Genetic and in utero environmental contributions to DNA methylation variation in placenta.

Genetic and prenatal environmental factors shape fetal development and cardiometabolic health in later life. A key target of genetic and prenatal environmental factors is the epigenome of the placenta, an organ that is implicated in fetal growth and diseases in later life. This study had two aims: (1) to identify and functionally characterize placental variably methylated regions (VMRs), which are regions in the epigenome with high inter-individual methylation variability; and (2) to investigate the contributions of fetal genetic loci and 12 prenatal environmental factors (maternal cardiometabolic-,psychosocial-, demographic- and obstetric-related) on methylation at each VMR. Akaike's information criterion was used to select the best model out of four models [prenatal environment only, genotype only, additive effect of genotype and prenatal environment (G + E), and their interaction effect (G × E)]. We identified 5850 VMRs in placenta. Methylation at 70% of VMRs was best explained by G × E, followed by genotype only (17.7%), and G + E (12.3%). Prenatal environment alone best explained only 0.03% of VMRs. We observed that 95.4% of G × E models and 93.9% of G + E models included maternal age, parity, delivery mode, maternal depression or gestational weight gain. VMR methylation sites and their regulatory genetic variants were enriched (P < 0.05) for genomic regions that have known links with regulatory functions and complex traits. This study provided a genome-wide catalog of VMRs in placenta and highlighted that variation in placental DNA methylation at loci with regulatory and trait relevance is best elucidated by integrating genetic and prenatal environmental factors, and rarely by environmental factors alone.

Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy.

Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10-8; log10BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10-8), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester. Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.

Admixture mapping identifies African and Amerindigenous local ancestry loci associated with fetal growth.

Fetal growth is an important determinant of cardiometabolic disease risk during childhood and adulthood. The genetic architecture of fetal growth remains largely understudied in ancestrally diverse populations. We conducted genome-wide admixture mapping scan and analysis of genetic ancestry among Hispanic American, African American, European American, and Asian American pregnant women to identify genetic loci associated with fetal growth measures across 13-40 weeks gestation. Fetal growth measures were associated with genome-wide average African, European, Amerindigenous and East Asian ancestry proportions (P ranged from10-3 to 4.8 × 10-2). Admixture mapping analysis identified ten African ancestry loci and three Amerindigenous ancestry loci significantly associated with fetal growth measures at Bonferroni-corrected levels of significance (P ranged from 2.18 × 10-8 to 3.71 × 10-6). At the chr2q23.3-24.2 locus in which higher African ancestry was associated with long bone (femur and humerus) lengths, the T allele of rs13030825 (GALNT13) was associated with longer humerus length in African Americans (ß = 0.44, P = 6.25 × 10-6 at week 27; ß = 0.39, P = 7.72 × 10-5 at week 40). The rs13030825 SNP accounted for most of the admixture association at the chr2q23.3-24.2 locus and has substantial allele frequency difference between African and European reference samples (FST = 0.55, P = 0.03). Regulatory annotation shows that rs13030825 overlaps with the serum response factor (SRF) transcription factor previously implicated in postnatal bone development of mice. Overall, we identified ancestry-related maternal genetic loci that influence fetal growth, shedding light on molecular pathways that regulate fetal growth and potential effects on health across the lifespan.Clinical trials registration ClinicalTrials.gov, NCT00912132.

Air pollution exposure and risk of adverse obstetric and neonatal outcomes among women with type 1 diabetes.

