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Introduction: A high frequency of single nucleotide somatic mutations in the placenta has been recently described, but its relationship to placental dysfunction is unknown., Methods: We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction., Results: Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111-870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381-779), 582 (450-735), and 338 (245-441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. -34, -351 to +419), and with no association with placental dysfunction (p = 0.7)., Discussion: We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nathan Blue reports financial support was provided by National Institute of Child Health and Human Development. Robert Silver reports financial support was provided by R Baby Foundation. Rachel Hess (non-author) reports financial support was provided by National Center for Advancing Translational Sciences. Wallace Akerley (non-author) reports financial support was provided by National Cancer Institute. The authors have no additional disclosures. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life., Results: We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta., Conclusion: We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases., Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.

Background: Maternal obesity prior to or during pregnancy influences fetal growth, predisposing the offspring to increased risk for obesity across the life course. Placental epigenetic mechanisms may underlie these associations. We conducted an epigenome-wide association study to identify placental DNA methylation changes associated with maternal prepregnancy body mass index (BMI) and rate of gestational weight gain at first (GWG1), second (GWG2), and third trimester (GWG3)., Method: Participants of the NICHD Fetal Growth Studies with genome-wide placental DNA methylation (n = 301) and gene expression (n = 75) data were included. Multivariable-adjusted regression models were used to test the associations of 1 kg/m 2 increase in prepregnancy BMI or 1 kg/week increase in GWG with DNA methylation levels. Genes harboring top differentially methylated CpGs (FDR P < 0.05) were evaluated for placental gene expression. We assessed whether DNA methylation sites known to be associated with BMI in child or adult tissues, were also associated with maternal prepregnancy BMI in placenta., Results: Prepregnancy BMI was associated with DNA methylation at cg14568196[EGFL7], cg15339142[VETZ], and cg02301019[AC092377.1] (FDR P < 0.05, P ranging from 1.4 × 10 -10 to 1.7 × 10 -9 ). GWG1 or GWG2 was associated with DNA methylation at cg17918270[MYT1L], cg20735365[DLX5], and cg17451688[SLC35F3] (FDR P < 0.05, P ranging from 6.4 × 10 -10 to 1.2 × 10 -8 ). Both prepregnancy BMI and DNA methylation at cg1456819 [EGFL7] were negatively correlated with EGFL7 expression in placenta (P < 0.05). Several CpGs previously implicated in obesity traits in children and adults were associated with prepregnancy BMI in placenta. Functional annotations revealed that EGFL7 is highly expressed in placenta and the differentially methylated CpG sites near EGFL7 and VEZT were cis-meQTL targets in blood., Conclusions: We identified placental DNA methylation changes at novel loci associated with prepregnancy BMI and GWG. The overlap between CpGs associated with obesity traits in placenta and other tissues in children and adults suggests that epigenetic mechanisms in placenta may give insights to early origins of obesity.

Aim: To identify placental DNA methylation changes that are associated with early pregnancy maternal dyslipidemia. Materials & methods: We analyzed placental genome-wide DNA methylation (n = 262). Genes annotating differentially methylated CpGs were evaluated for gene expression in placenta (n = 64). Results: We found 11 novel significant differentially methylated CpGs associated with high total cholesterol, low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol. High triglycerides were associated with decreased methylation of cg02785814 ( ALX4 ) and decreased expression of ALX4 in placenta. Genes annotating the differentially methylated CpGs play key roles in lipid metabolism and were enriched in dyslipidemia pathways. Functional annotation found  cis -methylation quantitative trait loci for genetic loci in ALX4 and EXT2 . Conclusion: Our findings lend novel insights into potential placental epigenetic mechanisms linked with maternal dyslipidemia. Trial Registration: ClinicalTrials.gov, NCT00912132.

Abnormal blood pressure during pregnancy is associated with impaired fetal growth, predisposing the offspring to cardiometabolic abnormalities over the life-course. Placental DNA methylation may be the regulatory pathway through which maternal blood pressure influences fetal and adult health outcomes. Epigenome-wide association study of 301 participants with placenta sample examined associations between DNA methylation and millimetre of mercury increases in systolic and diastolic blood pressure in each trimester. Findings were further examined using gene expression, gene pathway, and functional annotation analyses. Cytosine-(phosphate)-guanine (CpGs) known to be associated with cardiometabolic traits were evaluated. Increased maternal systolic and diastolic blood pressure were associated with methylation of 3 CpGs in the first, 6 CpGs in the second, and 15 CpGs in the third trimester at 5% false discovery rate ( P values ranging from 6.6×10 -15 to 2.3×10 -7 ). Several CpGs were enriched in pathways including cardiovascular-metabolic development ( P =1.0×10 -45 ). Increased systolic and diastolic blood pressure were associated with increased CpG methylation and gene expression at COL12A1 , a collagen family gene known for regulatory functions in the heart. Out of 304 previously reported CpGs known to be associated with cardiometabolic traits, 36 placental CpGs were associated with systolic and diastolic blood pressure in our data. The present study provides the first evidence for associations between placental DNA methylation and increased maternal blood pressure during pregnancy at genes implicated in cardiometabolic diseases. Identification of blood pressure-associated methylated sites in the placenta may provide clues to early origins of cardiometabolic dysfunction and inform guidelines for early prevention. Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00912132.

