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Placental genomic risk scores and early neurodevelopmental outcomes.

ABSTRACT: Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. Ursini et al., Nat. Med. 24, 792-801 (2018)]. Here, we analyze whether fractionated genomic risk scores for schizophrenia and other developmental disorders and traits, based on placental gene-expression loci (PlacGRSs), are linked with early neurodevelopmental outcomes in individuals with a history of ELCs. We found that schizophrenia's PlacGRSs are negatively associated with neonatal brain volume in singletons and offspring of multiple pregnancies and, in singletons, with cognitive development at 1 y and, less strongly, at 2 y, when cognitive scores become more sensitive to other factors. These negative associations are stronger in males, found only with GRSs fractionated by placental gene expression, and not found in PlacGRSs for other developmental disorders and traits. The relationship of PlacGRSs with brain volume persists as an anlage of placenta biology in adults with schizophrenia, again selectively in males. Higher placental genomic risk for schizophrenia, in the presence of ELCs and particularly in males, alters early brain growth and function, defining a potentially reversible neurodevelopmental path of risk that may be unique to schizophrenia.

SUBMITTER: Ursini G

PROVIDER: S-EPMC7896349 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Placental genomic risk scores and early neurodevelopmental outcomes.

Ursini Gianluca G Punzi Giovanna G Langworthy Benjamin W BW Chen Qiang Q Xia Kai K Cornea Emil A EA Goldman Barbara D BD Styner Martin A MA Knickmeyer Rebecca C RC Gilmore John H JH Weinberger Daniel R DR

Proceedings of the National Academy of Sciences of the United States of America 20210201 7

Tracing the early paths leading to developmental disorders is critical for prevention. In previous work, we detected an interaction between genomic risk scores for schizophrenia (GRSs) and early-life complications (ELCs), so that the liability of the disorder explained by genomic risk was higher in the presence of a history of ELCs, compared with its absence. This interaction was specifically driven by loci harboring genes highly expressed in placentae from normal and complicated pregnancies [G. ...[more]

PMID: 33558239

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Project description:Background and aimsIndividual macronutrient and micronutrient effects on placental growth have been widely investigated. However, the influence of overall maternal diet is relatively unknown. Therefore, the aim of this study is to examine associations between a range of maternal dietary scores during early pregnancy with placental outcomes, and to investigate whether there is evidence of sexual dimorphism.MethodsThis analysis of the Lifeways Cross-Generational Cohort includes 276 mother-child pairs. A validated 148-item semi-quantitative food frequency questionnaire assessed maternal diet in early pregnancy. Dietary scores reflecting dietary quality [Healthy Eating Index (HEI-2015), Dietary Approaches to Stop Hypertension (DASH)], dietary inflammatory potential [Dietary Inflammatory Index (DII) and the energy adjusted DII (E-DII)], dietary antioxidant status [Dietary Antioxidant Quality (DAQ)], and glycemic and insulinemic loads/indices (GL/GI, IL/II) were calculated. Linear regression analyses assessed maternal dietary score relationships with untrimmed placental weight (PW) and birth weight:placental weight (BW:PW) ratio.ResultsIn fully adjusted models, maternal E-DII and GI were positively associated, and HEI-2015 and DAQ were negatively associated with PW (B: 12.31, 95% CI: 0.41, 24.20, p = 0.04, B: 4.13, 95% CI: 0.10, 8.17, p = 0.04, B: -2.70, 95% CI: -5.03, -0.35, p = 0.02 and B: -15.03, 95% CI: -28.08, -1.98, p = 0.02, for E-DII, GI, HEI-2015 and DAQ respectively). Maternal DAQ associations with BW:PW ratio were attenuated. When stratified by sex, maternal GI and pregnancy-specific DAQ were associated with PW in female offspring (B: 5.61, 95% CI: 0.27, 10.96, p = 0.04 and B: -15.31, 95% CI: -30.35, -0.27, p = 0.046). Maternal E-DII and HEI-2015 were associated with PW in males (B: 24.31, 95% CI: 5.66, 42.96, p = 0.01 and B: -3.85, 95% CI: -7.47, -0.35, p = 0.03 respectively).ConclusionThe results of this novel investigation suggest that maternal diet may influence placental development. Female fetuses may be more sensitive to increased glucose levels whereas male fetuses may be more susceptible to in-utero stresses that are regulated by inflammatory pathways and overall diet quality. Hence, early pregnancy offers an opportune time for a mother to prioritize dietary changes that focus on reducing inflammatory and glycemic responses.

