Genetic vulnerability to DUSP22 promotor hypermethylation is involved in the relation between in utero famine exposure and schizophrenia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116380 | GEO | 2018/06/29
REPOSITORIES: GEO
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Project description:Epigenetic changes may account for the doubled risk to develop schizophrenia in individuals exposed to famine in utero. We therefore investigated DNA methylation in a unique sample of patients and healthy individuals conceived during the great famine in China. Subsequently we examined two case-control samples without famine exposure in whole blood and brain tissue. To shed light on the causality of the relation between famine exposure and DNA methylation we exposed human fibroblasts to nutritional deprivation. In the famine exposed schizophrenia patients we found significant hypermethylation of the dual specificity phosphatase 22 (DUSP22) gene promoter (Chr6:291687-293285) (N=153, p=0.01). In this sample DUSP22 methylation was also significantly higher in patients independent of famine exposure (p=0.025), suggesting that hypermethylation of DUSP22 is also more generally involved in schizophrenia risk. Similarly, DUSP22 methylation was also higher in two separate case-control sample not exposed to famine using DNA from whole blood (N=64, p=0.03) and postmortem brains (N=214, p=0.007). DUSP22 methylation showed strong genetic regulation across chromosomes by a region on chromosome 16 which was consistent with new 3D genome interaction data. The presence of a direct link between famine and DUSP22 transcription was supported by data from cultured human fibroblasts that showed increased methylation (p=0.048) and expression (p=0.019) in response to nutritional deprivation (N=10). These results highlight a first epigenetic locus that is genetically regulated across chromosomes and that is involved in the response to early life exposure to famine and that is relevant for a major psychiatric disorder.
2018-06-29 | GSE116378 | GEO
Project description:Epigenetic changes may account for the doubled risk to develop schizophrenia in individuals exposed to famine in utero. We therefore investigated DNA methylation in a unique sample of patients and healthy individuals conceived during the great famine in China. Subsequently we examined two case-control samples without famine exposure in whole blood and brain tissue. To shed light on the causality of the relation between famine exposure and DNA methylation we exposed human fibroblasts to nutritional deprivation. In the famine exposed schizophrenia patients we found significant hypermethylation of the dual specificity phosphatase 22 (DUSP22) gene promoter (Chr6:291687-293285) (N=153, p=0.01). In this sample DUSP22 methylation was also significantly higher in patients independent of famine exposure (p=0.025), suggesting that hypermethylation of DUSP22 is also more generally involved in schizophrenia risk. Similarly, DUSP22 methylation was also higher in two separate case-control sample not exposed to famine using DNA from whole blood (N=64, p=0.03) and postmortem brains (N=214, p=0.007). DUSP22 methylation showed strong genetic regulation across chromosomes by a region on chromosome 16 which was consistent with new 3D genome interaction data. The presence of a direct link between famine and DUSP22 transcription was supported by data from cultured human fibroblasts that showed increased methylation (p=0.048) and expression (p=0.019) in response to nutritional deprivation (N=10). These results highlight a first epigenetic locus that is genetically regulated across chromosomes and that is involved in the response to early life exposure to famine and that is relevant for a major psychiatric disorder.
2018-06-29 | GSE116379 | GEO
Project description:Epigenetic changes may account for the doubled risk to develop schizophrenia in individuals exposed to famine in utero. We therefore investigated DNA methylation in a unique sample of patients and healthy individuals conceived during the great famine in China. Subsequently, we examined two case-control samples without famine exposure in whole blood and brain tissue. To shed light on the causality of the relation between famine exposure and DNA methylation, we exposed human fibroblasts to nutritional deprivation. In the famine-exposed schizophrenia patients, we found significant hypermethylation of the dual specificity phosphatase 22 (DUSP22) gene promoter (Chr6:291687-293285) (N = 153, p = 0.01). In this sample, DUSP22 methylation was also significantly higher in patients independent of famine exposure (p = 0.025), suggesting that hypermethylation of DUSP22 is also more generally involved in schizophrenia risk. Similarly, DUSP22 methylation was also higher in two separate case-control samples not exposed to famine using DNA from whole blood (N = 64, p = 0.03) and postmortem brains (N = 214, p = 0.007). DUSP22 methylation showed strong genetic regulation across chromosomes by a region on chromosome 16 which was consistent with new 3D genome interaction data. The presence of a direct link between famine and DUSP22 transcription was supported by data from cultured human fibroblasts that showed increased methylation (p = 0.048) and expression (p = 0.019) in response to nutritional deprivation (N = 10). These results highlight an epigenetic locus that is genetically regulated across chromosomes and that is involved in the response to early-life exposure to famine and that is relevant for a major psychiatric disorder.
