A Data-Driven Review of the Genetic Factors of Pregnancy Complications.

Yury A Barbitoff,Liudmila V Kovalenko,Larisa D Belotserkovtseva,Alexander A Tsarev,Evgeniia M Maksiutenko,Andrey S Glotov,Elena S Vashukova

doi:10.3390/ijms21093384

Abstract

Over the recent years, many advances have been made in the research of the genetic factors of pregnancy complications. In this work, we use publicly available data repositories, such as the National Human Genome Research Institute GWAS Catalog, HuGE Navigator, and the UK Biobank genetic and phenotypic dataset to gain insights into molecular pathways and individual genes behind a set of pregnancy-related traits, including the most studied ones—preeclampsia, gestational diabetes, preterm birth, and placental abruption. Using both HuGE and GWAS Catalog data, we confirm that immune system and, in particular, T-cell related pathways are one of the most important drivers of pregnancy-related traits. Pathway analysis of the data reveals that cell adhesion and matrisome-related genes are also commonly involved in pregnancy pathologies. We also find a large role of metabolic factors that affect not only gestational diabetes, but also the other traits. These shared metabolic genes include IGF2, PPARG, and NOS3. We further discover that the published genetic associations are poorly replicated in the independent UK Biobank cohort. Nevertheless, we find novel genome-wide associations with pregnancy-related traits for the FBLN7, STK32B, and ACTR3B genes, and replicate the effects of the KAZN and TLE1 genes, with the latter being the only gene identified across all data resources. Overall, our analysis highlights central molecular pathways for pregnancy-related traits, and suggests a need to use more accurate and sophisticated association analysis strategies to robustly identify genetic risk factors for pregnancy complications.

Highlights

Around 15% of all pregnant women will develop complications that could lead to maternal and fetal morbidity and mortality [1]
At first stage of our analysis, we obtained data for pregnancy-related traits from the three major data sources: the Public Health Genomics and Precision Health Knowledge Base (PHGKB v6.2.1) HuGE Navigator [17], the National Human Genome Research Institute (NHGRI) genome-wide association studies (GWAS) Catalog [18], and the UK Biobank (UKB) genetic and phenotypic dataset
We primarily focused on the four most common pregnancy complications that require clinical decision making (gestational diabetes mellitus (GDM), placental abruption (PA), preeclampsia (PE), and preterm birth (PTB))

Summary

Introduction

Around 15% of all pregnant women will develop complications that could lead to maternal and fetal morbidity and mortality [1]. There is increasing evidence that, in some cases, pregnancy complications may have common pathogenetic mechanisms [2]. Pregnancy complications often share many risk factors, as well as biochemical and molecular markers [3,4,5]. Epidemiological observations indicate that pregnancy complications are risk factors for each other in one pregnancy as well as in the ones [2,5]. Different pregnancy pathologies are often associated with similar abnormalities, such as incorrect trophoblast invasion, spiral artery transformation, defective placental development, increased secretion of inflammatory factors, oxidative stress, or endothelial dysfunction [6,7]. Despite epidemiological and pathological evidence, it is unclear whether there are common molecular pathways underlying the various pregnancy complications

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