Disruption of physiological ageing of the placenta is associated with obstetric complications. Altered lipid metabolism is a known trigger of tissue ageing, but the effect of maternal dyslipidemia on placental ageing is not clearly understood. We examined the relationship between maternal dyslipidemia and placental age acceleration (PAA), an epigenetic ageing measure derived from the difference between DNA methylation age and chronological gestational age. We also assessed whether the association varies by maternal pre-pregnancy obesity status and fetal sex. Placental data were obtained as part of the NICHD Fetal Growth Studies that involved participants from four race/ethnic groups. Placental DNA methylation age was estimated using 62 CpGs that have previously been found to have high placental age prediction accuracy. We used multivariable linear regression to test associations between maternal dyslipidemia during early gestation (i.e., high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), total cholesterol (TChol), and triglycerides) and PAA adjusting for fetal sex and socio-demographic factors. Among normal-weight women, low HDLc, compared to high HDLc, was associated with 0.82 (95% CI: 0.00, 1.64) weeks higher PAA. Among women with female neonates, low HDLc, compared to high HDLc, was associated with 1.20 (95% CI: 0.17, 2.24) weeks higher PAA. High TChol was associated with 1.28 (95% CI: 0.12, 2.45) weeks higher PAA among Whites. In all, the study found that maternal dyslipidemia due to low HDLc was associated with accelerated epigenetic ageing of the placenta among mothers with normal pre-pregnancy weight and a female fetus.

Introduction: Vitamin D has pleiotropic functions that regulate fetal growth and development. We investigated associations of common placental genetic variations in vitamin D metabolism with birthweight., Methods: The study was conducted among participants (506 maternal-infant pairs) of a pregnancy cohort study. Data were collected using interviewer-administered questionnaires and post-delivery medical record abstraction. DNA, extracted from placental samples collected at delivery, was genotyped for eight single nucleotide polymorphisms (SNPs) in five vitamin D metabolism genes (CUBN, LRP2, VDR, GC, and CYP2R1). Linear and logistic regression models were used to evaluate associations of SNPs with birthweight and risk of low birthweight, respectively. Effect modification of associations by infant sex was examined using stratified analyses and interaction terms in regression models., Results: Mean (standard-deviation) birthweight among all, male, and female infants was 3482.1 (549.9), 3544.6 (579.0) and 3419.2 (512.5) grams, respectively. Each copy of the minor allele of rs2282679 (GC) was associated with a 68.6 g (95%CI:3.1134.7 g) increase in birthweight overall. Sex-specific associations were observed for SNP rs4667591 (LRP2) (p-value for interaction < 0.001). Each copy of the minor allele of rs4667591 was associated with a 124.7 g (95%CI:20.1229.0 g) increase in birthweight among female infants, and a suggested 81.6 g decrease in birthweight among male infants (95%CI:-183.7,20.5 g)., Discussion: Our study identified overall and sex-specific associations between placental genetic variations in vitamin D metabolism and birthweight. If confirmed by larger replication studies, observed associations may provide insight into mechanistic underpinnings of the relationships between placental vitamin D metabolism and birth size., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To examine the association of fetal/placental DNA copy number variants (CNVs) with pathologic placental lesions (PPLs) in pregnancies complicated by stillbirth. Design: A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network case–control study. Setting: Multicenter, 59 hospitals in five geographical regions in the USA. Population 387 stillbirth cases (2006–2008). Methods: Using standard definitions, PPLs were categorised by type including maternal vascular, fetal vascular, inflammatory and immune/idiopathic lesions. Single‐nucleotide polymorphism array detected CNVs of at least 500 kb. CNVs were classified into two groups: normal, defined as no CNV >500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. Main outcome measures: The proportions of abnormal CNVs and normal CNVs compared between stillbirth cases with and without PPLs using the Wald Chi‐square test. Results: Of 387 stillborn fetuses, 327 (84.5%) had maternal vascular PPLs and 60 (15.6%) had abnormal CNVs. Maternal vascular PPLs were more common in stillborn fetuses with abnormal CNVs than in those with normal CNVs (81.7% versus 64.2%; P = 0.008). The proportions of fetal vascular, maternal/fetal inflammatory and immune/idiopathic PPLs were similar among stillborn fetuses with abnormal CNVs and those with normal CNVs. Pathogenic CNVs in stillborn fetuses with maternal vascular PPLs spanned several known genes. Conclusions: Abnormal placental/fetal CNVs were associated with maternal vascular PPLs in stillbirth cases. The findings may provide insight into the mechanisms of specific genetic abnormalities associated with placental dysfunction and stillbirth. [ABSTRACT FROM AUTHOR]

