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

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.

Perinatal depression is associated with a higher polygenic risk for major depressive disorder than non‐perinatal depression

“…This is the largest GWAS of PND conducted to date; however, still far below the sample size that identified genetic variants associated with MDD, it failed to identify any genome‐wide significant SNPs. Although the most significant SNP did not meet genome‐wide significance, its location within the KAZN gene may be of relevance to the etiology of PND as this gene has previously been associated with post‐traumatic stress disorder (Nievergelt et al, 2019), endometriosis (Christofolini et al, 2019), complications of pregnancy (Barbitoff et al, 2020), albumin‐to‐creatinine‐ratio (Haplotype Reference Consortium, 2016) (which has also been associated with depression; Martens et al, 2018), and a reproductive subtype of polycystic ovary syndrome (Dapas et al, 2020).…”

Analysis of HLA-G long-read genomic sequences in mother–offspring pairs with preeclampsia

“…Although extensive studies have been conducted, the etiology of PE remains unknown. However, multiple factors have been implicated, including endothelial 4 , 5 , immunological 6 , and genetic factors 7 , 8 . It has been suggested that an inadequate maternal immunological response to the semiallogenic fetus and consequently abnormal placentation could cause PE.…”

Identification of Key Genes and Pathways Associated with Preeclampsia by a WGCNA and an Evolutionary Approach

“…Many PE-associated genes and pathways have been reported [ 52 , 53 ], but it is unlikely that the etiology of PE would be explained by any one of these factors; it is highly probable that multiple associated genes act together. Expanding our knowledge of the inter-connectivity of PE-associated genes in functional pathways is thus crucial to fully elucidate the mechanisms underlying PE.…”