Genetic regulation of the placental transcriptome underlies birth weight and risk of childhood obesity

Peng, Shouneng; Deyssenroth, Maya A.; Narzo, Antonio Fabio Di; Cheng, Haoxiang; Zhang, Zhongyang; Lambertini, Luca; Ruusalepp, Arno; Kovacic, Jason C.; Björkegren, Johan; Marsit, Carmen J.; Chen, Jia; Hao, Ke

doi:10.1371/journal.pgen.1007799

Cited by 51 publications

(57 citation statements)

References 31 publications

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“…Placental transcript profiling in birth cohorts with comprehensive longitudinal follow-up of the children may also potentially uncover new placental programming mechanisms that can influence extrauterine life in the longer term. Indeed, previously identified placental eQTLs were predictive of birthweight and subsequent childhood obesity in a cohort study, highlighting the role of placental gene expression in modulating postnatal outcomes, and such genes could serve as potential molecular targets for interventions ( Peng et al , 2018 ). Besides profiling more placentas from additional birth cohorts, it is of great interest to examine currently available birth cohort-related placental transcriptome datasets for any possible associations with childhood outcomes ( Binder et al , 2015 ; Cox et al , 2019 ).…”

Section: Knowledge Gaps and Future Directionsmentioning

confidence: 99%

Current approaches and developments in transcript profiling of the human placenta

Yong

Chan

2020

Human Reproduction Update

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BACKGROUND The placenta is the active interface between mother and foetus, bearing the molecular marks of rapid development and exposures in utero. The placenta is routinely discarded at delivery, providing a valuable resource to explore maternal-offspring health and disease in pregnancy. Genome-wide profiling of the human placental transcriptome provides an unbiased approach to study normal maternal–placental–foetal physiology and pathologies. OBJECTIVE AND RATIONALE To date, many studies have examined the human placental transcriptome, but often within a narrow focus. This review aims to provide a comprehensive overview of human placental transcriptome studies, encompassing those from the cellular to tissue levels and contextualize current findings from a broader perspective. We have consolidated studies into overarching themes, summarized key research findings and addressed important considerations in study design, as a means to promote wider data sharing and support larger meta-analysis of already available data and greater collaboration between researchers in order to fully capitalize on the potential of transcript profiling in future studies. SEARCH METHODS The PubMed database, National Center for Biotechnology Information and European Bioinformatics Institute dataset repositories were searched, to identify all relevant human studies using ‘placenta’, ‘decidua’, ‘trophoblast’, ‘transcriptome’, ‘microarray’ and ‘RNA sequencing’ as search terms until May 2019. Additional studies were found from bibliographies of identified studies. OUTCOMES The 179 identified studies were classifiable into four broad themes: healthy placental development, pregnancy complications, exposures during pregnancy and in vitro placental cultures. The median sample size was 13 (interquartile range 8–29). Transcriptome studies prior to 2015 were predominantly performed using microarrays, while RNA sequencing became the preferred choice in more recent studies. Development of fluidics technology, combined with RNA sequencing, has enabled transcript profiles to be generated of single cells throughout pregnancy, in contrast to previous studies relying on isolated cells. There are several key study aspects, such as sample selection criteria, sample processing and data analysis methods that may represent pitfalls and limitations, which need to be carefully considered as they influence interpretation of findings and conclusions. Furthermore, several areas of growing importance, such as maternal mental health and maternal obesity are understudied and the profiling of placentas from these conditions should be prioritized. WIDER IMPLICATIONS Integrative analysis of placental transcriptomics with other ‘omics’ (methylome, proteome and metabolome) and linkage with future outcomes from longitudinal studies is crucial in enhancing knowledge of healthy placental development and function, and in enabling the underlying causal mechanisms of pregnancy complications to be identified. Such understanding could help in predicting risk of future adversity and in designing interventions that can improve the health outcomes of both mothers and their offspring. Wider collaboration and sharing of placental transcriptome data, overcoming the challenges in obtaining sufficient numbers of quality samples with well-defined clinical characteristics, and dedication of resources to understudied areas of pregnancy will undoubtedly help drive the field forward.

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Section: Knowledge Gaps and Future Directionsmentioning

confidence: 99%

Current approaches and developments in transcript profiling of the human placenta

Yong

Chan

2020

Human Reproduction Update

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“…38 Molecular studies could include the placental transcriptome for genetic variants of gene expression (eQTLs) that predict childhood obesity and BMI. 39 Epigenomic methylation of DNA and histones should be monitored across the lifespan of the infant. DNA methylation measures represented as epigenetic clocks that represent "aging" can be estimated in pediatric and then adult years.…”

Section: Neonatal Outcomesmentioning

confidence: 99%

Will prenatal exposure to SARS-CoV-2 define a birth cohort with accelerated aging in the century ahead?

Easterlin

Crimmins

Finch

2020

J Dev Orig Health Dis

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The 1918 Influenza pandemic had long-term impacts on the cohort exposed in utero which experienced earlier adult mortality, and more diabetes, ischemic heart disease, and depression after age 50. It is possible that the Coronavirus Disease 2019 (COVID-19) pandemic will also have long-term impacts on the cohort that was in utero during the pandemic, from exposure to maternal infection and/or the stress of the pandemic environment. We discuss how COVID-19 disease during pregnancy may affect fetal and postnatal development with adverse impacts on health and aging. Severe maternal infections are associated with an exaggerated inflammatory response, thromboembolic events, and placental vascular malperfusion. We also discuss how in utero exposure to the stress of the pandemic, without maternal infection, may impact health and aging. Several recently initiated birth cohort studies are tracking neonatal health following in utero severe acute respiratory syndrome virus 2 (SARS-CoV-2) exposure. We suggest these cohort studies develop plans for longer-term observations of physical, behavioral, and cognitive functions that are markers for accelerated aging, as well as methods to disentangle the effects of maternal infection from stresses of the pandemic environment. In utero exposure to COVID-19 disease could cause developmental difficulties and accelerated aging in the century ahead. This brief review summarizes elements of the developmental origins of health, disease, and ageing and discusses how the COVID-19 pandemic might exacerbate such effects. We conclude with a call for research on the long-term consequences of in utero exposure to maternal infection with COVID-19 and stresses of the pandemic environment.

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“…A SNP intronic in ITPR2 (chr12:26958660, hg19) has been reported to be cis-eQTL with ITPR2 in human placenta [43]. A recent study found that rs12812999, a SNP in strong linkage disequilibrium (LD) (r 2 = 0.94) with the birthweight GWAS lead SNP rs2306547, influences ITPR2 transcript levels in placenta [44].…”

Section: Plos Geneticsmentioning

confidence: 99%

“…that found decreased expression of ITPR1 in skeletal muscle of aged mice [44], and association of placental epigenetic age acceleration with fetal growth [36]. A more direct way to assess the mechanism is first to identify the intrauterine factor influenced by rs746039, and then examine the relationship between the putative intrauterine factor and ITPR1 expression.…”

Section: Plos Geneticsmentioning

confidence: 99%

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

Tekola‐Ayele

Zhang

et al. 2020

PLoS Genet

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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 ; log 10 BF>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. Transethnic 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.

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Genetic regulation of the placental transcriptome underlies birth weight and risk of childhood obesity

Cited by 51 publications

References 31 publications

Current approaches and developments in transcript profiling of the human placenta

Current approaches and developments in transcript profiling of the human placenta

Will prenatal exposure to SARS-CoV-2 define a birth cohort with accelerated aging in the century ahead?

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

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