Genetic regulation of the placental transcriptome underlies birth weight and risk of childhood obesity.
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ABSTRACT:
SUBMITTER: Peng S
PROVIDER: S-EPMC6329610 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC7794220 | biostudies-literature
Project description:Few studies have investigated the association between the full range of birth weight and the risk of childhood obesity in high-, middle- and low-income countries. The aim of the present study is to assess the association between different levels of birth weight and the risk of obesity among children aged 9-11 years in 12 countries.A multinational, cross-sectional study of 5141 children aged 9-11 years was conducted in 12 countries. Height and weight were obtained using standardized methods. Time spent in moderate-to-vigorous physical activity (MVPA), sedentary and sleeping were objectively measured using 24-h, waist-worn accelerometer (Actigraph GT3X+) monitored for 7 days. Birth weight and other factors (regions, parental education, maternal history of gestational diabetes, children age, gender, breast feeding, gestational age, unhealthy diet scores and healthy diet scores) were collected by parental and children's questionnaires. Multilevel modeling was used to account for the nested nature of the data.The overall prevalence of obesity (BMI z-score>+2 s.d.) was 15.4% for boys and 10.0% for girls. There was a positive association between birth weight and BMI z-scores. The multivariable-adjusted odds ratios (ORs) of childhood obesity were significantly higher among children whose birth weights were 3500-3999 g (OR 1.45; 95% confidence interval (CI): 1.10-1.92), and >4000 g (OR 2.08; 95% CI: 1.47-2.93), compared with the reference group (2500-2999 g). The positive association between birth weight and the odds of childhood obesity was seen in girls, whereas a U-shaped association appeared in boys.High levels of birth weight, defined as birth weight ⩾3500 g, were associated with increased odds of obesity among 9-11-year-old children in 12 countries. However, sex differences in the association between birth weight and the risk of obesity need to be considered when planning interventions to reduce childhood obesity.
| S-EPMC4850624 | biostudies-other
Project description:BackgroundThere are both genetic and environmental factors which contribute to a child's chances of being obese. When low birth weight (LBW) has been specifically evaluated relative to its association with childhood obesity, the results have produced conflicting findings. This study aims to describe the relationship between birth weight and childhood obesity and investigate the influence that residence and household wealth has on this relationship.MethodsI performed a secondary analysis on the 2013 Riskesdas (or Basic Health Research), a cross-sectional, nationally representative survey of the Indonesian population. Height, weight, information regarding child's birth weight, and basic characteristics of the study population were collected from parents with children aged 0 to 5 years (n = 63,237) in 2013. The exposure was child's birth weight and the outcomes were child's current weight, BMI z-score, and obesity. Data were analyzed by using multiple linear regression and multiple logistic regression.ResultsI found a significant increase in the weight, BMI z-score, and risk of childhood obesity to be associated with LBW. LBW children in rural area were associated with higher BMI z-score (mean ± standard error: 1.44 ± 0.02) and higher odds (odds ratio (95% confidence interval): 7.46 (6.77-8.23)) of obesity than those in urban area. LBW children from low class families were associated with higher BMI z-score (1.79 ± 0.04) and had higher odds (14.79 (12.47-17.54)) of obesity than those from middle class and wealthy families.ConclusionsEffective prevention and intervention to childhood obesity as early as possible are imperative. As far as this study was concerned, efforts, policies, and targets are required to reduce the prevalence of LBW. Children born of LBW, who live in a rural area and from low income families, should be emphatically intervened as early as possible.
| S-EPMC8111737 | biostudies-literature
Project description:Dynamic changes in body weight have long been recognized as important indicators of risk for human health. Many population-based observational studies have shown that rapid weight gain during infancy, including a catch-up growth phenomenon or adiposity rebound in early childhood, predisposes a person to the development of obesity, type 2 diabetes, and cardiovascular diseases later in life. However, a consensus has not been established regarding which period of weight gain contributes to future risks. This review evaluates recent evidence on the relationship between early rapid growth and future obesity and cardiometabolic risk, with a focus on the differential significance of rapid weight gain in infancy and early childhood. Although there is a need for attention to childhood growth during early infancy before 1 yr of age as it may be related to future obesity, emerging evidence strongly suggests that toddlers showing an increase in body mass index (BMI) before 3 yr of age, a period normally characterized by decreased BMI, are prone to developing later cardiometabolic risk.