AIMS/HYPOTHESIS: Women with type 1 diabetes have increased risk for poor obstetric outcomes. Prenatal air pollution exposure is also associated with adverse outcomes for women and infants. We examined whether women with type 1 diabetes are more vulnerable than other women to pollution-associated risks during pregnancy. METHODS: In singleton deliveries from the Consortium on Safe Labor (2002-2008), obstetric and neonatal outcomes were compared for women with type 1 diabetes (n = 507) and women without autoimmune disease (n = 204,384). Preconception, trimester, and whole pregnancy average air pollutant exposure (ozone (O3), carbon monoxide (CO), particulate matter >10 µm (PM10), PM > 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen oxides (NOx)) were estimated using modified Community Multiscale Air Quality models. Poisson regression models with diabetes*pollutant interaction terms estimated relative risks and 95% confidence intervals for adverse outcomes, adjusted for maternal characteristics and geographic region. RESULTS: For whole pregnancy exposure to SO2, women with type 1 diabetes had 15% increased risk (RR:1.15 95%CI:1.01,1.31) and women without autoimmune disease had 5% increased risk (RR:1.05 95%CI:1.05,1.06) for small for gestational age birth (pinteraction = 0.09). Additionally, whole pregnancy O3 exposure was associated with 10% increased risk (RR:1.10 95%CI:1.02,1.17) among women with type 1 diabetes and 2% increased risk (RR:1.02 95%CI:1.00,1.04) among women without autoimmune disease for perinatal mortality (pinteraction = 0.08). Similar patterns were observed between PM2.5 exposure and spontaneous preterm birth. CONCLUSIONS: Pregnant women with type 1 diabetes may be at greater risk for adverse outcomes when exposed to air pollution than women without autoimmune disease.

Acute ambient air pollution exposure and placental Doppler results in the NICHD fetal growth studies - Singleton cohort.

BACKGROUND: Increased placental vascular resistance is a proposed mechanism by which air pollution exposure during pregnancy lowers birth weight and increases pregnancy-induced hypertensive disorders. OBJECTIVE: To examine the impact of acute air pollution exposure during pregnancy on uterine and umbilical artery Doppler indicators of placental vascular resistance. METHODS: After a first ultrasound to confirm gestational age, 2562 pregnant women recruited in 12 clinics throughout the United States underwent up to five standardized ultrasounds with Doppler measurements. Exposures to 11 air pollutants were estimated for the hour of ultrasound and each of the 2 h prior to ultrasound at the clinics using the National Air Quality Forecast Capability reanalysis products. We used mixed logistic regression to study the longitudinal odds ratio (OR) of any, uni- or bi-lateral systolic and diastolic uterine artery notching compared to no notching and the longitudinal OR of abnormal end diastolic flow of the umbilical artery compared to forward flow. Uterine and umbilical artery resistance indexes were studied using linear mixed models. RESULTS: Each inter-quartile range (IQR) increase of particulate matter < 2.5 µm, nitrate, ammonium, primary organic matter (POM) and nitrogen dioxide during the hour of ultrasound was associated with a decreased risk of unilateral systolic notch and with increased resistance index of the left uterine artery. For the umbilical artery, each IQR increase in ozone was associated with decreased resistance index (b: -0.26, 95 % CI: -0.52, -0.01) and with a decreased risk of abnormal end diastolic flow (OR: 0.36, 95 % CI: 0.14, 0.94); while each IQR increase of elemental carbon and POM was associated with increased risk of abnormal end diastolic flow (OR: 1.47, 95 % CI: 1.02, 2.13 and OR: 1.67, 95 % CI: 1.17, 2.39, respectively). DISCUSSION: Our results suggest acute air pollution exposure may influence placental vascular resistance.

Placental DNA methylation changes associated with maternal prepregnancy BMI and gestational weight gain.

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/m2 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.

Ambient temperature and stillbirth: Risks associated with chronic extreme temperature and acute temperature change.

BACKGROUND: Ambient temperature events are increasing in frequency and intensity. Our prior work in a U.S. nationwide study suggests a strong association between both chronic and acute temperature extremes and stillbirth risk. OBJECTIVE: We attempted to replicate our prior study by assessing stillbirth risk associated with average whole-pregnancy temperatures and acute ambient temperature changes in a low-risk U.S. METHODS: Singleton deliveries in the NICHD Consecutive Pregnancies Study (Utah, 2002-2010; n = 112,005) were identified using electronic medical records. Ambient temperature was derived from the Weather Research and Forecasting model. Binary logistic regression determined the adjusted odds ratio (aOR) and 95% confidence interval (95% CI) for stillbirth associated with whole-pregnancy exposure to extreme cold (<10th percentile) and hot (>90th percentile) versus moderate (10th-90th percentiles) average temperature, adjusting for maternal demographics, season of conception, hypertensive disorders of pregnancy, and gestational diabetes. In a case-crossover analysis, we estimated the stillbirth aOR and 95% CI for each 1° Celsius increase during the week prior to delivery using conditional logistic regression. In both models, we adjusted for relative humidity, ozone, and fine particulates. RESULTS: We observed 500 stillbirth cases among 498 mothers. Compared to moderate temperatures, whole-pregnancy exposure to extreme cold (aOR: 4.42, 95% CI:3.43, 5.69) and hot (aOR: 5.06, 95% CI: 3.34, 7.68) temperatures were associated with stillbirth risk. Case-crossover models observed a 7% increased odds (95% CI: 1.04, 1.10) associated with each 1° Celsius increase during the week prior to delivery. DISCUSSION: Both chronic and acute ambient temperature were associated with odds of stillbirth in this low-risk population, similar to our prior nationwide findings. Future increases in temperature extremes are likely and the observed risk in a low-risk population suggests this association merits attention.