Abnormal birthweight is associated with increased risk for cardiometabolic diseases in later life. Although the placenta is critical to fetal development and later life health, it has not been integrated into largescale functional genomics initiatives, and mechanisms of birthweight-associated variants identified by genome wide association studies (GWAS) are unclear. The goal of this study is to provide functional mechanistic insight into the causal pathway from a genetic variant to birthweight by integrating placental methylation and gene expression with established GWAS loci for birthweight. We identify placental DNA methylation and gene expression targets for several birthweight GWAS loci. The target genes are broadly enriched in cardiometabolic, immune response, and hormonal pathways. We find that methylation causally influences WNT3A, CTDNEP1, and RANBP2 expression in placenta. Multi-trait colocalization identifies PLEKHA1, FES, CTDNEP1, and PRMT7 as likely functional effector genes. These findings reveal candidate functional pathways that underpin the genetic regulation of birthweight via placental epigenetic and transcriptomic mechanisms. Clinical trial registration; ClinicalTrials.gov, NCT00912132. The placenta plays key roles in fetal development and subsequent health. Here, the authors integrate placental methylation and transcriptome data with genetic loci associated with birthweight to identify functional genes underpinning fetal growth regulation. [ABSTRACT FROM AUTHOR]

Background: Abruptio placentae is a complex multifactorial disease that is associated with maternal and neonatal death and morbidity. Abruptio placentae's high recurrence rate, high prevalence of heritable thrombophilia among women with abruptio placentae, and aggregation of cases in families of women with the disease support the possibility of a genetic predisposition. Previous genome-wide and candidate gene association studies have identified single nucleotide polymorphisms in mitochondrial biogenesis and oxidative phosphorylation genes that potentially are associated with abruptio placentae risk. Perturbations in mitochondrial biogenesis and oxidative phosphorylation, which results in mitochondrial dysfunction, can lead to the impairment of differentiation and invasion of the trophoblast and to several obstetrics complications that include abruptio placentae.Objective: The purpose of this study was to determine whether the results of a candidate genetic association study that indicated a link between DNA variants (implicated in mitochondrial biogenesis and oxidative phosphorylation) and abruptio placentae could be replicated.Study Design: The study was conducted among participants (507 abruptio placentae cases and 1090 control subjects) of the Placental Abruption Genetic Epidemiology study. Weighted genetic risk scores were calculated with the use of abruptio placentae risk-increasing alleles of 11 single nucleotide polymorphisms in 9 mitochondrial biogenesis and oxidative phosphorylation genes (CAMK2B, NR1H3, PPARG, PRKCA, THRB, COX5A, NDUFA10, NDUFA12, and NDUFC2), which previously was reported in the Peruvian Abruptio Placentae Epidemiology study, a study with similar design and study population to the Placental Abruption Genetic Epidemiology study. Logistic regression models were fit to examine associations of weighted genetic risk scores (quartile 1, <25th percentile; quartile 2, 25-50th percentile; quartile 3, 50-70th percentile, and quartile 4, >75th percentile) with risk of abruptio placentae, adjusted for population admixture (the first 4 principal components), maternal age, infant sex, and preeclampsia. The weighted genetic risk score was also modeled as a continuous predictor. To assess potential effect modification, analyses were repeated among strata that were defined by preeclampsia status, maternal age (≥35 vs 18-34 years), and infant sex.Results: Abruptio placentae cases were more likely to have preeclampsia, shorter gestational age, and lower infant birthweight. Participants in quartile 2 (score, 12.6-13.8), quartile 3 (score, 13.9-15.0) and quartile 4 (score, ≥15.1) had a genetic risk score of 1.45-fold (95% confidence interval, 1.04-2.02; P=.03), a 1.42-fold (95% confidence interval, 1.02-1.98; P=.04), and a 1.75-fold (95% confidence interval, 1.27-2.42; P=7.0E-04) higher odds of abruptio placentae, respectively, compared with those in quartile 1 (score,<12.6; P-for trend=.0003). The risk of abruptio placentae was 1.12-fold (95% confidence interval, 1.05-1.19; P=3.0×1004) higher per 1-unit increase in the score. Among women with preeclampsia, those in quartile 4 had a 3.92-fold (95% confidence interval, 1.48-10.36; P=.01) higher odds of abruptio placentae compared with women in quartile 1. Among normotensive women, women in quartile 4 had a 1.57-fold (95% confidence interval, 1.11-2.21; P=.01) higher odds of abruptio placentae compared with those in quartile 1 (P-for interaction=.12). We did not observe differences in associations among strata defined by maternal age or infant sex.Conclusion: In this study, we replicated previous findings and provide strong evidence for DNA variants that encode for genes that are involved in mitochondrial biogenesis and oxidative phosphorylation pathways, which confers risk for abruptio placentae. These results shed light on the mechanisms that implicate DNA variants that encode for proteins in mitochondrial function that are responsible for abruptio placentae risk. Therapeutic efforts to reduce risk of abruptio placentae can be enhanced by improved biologic understanding of maternal mitochondrial biogenesis/oxidative phosphorylation pathways and identification of women who would be at high risk for abruptio placentae. [ABSTRACT FROM AUTHOR]