| S-EPMC6104043 | biostudies-literature
Project description:Genetic vulnerability to DUSP22 promotor hypermethylation is involved in the relation between in utero famine exposure and schizophrenia
| PRJNA478327 | ENA
Project description:Genetic vulnerability to DUSP22 promotor hypermethylation is involved in the relation between in utero famine exposure and schizophrenia (DUTCHSCZ Data Set)
| PRJNA478330 | ENA
Project description:Genetic vulnerability to DUSP22 promotor hypermethylation is involved in the relation between in utero famine exposure and schizophrenia (CHINFAM Data Set)
| PRJNA478331 | ENA
Project description:BackgroundThere is a growing body of evidence that prenatal and early childhood exposure to arsenic from drinking water can have serious long-term health implications.ObjectivesOur goal was to understand the potential long-term health and disease risks associated with in utero and early life exposure to arsenic, as well as to examine parallels between findings from epidemiological studies with those from experimental animal models.MethodsWe examined the current literature and identified relevant studies through PubMed by using combinations of the search terms "arsenic", "in utero", "transplacental", "prenatal" and "fetal".DiscussionEcological studies have indicated associations between in utero and/or early life exposure to arsenic at high levels and increases in mortality from cancer, cardiovascular disease and respiratory disease. Additional data from epidemiologic studies suggest intermediate effects in early life that are related to risk of these and other outcomes in adulthood. Experimental animal studies largely support studies in humans, with strong evidence of transplacental carcinogenesis, atherosclerosis and respiratory disease, as well as insight into potential underlying mechanisms of arsenic's health effects.ConclusionsAs millions worldwide are exposed to arsenic and evidence continues to support a role for in utero arsenic exposure in the development of a range of later life diseases, there is a need for more prospective studies examining arsenic's relation to early indicators of disease and at lower exposure levels.
| S-EPMC3783578 | biostudies-literature
Project description:The age of pubertal onset for girls has declined over past decades. Research suggests that endocrine disrupting chemicals (EDCs) may play a role but exposure at multiple stages of development has not been considered. We examined in utero and peripubertal exposure to bisphenol-A (BPA) and phthalates in relation to serum hormones and sexual maturation among females in a Mexico City birth cohort. We measured phthalate metabolite and BPA concentrations in urine collected from mothers during their third trimester (n=116) and from their female children at ages 8-13 years (n=129). Among girls, we measured concurrent serum hormone concentrations, Tanner stages for breast and pubic hair development, and collected information on menarche onset. We used linear and logistic regression to model associations between in utero and peripubertal measures of exposure with hormones and sexual maturation, respectively, controlling for covariates. An interquartile range (IQR) increase in in utero urinary mono-2-ethylhexyl phthalate (MEHP) was positively associated with 29% (95% CI: 9.2-52.6%) higher dehydroepiandrosterone sulfate (DHEA-S), an early indicator of adrenarche, and 5.3 (95% CI: 1.13-24.9) times higher odds of a Tanner stage >1 for pubic hair development. Similar relationships were observed with other in utero but not peripubertal di-2-ethylhexyl phthalate (DEHP) metabolites. IQR increases in in utero monobenzyl phthalate (MBzP) and monoethyl phthalate (MEP) were associated with 29% and 25% higher serum testosterone concentrations (95% CI: 4.3-59.3; 2.1-54.1), respectively. In addition, we observed suggestive associations between in utero and peripubertal MEP concentrations and increased odds of having undergone menarche, and between peripubertal MnBP concentrations and increased odds of having a Tanner stage >1 for both breast and pubic hair development. BPA was not associated with in utero or peripubertal serum hormones or sexual maturation. Our findings suggest in utero phthalate exposure may impact hormone concentrations during peripubescence and timing of sexual maturation. Efforts to control phthalate exposure during pregnancy should be of high priority.
