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The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Background: Although late‐onset Alzheimer's disease (LOAD) occurs in older individuals (age 65 or older), multiple lines of evidence suggests that the dysregulation of brain functions initiates decades earlier. Through examining multiple large‐scale human brain transcriptomic data, we demonstrated that cognitively normal brain aging from donors in their 40s‐60s can group into several subtypes based on their hippocampal transcriptomes. One subtype represents healthy brain aging and some evidence suggests these donors may remain cognitively normal in much older ages, while some brain aging subtypes showed gene expression changes highly similar to those observed in AD, supporting molecular changes linked to AD have occurred much earlier than the manifestation of cognitive impairment. However, whether the brain aging subtype is a common phenomenon across multiple brain regions or very specific to the hippocampus remains unknown. Method: We compiled and studied transcriptomic data in another commonly studied human brain region (prefrontal cortex) from donors who were cognitively normal. We performed hierarchical clustering in these samples to infer subtypes, differential gene expression analysis was done between samples from different subtypes. We annotated and compared these DEGs with other AD gene expression signatures. Result: We discovered that aging subtypes could also be observed in the prefrontal cortical region. Similarly to the hippocampus, the differentially expressed genes among aging subtypes also highly overlapped with AD gene signatures. By comparing aging subtypes defined from hippocampal vs. cortical transcriptomes from the same individuals, we found that an AD similar hippocampal sample does not necessarily correspond to AD similar cortical sample in the same donor, suggesting the brain regional complexity of the disease. Conclusion: Our analysis of the transcriptomic data from multiple brain regions from cognitively normal individual supports that gene regulation changes related to AD occurs decades earlier than the manifestation of clinical phenotype. Understanding the molecular changes in these early changes in multiple brain regions could be critical to gain new insights into the mechanisms of AD initiation. [ABSTRACT FROM AUTHOR]

Background: A growing body of evidence links maternal exposure to particulate matter <2.5 μM in diameter (PM 2.5 ) and deviations in fetal growth. Several studies suggest that the placenta plays a critical role in conveying the effects of maternal PM 2.5 exposure to the developing fetus. These include observed associations between air pollutants and candidate placental features, such as mitochondrial DNA content, DNA methylation and telomere length. However, gaps remain in delineating the pathways linking the placenta to air pollution-related health effects, including a comprehensive profiling of placental processes impacted by maternal PM 2.5 exposure. In this study, we examined alterations in a placental transcriptome-wide network in relation to maternal PM 2.5 exposure prior to and during pregnancy and infant birthweight., Methods: We evaluated PM 2.5 exposure and placental RNA-sequencing data among study participants enrolled in the Rhode Island Child Health Study (RICHS). Daily residential PM 2.5 levels were estimated using a hybrid model incorporating land-use regression and satellite remote sensing data. Distributed lag models were implemented to assess the impact on infant birthweight due to PM 2.5 weekly averages ranging from 12 weeks prior to gestation until birth. Correlations were assessed between PM 2.5 levels averaged across the identified window of susceptibility and a placental transcriptome-wide gene coexpression network previously generated using the WGCNA R package., Results: We identified a sensitive window spanning 12 weeks prior to and 13 weeks into gestation during which maternal PM 2.5 exposure is significantly associated with reduced infant birthweight. Two placental coexpression modules enriched for genes involved in amino acid transport and cellular respiration were correlated with infant birthweight as well as maternal PM 2.5 exposure levels averaged across the identified growth restriction window., Conclusion: Our findings suggest that maternal PM 2.5 exposure may alter placental programming of fetal growth, with potential implications for downstream health effects, including susceptibility to cardiometabolic health outcomes and viral infections., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)