, we performed the analysis again, removing the disease status from the covariates, and we identified 54 e-genes, 16 of which are identified de novo and, thus, possibly related to placental disease. We found a highly significant overlap with previous studies for the list of 43 e-genes, validating our methodology and findings. Among the 16 disease-specific e-genes, several are intrinsic to trophoblast biology and, therefore, constitute novel targets of interest to better characterize placental pathology and its varied clinical consequences. The approach that we used may also be applied to the study of other human diseases where confounding factors have hampered a better understanding of the pathology.
