TY - JOUR

T1 - A data-driven review of the genetic factors of pregnancy complications

AU - Barbitoff, Yury A.

AU - Tsarev, Alexander A.

AU - Vashukova, Elena S.

AU - Maksiutenko, Evgeniia M.

AU - Kovalenko, Liudmila V.

AU - Belotserkovtseva, Larisa D.

AU - Glotov, Andrey S.

N1 - Funding Information: Funding: This study was financially supported in parts by a Russian Science Foundation grant 19-75-20033 (Y.A.B., A.S.G., E.S.V.), and a Russian Foundation for Basic Research grant 18-415-860006 r_a (L.V.K. and L.D.B.). Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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.

AB - 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.

KW - Genetic variant

KW - Genome-wide association study

KW - Gestational diabetes

KW - Placental abruption

KW - Preeclampsia

KW - Pregnancy complications

KW - Preterm birth

KW - preterm birth

KW - PLACENTA

KW - PRETERM BIRTH

KW - RISK

KW - GESTATIONAL DIABETES-MELLITUS

KW - PREECLAMPSIA

KW - preeclampsia

KW - MATRIX METALLOPROTEINASES

KW - gestational diabetes

KW - genome-wide association study

KW - placental abruption

KW - pregnancy complications

KW - MIRNAS

KW - genetic variant

KW - EXPRESSION

KW - GENOME-WIDE ASSOCIATION

UR - http://www.scopus.com/inward/record.url?scp=85084627573&partnerID=8YFLogxK

U2 - 10.3390/ijms21093384

DO - 10.3390/ijms21093384

M3 - Review article

C2 - 32403311

AN - SCOPUS:85084627573

VL - 21

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 9

M1 - 3384

ER -