scholarly journals Distal mediator-enriched, placental transcriptome-wide analyses illustrate the Developmental Origins of Health and Disease

2021 ◽  
Author(s):  
Arjun Bhattacharya ◽  
Anastasia N. Freedman ◽  
Vennela Avula ◽  
Rebeca Harris ◽  
Weifang Liu ◽  
...  
Keyword(s):  
Association Studies ◽  
Specific Gene ◽  
Developmental Origins ◽  
Functional Validation ◽  
Intrauterine Environment ◽  
Health And Disease ◽  
Genomic Regulation ◽  
The Life Course ◽  
Omic Data ◽  
Trait Associations

ABSTRACTAs the master regulator of the intrauterine environment, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) but is understudied in relation to tissue-specific gene and trait regulation. We performed distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 health traits across 5 physiological categories, using gene expression models trained with multi-omic data from the Extremely Low Gestational Age Newborn Study (N = 272). At P < 2.5 × 10−6, we detected 248 gene-trait associations (GTAs) across 176 genes, mostly for metabolic and neonatal traits and enriched for cell growth and immunological pathways. Of these GTAs, 89 showed significant mediation through genetic variants distal to the gene, identifying potential targets for functional validation. Functional validation of a mediator gene (EPS15) in human placenta-derived JEG-3 trophoblasts resulted in increased expression of its predicted targets, SPATA13 and FAM214A, both associated with the trait of waist-hip ratio in TWAS. These results illustrate the profound health impacts of placental genetic and genomic regulation in developmental programming across the life course.

scholarly journals Metabolomics in the developmental origins of obesity and its cardiometabolic consequences

2015 ◽  
Vol 6 (2) ◽  
pp. 65-78 ◽  
Author(s):  
M. F. Hivert ◽  
W. Perng ◽  
S. M. Watkins ◽  
C. S. Newgard ◽  
L. C. Kenny ◽  
...  
Keyword(s):  
Life Course ◽  
Potential Role ◽  
Human Populations ◽  
Developmental Origins ◽  
Excess Adiposity ◽  
Health And Disease ◽  
The Life Course ◽  
Analytical Approaches ◽  
Review Current

In this review, we discuss the potential role of metabolomics to enhance understanding of obesity-related developmental origins of health and disease (DOHaD). We first provide an overview of common techniques and analytical approaches to help interested investigators dive into this relatively novel field. Next, we describe how metabolomics may capture exposures that are notoriously difficult to quantify, and help to further refine phenotypes associated with excess adiposity and related metabolic sequelae over the life course. Together, these data can ultimately help to elucidate mechanisms that underlie fetal metabolic programming. Finally, we review current gaps in knowledge and identify areas where the field of metabolomics is likely to provide insights into mechanisms linked to DOHaD in human populations.

scholarly journals Analyzing Policies Through a DOHaD Lens: What Can We Learn?

2018 ◽  
Vol 15 (12) ◽  
pp. 2906 ◽  
Author(s):  
Julia Goodman ◽  
Janne Boone-Heinonen ◽  
Dawn Richardson ◽  
Sarah Andrea ◽  
Lynne Messer
Keyword(s):  
Life Course ◽  
Life Experiences ◽  
Evidence Base ◽  
Policy Impact ◽  
Full Potential ◽  
Developmental Origins ◽  
Health Trajectories ◽  
Health And Disease ◽  
Potential Impact ◽  
The Life Course

Social, health, and environmental policies are critical tools for providing the conditions needed for healthy populations. However, current policy analyses fall short of capturing their full potential impacts across the life course and from generation to generation. We argue that the field of Developmental Origins of Health and Disease (DOHaD), a conceptual and research framework positing that early life experiences significantly affect health trajectories across the lifespan and into future generations, provides an important lens through which to analyze social policies. To illustrate this point, we synthesized evidence related to policies from three domains—family leave, nutrition, and housing—to examine the health implications for multiple generations. We selected these policy domains because they represent increasing distance from a reproductive health focus, each with a growing evidence base to support a potential impact on pregnant women and their offspring. Each of these examples represents an opportunity to extend our understanding of policy impact using a DOHaD lens, taking into account the potential life course and intergenerational effects that have previously been overlooked.

scholarly journals Pakistan Developmental Origins of Health and Disease (DOHaD) Society: addressing the ‘DO’ component of DOHaD

2018 ◽  
Vol 10 (02) ◽  
pp. 141-143
Author(s):  
N. Mohammed ◽  
R. Nuruddin ◽  
A. Shoukat Ali
Keyword(s):  
Fetal Programming ◽  
In Utero ◽  
Learning Disorders ◽  
Developmental Origins ◽  
Early Screening ◽  
Future Health ◽  
Double Burden ◽  
Research Findings ◽  
Health And Disease ◽  
The Life Course