Obstetric and neonatal complications among women with autoimmune disease.

BACKGROUND: The impact of autoimmune diseases on pregnancy remains understudied on a population level. Examination of obstetric and neonatal outcomes among women with autoimmune disease and their infants can provide important insights for clinical management. METHODS: Autoimmune diseases and outcomes were identified using medical records. Cesarean delivery, preterm birth, preeclampsia, small for gestational age (SGA), neonatal intensive care (NICU) admission, neonatal respiratory distress syndrome (RDS), and perinatal mortality risk was assessed. Poisson regression with robust standard errors estimated relative risks (RR) and 95% confidence intervals (95% CI) with adjustment for maternal characteristics and other chronic conditions. RESULTS: Women with T1DM were at increased risk for nearly all outcomes including RDS (RR: 3.62; 95% CI: 2.84, 4.62), perinatal mortality (RR: 2.35; 95% CI: 1.12, 4.91), cesarean delivery (RR: 2.16; 95% CI: 2.02, 2.32) and preterm birth (RR: 3.52; 95% CI: 3.17, 3.91). Women with SLE also had higher risk for preterm delivery (RR: 2.90; 95% CI: 2.42, 3.48) and RDS (RR:2.99; 95% CI: 1.99, 4.51) as did women with Crohn's (cesarean delivery RR:1.31, 95% CI: 1.08, 1.60; preterm delivery RR: 1.84, 95% CI: 1.37, 2.49. RA increased risk for SGA (RR:1.66; 95% CI: 1.08, 2.55). CONCLUSION(S): Despite the heterogeneity in autoimmune diseases, we observed elevated preterm birth risk for most women with autoimmune disease. SLE and T1DM appeared to confer increased risk for a wide range of adverse outcomes.

Analyzing the impact of phthalate and DINCH exposure on fetal growth in a cohort with repeated urine collection.

BACKGROUND: Most previous studies investigating the associations between prenatal exposure to phthalates and fetal growth relied on measurements of phthalate metabolites at a single time point. They also focused on weight at birth without assessing growth over pregnancy, preventing the identification of potential periods of fetal vulnerability. We examined the associations between pregnancy urinary phthalate metabolites and fetal growth outcomes measured twice during pregnancy and at birth. METHODS: For 484 pregnant women, we assessed 13 phthalate and two 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) metabolite concentrations from two within-subject weekly pools of up to 21 urine samples (median of 18 and 34 gestational weeks, respectively). Fetal biparietal diameter, femur length, head and abdominal circumferences were measured during two routine pregnancy follow-up ultrasonographies (median 22 and 32 gestational weeks, respectively) and estimated fetal weight (EFW) was calculated. Newborn weight, length, and head circumference were measured at birth. Associations between phthalate/DINCH metabolite and growth parameters were investigated using adjusted linear regression and Bayesian kernel machine regression models. RESULTS: Detection rates were above 99 % for all phthalate/DINCH metabolites. While no association was observed with birth measurements, mono-iso-butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were positively associated with most fetal growth parameters measured at the second trimester. Specifically, MiBP was positively associated with biparietal diameter, head and abdominal circumferences, while MnBP was positively associated with EFW, head and abdominal circumferences, with stronger associations among males. Pregnancy MnBP was positively associated with biparietal diameter and femur length at third trimester. Mixture of phthalate/DINCH metabolites was positively associated with EFW at second trimester. CONCLUSIONS: In this pregnancy cohort using repeated urine samples to assess exposure, MiBP and MnBP were associated with increased fetal growth parameters. Further investigation on the effects of phthalates on child health would be relevant for expanding current knowledge on their long-term effects.