| S-EPMC4262586 | biostudies-literature
Project description:BackgroundThe associations of individual antiepileptic drugs (AEDs) with pregnancy duration and size at birth, and potential dose relations, are not well characterized.MethodsThis cohort study used nationwide Swedish register data (1996-2013). Adjusting for smoking, epilepsy and other AED indications, we used linear and quantile regression to explore associations with pregnancy duration, and birth weight, length, and head circumference (the last three operationalized as z-scores). We used logistic regression for preterm delivery, small for gestational age, and microcephaly. Lamotrigine was the reference drug.Results6,720 infants were exposed to AEDs in utero; AED exposure increased over the study period. Relative to lamotrigine-exposed infants, carbamazepine-exposed infants were born, on average, 1.3 days earlier (mean [95% confidence interval]: -1.3 [-2.3 to -0.3]); were 0.1 standard deviations (SDs) lighter (-0.1 [-0.2 to 0.0]); and had a head circumference that was 0.2 SDs smaller (-0.2 [-0.3 to -0.1]). Pregabalin-exposed infants were born, on average, 1.1 days earlier (-1.1 [-3.0 to 0.8]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had the same head circumference as lamotrigine-exposed infants. Levetiracetam-exposed infants were born, on average, 0.5 days earlier (-0.5 [-2.6 to 1.6]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had a head circumference 0.1 SDs smaller (-0.1 [-0.3 to 0.1]). Valproic acid-exposed infants had, on average, the same duration of gestation and birth weight z-score as lamotrigine-exposed infants, but had a head circumference 0.2 SDs smaller (-0.2 [-0.2 to -0.1]). Associations between carbamazepine exposure and pregnancy duration and between valproic acid exposure and pregnancy duration and birth weight z-score were more negative at the left than at the right tails of the outcome distributions. Effect-measure modification and dose-response relations were noted for some of the associations.ConclusionsRelative to lamotrigine, valproic acid and carbamazepine were associated with smaller head circumference.
| S-EPMC6681941 | biostudies-literature
Project description:Prenatal exposure to alcohol is thought to be the most prevalent nongenetic cause of a wide range of neurodevelopmental deficits. Insufficient thyroid hormone levels are one mechanism that hampers development of the alcohol-exposed brain, and we hypothesized that altered dosage of the imprinted thyroid hormone-inactivating gene deiodinase-III (Dio3) is responsible. To follow parent-of-origin allelic expression of Dio3 in the fetal and adult offspring of alcohol-consuming and control dams, we reciprocally crossed 2 polymorphic rat strains. In the frontal cortex, prenatal alcohol exposure altered imprinting patterns and total expression of Dio3 in the fetus and produced a permanent hypothyroid milieu in the adult. In the hippocampus, alcohol affected the paternal and total expression of Dio3 in the fetus and in the adult male, where thyroid hormone levels were concomitantly increased. Hippocampus-dependent behavioral deficits were identified exclusively in males, suggesting they are dependent on aberrant allelic Dio3 expression. None of these effects were observed in offspring of the reciprocal cross. Thus, genetic background and sex modify vulnerability to prenatal alcohol via brain region-specific expression of Dio3. This finding implies that phenotypic heterogeneity in human fetal alcohol spectrum disorder can be linked to genetic vulnerability in affected brain regions.
| S-EPMC3114527 | biostudies-literature