Project description:BackgroundInflammation may be an important predictor of long-term neurodevelopment in preterm infants. The identification of specific inflammatory biomarkers that predict outcomes is an important research goal.ObjectivesThe purpose of this analysis was to identify associations between an early measure of inflammation and neurodevelopment in very preterm infants and to identify differences in the relationship between inflammation and neurodevelopment based on infant gender and race.MethodsWe conducted a secondary analysis of data from a randomized controlled trial of a caregiving intervention for preterm infants born less than 33 weeks postmenstrual age. Plasma was collected with a clinically indicated laboratory draw by neonatal intensive care unit nurses and analyzed by multiplex assay for cytokines, chemokines, and growth factors. Neurobehavior was assessed by research nurses at the time of discharge from the neonatal intensive care unit using the motor development and vigor and alertness/orientation clusters from the Neurobehavioral Assessment of the Preterm Infant. Neurodevelopment was assessed at 6 months corrected age by the developmental specialist in the hospital's neonatal follow-up clinic using the Bayley Scales of Infant Development, Third Edition. We used linear regressions to estimate the effect of cytokine levels on neurodevelopment and allowed the effects to differ by infant gender and race.ResultsIn a sample of 62 preterm infants with discharge neurobehavioral assessments and a sample of 40 preterm infants with 6-month neurodevelopmental assessments, we found inconsistent associations between single-time point inflammatory measures and neurobehavior or neurodevelopment in analyses of the total sample. However, regressions with interactions revealed effects for multiple inflammatory measures on early neurobehavior and neurodevelopment that differed by infant gender and race.DiscussionAlthough early single-time point measures of inflammation may be insufficient to predict neurodevelopment for all preterm infants, the effect of inflammation appears to differ by infant gender and race. These demographic factors may be important considerations for future studies of inflammation and neurodevelopment as well was the development of future interventions to optimize outcomes.

Project description:BackgroundPrevious results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses.MethodsUsing a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age.ResultsThe primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P=0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P=0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P=0.046).ConclusionsWe found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.).

Project description:BackgroundFor genetic conditions associated with neurodevelopmental disorder (GCAND), developmental domains such as motor ability, thinking and learning, social abilities, and communication are potential intervention targets. Performance on measures of developmental concepts can be expressed using several types of scores. Norm-referenced scores are intended for the diagnostic context, allowing for the identification of impairment relative to age-based expectations, and can exhibit dramatic floor effects when used in individuals with more significant limitations. Person ability scores, which are derived via Rasch analysis or item response theory, are available on many standardized tests and are intended to measure within-person change. However, they have not been used or evaluated as primary endpoints in GCAND clinical trials. In this study, we simulated a series of parallel-arm clinical trials under several chronological age and impairment conditions, to compare empirically the power and type I error rate of operationalizing test performance using ability scores rather than norm-referenced scores.ResultsUsing the Vineland Adaptive Behavior Scales as the example, we demonstrated an advantage in statistical power of ability scores over norm-referenced scores at extreme levels of impairment. This advantage was at least partially driven by floor effects in norm-referenced scores. For simulated conditions where impairment was less severe, ability scores outperformed norm-referenced scores, but they were more similar. The type I error rate closely approximated the nominal type I error rate of 5% for both scores.ConclusionThe results of this simulation demonstrate a substantial power and interpretative advantage of ability scores over norm-referenced scores for studies of GCAND that will enroll participants with high levels of impairment. These results are expected to generalize to studies of developmental concepts, regardless of the etiology or specific test. However, the relative advantage of ability scores is expected to be even greater for tests with a higher floor than the Vineland.

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Placental genomic risk scores and early neurodevelopmental outcomes.

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Placental genomic risk scores and early neurodevelopmental outcomes.

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