Fetal and Infancy Exposure to Phenols, Parabens, and Phthalates and Anthropometric Measurements up to 36 Months, in the Longitudinal SEPAGES Cohort.

BACKGROUND: Endocrine-disrupting chemicals may play a role in adiposity development during childhood. Until now literature in this scope suffers from methodologic limitations in exposure assessment using one or few urine samples and missing assessment during the infancy period. OBJECTIVES: We investigated the associations between early-life exposure to quickly metabolized chemicals and post-natal growth, relying on repeated within-subject urine collections over pregnancy and infancy. METHODS: We studied the associations of four phenols, four parabens, seven phthalates, and one nonphthalate plasticizer from weekly pooled urine samples collected from the mother during second and third trimesters (median 18 and 34 gestational weeks, respectively) and infant at 2 and 12 months of age, and child growth until 36 months. We relied on repeated measures of height, weight and head circumference from study visits and the child health booklet to predict growth outcomes at 3 and 36 months using the Jenss-Bayley nonlinear mixed model. We assessed associations with individual chemicals using adjusted linear regression and mixtures of chemicals using a Bayesian kernel machine regression model. RESULTS: The unipollutant analysis revealed few associations. Bisphenol S (BPS) at second trimester was positively associated with all infant growth parameters at 3 and 36 months, with similar patterns between exposure at third trimester and all infant growth parameters at 3 months. Mono-n-butyl phthalate (MnBP) at 12 months was positively associated with body mass index (BMI), weight, and head circumference at 36 months. Mixture analysis revealed positive associations between exposure at 12 months and BMI and weight at 36 months, with MnBP showing the highest effect size within the mixture. CONCLUSIONS: This study suggests that exposure in early infancy may be associated with increased weight and BMI in early childhood, which are risk factors of obesity in later life. Furthermore, this study highlighted the impact of BPS, a compound replacing bisphenol A, which has never been studied in this context. https://doi.org/10.1289/EHP13644.

Genomic study of maternal lipid traits in early pregnancy concurs with four known adult lipid loci.

BACKGROUND: Blood lipids during pregnancy are associated with cardiovascular diseases and adverse pregnancy outcomes. Genome-wide association studies (GWAS) in predominantly male European ancestry populations have identified genetic loci associated with blood lipid levels. However, the genetic architecture of blood lipids in pregnant women remains poorly understood. OBJECTIVE: Our goal was to identify genetic loci associated with blood lipid levels among pregnant women from diverse ancestry groups and to evaluate whether previously known lipid loci in predominantly European adults are transferable to pregnant women. METHODS: The trans-ancestry GWAS were conducted on serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL) and triglycerides during first trimester among pregnant women from four population groups (608 European-, 623 African-, 552 Hispanic- and 235 East Asian-Americans) recruited in the NICHD Fetal Growth Studies cohort. The four GWAS summary statistics were combined using trans-ancestry meta-analysis approaches that account for genetic heterogeneity among populations. RESULTS: Loci in CELSR2 and APOE were genome-wide significantly associated (p-value < 5×10-8) with total cholesterol and LDL levels. Loci near CETP and ABCA1 approached genome-wide significant association with HDL (p-value = 2.97×10-7 and 9.71×10-8, respectively). Less than 20% of previously known adult lipid loci were transferable to pregnant women. CONCLUSION: This trans-ancestry GWAS meta-analysis in pregnant women identified associations that concur with four known adult lipid loci. Limited replication of known lipid-loci from predominantly European study populations to pregnant women underlines the need for genomic studies of lipids in ancestrally diverse pregnant women. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00912132.

Early Pregnancy Maternal Plasma Phospholipid Saturated Fatty Acids and Fetal Growth: Findings from a Multi-Racial/Ethnic Birth Cohort in US.