| S-EPMC7534524 | biostudies-literature
Project description:INTRODUCTION:Preterm birth (PTB) and in-utero inflammation are recognized risk factors of neurodevelopmental disabilities (NDDs); however, their combined role in NDDs is unknown. We examined the independent and joint association of PTB and placental histological findings with the childhood risk of NDDs (overall and by subgroups including autism spectrum disorder (ASD) and ADHD). METHODS:We analyzed data from the Boston Birth Cohort, where mother-infant pairs were enrolled at birth and followed from birth onwards. Birth outcomes, placental pathology and NDDs were obtained from electronic medical records. Placental pathology was categorized using a standardized classification system proposed by the Amsterdam Placental Workshop Group. RESULTS:PTB (all, including spontaneous, medically indicated) was an independent risk factor for NDDs. Placental histological chorioamnionitis (CA) and PTB additively increased the odds of NDDs (aOR: 2.16, 95% CI: 1.37, 3.39), as well as ADHD (aOR: 2.75, 95% CI: 1.55, 4.90), other developmental disabilities (aOR: 1.96, 95% CI: 1.18, 3.25) and possibly ASD (aOR: 2.31, 95% CI: 0.99, 5.39). The above associations were more pronounced in spontaneous than medically indicated PTB. PTB alone in the absence of CA only had a moderate association with ASD and ADHD. Placental maternal vascular malperfusion alone or in combination with PTB was not associated with the risk of NDDs. DISCUSSION:Our study provided new insights on PTB and NDDs by further considering preterm subtypes and placental histology. We revealed that children of spontaneous PTB along with histological CA were at the highest risk for a spectrum of NDDs.
| S-EPMC6727987 | biostudies-literature
Project description:Heavy metal exposures, such as cadmium, can have negative effects on infant birth weight (BW)-among other developmental outcomes-with placental dysfunction potentially playing a role in these effects. In this study, we examined how differential placental expression of long non-coding RNAs (lncRNAs) may be associated with cadmium levels in placenta and whether differences in the expression of those lncRNAs were associated with fetal growth. In the Rhode Island Child Health Study, we used data from Illumina HiSeq whole transcriptome RNA sequencing (n = 199) to examine association between lncRNA expression and measures of infant BW as well as placental cadmium concentrations controlled for appropriate covariates. Of the 1191 lncRNAs sequenced, 46 demonstrated associations (q < 0.05) with BW in models controlling for infant sex, maternal age, BMI, maternal education, and smoking during pregnancy. Furthermore, four of these transcripts were associated with placental cadmium concentrations, with MIR22HG and ERVH48-1 demonstrating increases in expression associated with increasing cadmium exposure and elevated odds of small for gestational age birth, while AC114763.2 and LINC02595 demonstrated reduced expression associated with cadmium, but elevated odds of large for gestational age birth with increasing expression. We identified relationships between lncRNA expression with both placental cadmium concentrations and BW. This study provides evidence that disrupted placental expression of lncRNAs may be a part of cadmium's mechanisms of reproductive toxicity.
| S-EPMC7211362 | biostudies-literature
Project description:The quality of the intrauterine environment, in which the placenta plays a critical role, affects birth outcomes and lifelong health. The effect of metal contaminants on the growth and functioning of the placenta have not been widely reported but may provide insights into how metal exposures lead to these outcomes. We examined relationships between placental concentrations of cadmium (Cd), arsenic (As), mercury (Hg) and lead (Pb) and measures of placental growth and functioning (placental weight, placental efficiency (the log ratio of placental weight and birth weight), chorionic disc area and disc eccentricity) as part of the New Hampshire Birth Cohort Study (N?=?1159). We additionally examined whether these associations were modified by placental concentrations of essential elements zinc (Zn) and selenium (Se). Associations were evaluated using generalized linear models. Multivariable-adjusted differences in placental weight were -?7.81?g (95% CI: -15.42, -2.48) with every ng/g increase in the Cd concentration of placenta (p-Value?=?0.0009). Greater decrements in placental weight and efficiency associated with placental Cd were observed for females. For placentae with below median Zn and Se concentrations, decrements in placental weight were -?8.81?g (95% CI: -16.85, -0.76) and -?13.20?g (95% CI: -20.70, -5.70) respectively. The Cd concentration of placenta was also associated with reductions in placental efficiency both overall, and in Zn- and Se-stratified models. No appreciable differences were observed with other elements (As, Hg or Pb) and with other placental measures (chorionic disc area and disc eccentricity). In structural equation models, placental weight was a mediator in the relation between placental Cd concentration and reduced birth weight. Our findings suggest a role of interacting essential and contaminant elements on birth weight that may be mediated by changes in the growth and function of the placenta.