Saturated fatty acids (SFAs) during pregnancy are associated with disrupted metabolic programming among offspring at birth and later growth. We examined plasma phospholipid SFAs in early pregnancy and fetal growth throughout pregnancy. We enrolled 321 pregnant women from the NICHD Fetal Growth Studies-Singleton Cohort at gestational weeks 8-13. Ultrasonogram schedules were randomly assigned to capture weekly fetal growth. We measured plasma phospholipid SFAs at early pregnancy using blood samples and modeled fetal growth trajectories across tertiles of SFAs with cubic splines using linear mixed models after full adjustment. We then compared pairwise weekly fetal growth biometrics referencing the lowest tertile in each SFA using the Wald test. We found that even-chain and very long even-chain SFAs were inversely associated, whereas odd-chain SFAs were positively associated with fetal weight and size. Compared with the lowest tertile, the highest tertile of pentadecanoic acid (15:0) had a greater fetal weight and size, starting from week 13 until late pregnancy (at week 39: 3429.89 vs. 3269.08 g for estimated fetal weight; 328.14 vs. 323.00 mm for head circumference). Our findings could inspire future interventions using an alternative high-fat diet rich in odd-chain SFAs for optimal fetal growth.

Maternal asthma in relation to infant size and body composition.

Background: Asthma affects 10% of pregnancies and may influence offspring health, including infant size and body composition, through hypoxic and inflammatory pathways. Objective: We sought to determine associations between maternal asthma and asthma phenotypes during pregnancy and infant size and body composition. Methods: The B-WELL-Mom study (2015-19) is a prospective cohort of 418 pregnant persons with and without asthma recruited in the first trimester of pregnancy from 2 US obstetric clinics. Exposures were maternal self-reported active asthma (n = 311) or no asthma (n = 107), and asthma phenotypes were classified on the bases of atopy, onset, exercise induced, control, severity, symptomology, and exacerbations. Outcomes were infant weight, length, head circumference, and skinfold measurements at birth and postnatal follow-up, as well as fat and lean mass assessed by air displacement plethysmography at birth. Adjusted multivariable linear regression examined associations of maternal asthma and asthma phenotypes with infant outcomes. Results: Offspring were born at a mean ± SD of 38 ± 2.3 weeks' gestation and were 18 ± 2.2 weeks of age at postnatal follow-up. Infants of participants with asthma had a mean ± SD fat mass of 11.0 ± 4.2%, birth weight of 3045.8 ± 604.3 g, and postnatal follow-up weight of 6696.4 ± 964.2 g, which were not different from infants of participants without asthma (respectively, ß [95% confidence interval]: -0.1 [-1.4, 1.3], -26.7 [-156.9, 103.4], and 107.5 [-117.3, 332.3]). Few associations were observed between asthma or asthma phenotypes and infant size or body composition. Conclusions: In a current obstetric cohort, maternal asthma during pregnancy was not associated with differential infant size or body composition.

Personal exposure to PM2.5 oxidative potential and its association to birth outcomes.

BACKGROUND: Prenatal exposure to fine particulate matter (PM2.5) assessed through its mass concentration has been associated with foetal growth restriction in studies based on outdoor levels. Oxidative potential of PM2.5 (OP) is an emerging metric a priori relevant to mechanisms of action of PM on health, with very limited evidence to indicate its role on birth outcomes. OBJECTIVES: We investigated the association of OP with birth outcomes and compared it with that of PM2.5 mass concentration. METHODS: 405 pregnant women from SEPAGES cohort (Grenoble area) carried PM2.5 personal dosimeters for one or two one-week periods. OP was measured using dithiothreitol (DTT) and ascorbic acid (AA) assays from the collected filters. Associations of each exposure metric with offspring weight, height, and head circumference at birth were estimated adjusting for potential confounders. RESULTS: The correlation between PM2.5 mass concentration and [Formula: see text] was 0.7. An interquartile range increase in .. was associated with reduced weight (adjusted change, -64 g, -166 to -11, p = 0.02) and height (-4 mm, -6 to -1, p = 0.01) at birth. PM2.5 mass concentration showed similar associations with weight (-53 g, -99 to -8, p = 0.02) and height (-2 mm, -5 to 0, p = 0.05). In birth height models mutually adjusted for the two exposure metrics, the association with [Formula: see text] was less attenuated than that with mass concentration, while for weight both effect sizes attenuated similarly. There was no clear evidence of associations with head circumference for any metric, nor for [Formula: see text] with any growth parameter. IMPACT: PM2.5 pregnancy exposure assessed from personal dosimeters was associated with altered foetal growth. Personal OP exposure was associated with foetal growth restrictions, specifically decreased weight and height at birth, possibly to a larger extent than PM2.5 mass concentration alone. These results support OP assessed from DTT as being a health-relevant metric. Larger scale cohort studies are recommended to support our findings.

Ancestry-Matched and Cross-Ancestry Genetic Risk Scores of Type 2 Diabetes in Pregnant Women and Fetal Growth: A Study in an Ancestrally Diverse Cohort.

Maternal genetic variants associated with offspring birth weight and adult type 2 diabetes (T2D) risk loci show some overlap. Whether T2D genetic risk influences longitudinal fetal weight and the gestational timing when these relationships begin is unknown. We investigated the associations of T2D genetic risk scores (GRS) with longitudinal fetal weight and birth weight among 1,513 pregnant women from four ancestral groups. Women had up to five ultrasonography examinations. Ancestry-matched GRS were constructed separately using 380 European- (GRSeur), 104 African- (GRSafr), and 189 East Asian- (GRSeas) related T2D loci discovered in different population groups. Among European Americans, the highest quartile GRSeur was significantly associated with 53.8 g higher fetal weight (95% CI 19.2-88.5) over the pregnancy. The associations began at gestational week 24 and continued through week 40, with a 106.8 g (95% CI 6.5-207.1) increase in birth weight. The findings were similar in analysis further adjusted for maternal glucose challenge test results. No consistent association was found using ancestry-matched or cross-ancestry GRS in non-Europeans. In conclusion, T2D genetic susceptibility may influence fetal growth starting at midsecond trimester among Europeans. Absence of similar associations in non-Europeans urges the need for further genetic T2D studies in diverse ancestries.

Sex-specific placental gene expression signatures of small for gestational age at birth.

INTRODUCTION: Small for gestational age at birth (SGA), often a consequence of placental dysfunction, is a risk factor for neonatal morbidity and later life cardiometabolic diseases. There are sex differences in placental gene expression and fetal growth. Here, we investigated sex-specific associations between gene expression in human placenta measured using RNA sequencing and SGA status using data from ethnic diverse pregnant women in the NICHD Fetal Growth Studies cohort (n = 74). METHODS: Gene expression measures were obtained using RNA-Sequencing and differential gene expression between SGA (birthweight <10th percentile) and appropriate for gestational age (AGA: ≥10th and <90th percentile) was tested separately in males (12 SGA and 27 AGA) and females (9 SGA and 26 AGA) using a weighted mean of log ratios method with adjustment for mode of delivery and ethnicity. RESULTS: At 5% false discovery rate (FDR), we identified 40 differentially expressed genes (DEGs) related to SGA status among males (95% up- and 5% down-regulated) and 314 DEGs among females (32.5% up- and 67.5% down-regulated). Seven female-specific DEGs overlapped with known imprinted genes (AXL, CYP24A1, GPR1, PLAGL1, CMTM1, DLX5, LY6D). The DEGs in males were significantly enriched for immune response and inflammation signaling pathways whereas the DEGs in females were enriched for organ development signaling pathways (FDR<0.05). Sex-combined analysis identified no additional DEGs, rather 98% of the sex-specific DEGs were no longer significant and the remaining 2% were attenuated. DISCUSSION: This study revealed sex-specific human placental gene expression changes and molecular pathways associated with SGA and underscored that unravelling the pathogenesis of SGA warrants consideration of fetal sex as a biological variable. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov, Unique identifier: NCT00912132.

Associations of maternal blood pressure-raising polygenic risk scores with fetal weight.