| S-EPMC6475117 | biostudies-literature
Project description:BACKGROUND: It is believed that the main factors of low prenatal growth in mammals are genetic and environmental. We used isogenic mice maintained in standard conditions to analyze how natural non-genetic microsomia (low birth weight) is produced in inbred mice and its long term effect on health. To better understand the molecular basis of non-genetic microsomia, we undertook transcriptome profiling of both male and female livers from small and normal size mice at birth. RESULTS: Naturally occurring neonatal microsomia was defined as a gender-specific weanling weight under the 10th percentile of the colony. Birth weight variation was similar in inbred and outbred lines. Mice were phenotyped by weight, size, blood pressure, organ size, their response to a glucose challenge, and survival rates. Regardless of diet, adult mice born with microsomia showed a significantly lower body weight and size, and differences in the weight of several organs of microsomic adult mice compared to normal birth weight adults were found. After a high-fat diet, microsomic mice were less prone to obesity, showing a better glucose tolerance and lower blood pressure. Through a transcriptome analysis, we detected a different pattern of mRNA transcription in the liver at birth comparing male vs female and microsomic vs normal mice, noting some modifications in epigenetic regulatory genes in females and modifications in some growth factor genes in males. Finally, using embryo transfer of embryos of different quality and age, we identified a putative preimplantation origin of this non-genetic microsomia. CONCLUSIONS: (1) neonatal microsomia is not always a risk factor for adult metabolic syndrome, (2) neonatal non-genetic microsomia displays changes in the expression of important epigenetic genes and changes in liver mRNA transcription profile at birth, exaggerating sexual dimorphism, and (3) random preimplantation phenotypic variability could partially explain body birth weight variation in isogenic lines.
| S-EPMC4229907 | biostudies-other
Project description:Low birth-weight has been associated with depression and related outcomes in adults, and with problem behaviours in children. This study aimed to examine the association between low birth-weight for gestation and depressive symptoms in children and adolescents and to examine whether the relationship is moderated by genetic risk for depression. An epidemiological, genetically sensitive design was used including 2,046 twins aged 8-17 years (1,023 families). Data were obtained by parental report and analysed using regression analysis. A small but significant association between birth-weight for gestation and early depressive symptoms was observed. The unit increase in depressive symptoms per unit decrease in birth-weight for gestation was greater for individuals at genetic or familial risk for depression. For low birth-weight children, genetic risk for depression moderated the influence of birth-weight for gestation in predicting early depressive symptoms. Birth-weight for gestation is moderated by genetic and familial risk for depression in influencing early depression symptoms. These observations have clinical implications in that the impact of being small for gestational age on depressive symptoms is greater in children at familial/genetic risk although the association between birth weight and depression does not imply causality.
| S-EPMC1705530 | biostudies-other
Project description:The importance of imprinted genes in regulating feto-placental development has been long established. However, a comprehensive assessment of the role of placental imprinted gene expression on fetal growth has yet to be conducted. In this study, we examined the association between the placental expression of 108 established and putative imprinted genes and birth weight in 677 term pregnancies, oversampled for small for gestational age (SGA) and large for gestational age (LGA) infants. Using adjusted multinomial regression analyses, a 2-fold increase in the expression of 9 imprinted genes was positively associated with LGA status: BLCAP [odds ratio (OR) = 3.78, 95% confidence interval (CI): 1.83, 7.82], DLK1 [OR = 1.63, 95% CI: 1.27, 2.09], H19 [OR = 2.79, 95% CI: 1.77, 4.42], IGF2 [OR = 1.43, 95% CI:1.31, 2.40], MEG3 [OR = 1.42, 95% CI: 1.19, 1.71], MEST [OR = 4.78, 95% CI: 2.64, 8.65], NNAT [OR = 1.40, 95% CI: 1.05, 1.86], NDN [OR = 2.52, 95% CI: 1.72, 3.68], and PLAGL1 [OR = 1.85, 95% CI: 1.40, 2.44]. For SGA status, a 2-fold increase in MEST expression was associated with decreased risk [OR = 0.31, 95% CI: 0.17, 0.58], while a 2-fold increase in NNAT expression was associated with increased risk [OR = 1.52, 95% CI: 1.1, 2.1]. Following a factor analysis, all genes significantly associated with SGA or LGA status loaded onto 2 of the 8 gene-sets underlying the variability in the dataset. Our comprehensive placental profiling of imprinted genes in a large birth cohort supports the importance of these genes for fetal growth. Given that abnormal birth weight is implicated in numerous diseases and developmental abnormalities, the expression pattern of placental imprinted genes has the potential to be developed as a novel biomarker for postnatal health outcomes.
| S-EPMC4623427 | biostudies-literature