Maternal blood pressure (BP) is associated with variations in fetal weight, an important determinant of neonatal and adult health. However, the association of BP-raising genetic risk with fetal weight is unknown. We tested the associations of maternal BP-raising polygenic risk scores (PRS) with estimated fetal weights (EFWs) at 13, 20, 27, and 40 weeks of gestation. This study included 622 White, 637 Black, 568 Hispanic, and 238 Asian pregnant women with genotype data from the NICHD Fetal Growth Studies. PRS of systolic (SBP) and diastolic BP (DBP) were calculated for each participant based on summary statistics from a recent genome-wide association study. Linear regression models were used to compare mean EFW differences between the highest versus lowest tertile of PRS, adjusting for maternal age, education, parity, genetic principal components and fetal sex. Hispanics in the highest DBP PRS tertile, compared to those in the lowest, had 8.1 g (95% CI: -15.1, -1.1), 32.4 g (-58.4, -6.4) and 119.4 g (-218.1, -20.7) lower EFW at 20, 27 and 40 weeks, respectively. Similarly, Asians in the highest DBP PRS tertile had 137.2 g (-263.5, -10.8) lower EFW at week 40, and those in the highest tertile of SBP PRS had 3.2 g (-5.8, -0.7), 12.9 g (-23.5, -2.4), and 39.8 g (-76.9, -2.7) lower EFWs at 13, 20, and 27 weeks. The findings showed that pregnant women's genetic susceptibility to high BP contributes to reduced fetal growth, suggesting a potential future clinical application in perinatal health.

Placental multi-omics integration identifies candidate functional genes for birthweight.

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.

Recreational physical activity before and during pregnancy and placental DNA methylation-an epigenome-wide association study.

BACKGROUND: Physical activity (PA) prior to and during pregnancy may have intergenerational effects on offspring health through placental epigenetic modifications. We are unaware of epidemiologic studies on longitudinal PA and placental DNA methylation. OBJECTIVES: We evaluated the association between PA before and during pregnancy and placental DNA methylation. METHODS: Placental tissues were obtained at delivery and methylation was measured using HumanMethylation450 Beadchips for participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons among 298 participants. Using the Pregnancy Physical Activity Questionnaire, women recalled periconception PA (past 12 mo) at 8-13 wk of gestation and PA since last visit at 4 follow-up visits at 16-22, 24-29, 30-33, and 34-37 wk. We conducted linear regression for associations of PA at each visit with methylation controlling for false discovery rate (FDR). Top 100 CpGs were queried for enrichment of functional pathways using Ingenuity Pathway Analysis. RESULTS: Periconception PA was significantly associated with 1 CpG site. PA since last visit for visits 1-4 was associated with 2, 2, 8, and 0 CpGs (log fold changes ranging from -0.0319 to 0.0080, after controlling for FDR). The largest change in methylation occurred at a site in TIMP2 , which is known to encode a protein critical for vasodilation, placentation, and uterine expansion during pregnancy (log fold change: -0.05; 95% CI: -0.06, -0.03 per metabolic equivalent of task-h/wk at 30-33 wk). Most significantly enriched pathways include cardiac hypertrophy signaling, B-cell receptor signaling, and netrin signaling. Significant CpGs and enriched pathways varied by visit. CONCLUSIONS: Recreational PA in the year prior and during pregnancy was associated with placental DNA methylation. The associated CpG sites varied based on timing of PA. If replicated, the findings may inform the mechanisms underlying the impacts of PA on placenta health. This study was registered at clinicaltrials.gov as NCT00912132.

Pleiotropic genetic influence on birth weight and childhood obesity.

Childhood obesity is a global public health problem. Understanding the molecular mechanisms that underlie early origins of childhood obesity can facilitate interventions. Consistent phenotypic and genetic correlations have been found between childhood obesity traits and birth weight (a proxy for in-utero growth), suggesting shared genetic influences (pleiotropy). We aimed to (1) investigate whether there is significant shared genetic influence between birth weight and childhood obesity traits, and (2) to identify genetic loci with shared effects. Using a statistical approach that integrates summary statistics and functional annotations for paired traits, we found strong evidence of pleiotropy (P < 3.53 × 10-127) and enrichment of functional annotations (P < 1.62 × 10-39) between birth weight and childhood body mass index (BMI)/obesity. The pleiotropic loci were enriched for regulatory features in skeletal muscle, adipose and brain tissues and in cell lines derived from blood lymphocytes. At 5% false discovery rate, 6 loci were associated with birth weight and childhood BMI and 13 loci were associated with birth weight and childhood obesity. Out of these 19 loci, one locus (EBF1) was novel to childhood obesity and one locus (LMBR1L) was novel to both birth weight and childhood BMI/obesity. These findings give evidence of substantial shared genetic effects in the regulation of both fetal growth and childhood obesity.