AbstractAdverse intrauterine environment could serve as an important stimulus for postnatal altered health status and for increased susceptibility to long-term non-communicable diseases (NCDs). The notion is now recognized as the Developmental Origins of Health and Disease (DOHaD), which was first proposed by Sir David Barker. Since then, several scientific disciplines have strived to measure the magnitude of the early fetal programming and later risk of diseases. Pakistan, with striking figures of morbidity and mortality from NCDs, is currently tackling with double burden of diseases and requires planned efforts to counteract the threat of NCDs. Considering the growing needs and available evidences, Pakistan DOHaD Society was officially instigated in September 2016. The Society aims to explicitly address the association of life in utero with future health and disease and to endorse early screening and interventions to reduce the burden of NCDs, mental health issues and learning disorders along the life course. It has shown significant progress toward investigating the influence of adverse in utero environment such as diabetes, maternal under-nutrition and pre-eclampsia on fetal programming under two major research lines, that is, cardiovascular and cerebrovascular programming. The Society has been successful in disseminating its research findings through several esteemed international scientific conferences. Pakistan DOHaD Society encourages scientific community for collaborative research aimed at improving the quality of life during early childhood, adolescence and adulthood through provision of appropriate pre-pregnancy and antenatal interventions targeted to address at-risk in utero conditions.

scholarly journals Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323906
Author(s):  
Jue-Sheng Ong ◽  
Jiyuan An ◽  
Xikun Han ◽  
Matthew H Law ◽  
Priyanka Nandakumar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Testing ◽  
Association Studies ◽  
Barrett’S Oesophagus ◽  
Oesophageal Reflux ◽  
Oesophageal Adenocarcinoma ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Disease Heterogeneity ◽  
Barrett's Oesophagus

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

scholarly journals Targeting the Renin–Angiotensin–Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins

2021 ◽  
Vol 22 (5) ◽  
pp. 2298
Author(s):  
Chien-Ning Hsu ◽  
You-Lin Tain
Keyword(s):  
Kidney Disease ◽  
Current Knowledge ◽  
Current Evidence ◽  
Developmental Origins ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin ◽  
Health And Disease ◽  
Nitric Oxide Deficiency ◽  
Developing Kidney ◽  
Prevention Of Hypertension

The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.

scholarly journals Science for the Next Century: Deep Phenotyping

2021 ◽  
pp. 002203452110018
Author(s):  
J.T. Wright ◽  
M.C. Herzberg
Keyword(s):  
Health Care ◽  
Human Health ◽  
Care Delivery ◽  
The Past ◽  
Large Populations ◽  
Health And Disease ◽  
Methodological Approaches ◽  
Omic Data ◽  
Precision Health ◽  
Deep Phenotyping

Our ability to unravel the mysteries of human health and disease have changed dramatically over the past 2 decades. Decoding health and disease has been facilitated by the recent availability of high-throughput genomics and multi-omics analyses and the companion tools of advanced informatics and computational science. Understanding of the human genome and its influence on phenotype continues to advance through genotyping large populations and using “light phenotyping” approaches in combination with smaller subsets of the population being evaluated using “deep phenotyping” approaches. Using our capability to integrate and jointly analyze genomic data with other multi-omic data, the knowledge of genotype-phenotype relationships and associated genetic pathways and functions is being advanced. Understanding genotype-phenotype relationships that discriminate human health from disease is speculated to facilitate predictive, precision health care and change modes of health care delivery. The American Association for Dental Research Fall Focused Symposium assembled experts to discuss how studies of genotype-phenotype relationships are illuminating the pathophysiology of craniofacial diseases and developmental biology. Although the breadth of the topic did not allow all areas of dental, oral, and craniofacial research to be addressed (e.g., cancer), the importance and power of integrating genomic, phenomic, and other -omic data are illustrated using a variety of examples. The 8 Fall Focused talks presented different methodological approaches for ascertaining study populations and evaluating population variance and phenotyping approaches. These advances are reviewed in this summary.

scholarly journals Endocrine Disrupting Chemicals: Current Understanding, New Testing Strategies and Future Research Needs

2021 ◽  
Vol 22 (2) ◽  
pp. 933
Author(s):  
Maria E. Street ◽  
Karine Audouze ◽  
Juliette Legler ◽  
Hideko Sone ◽  
Paola Palanza
Keyword(s):  
Endocrine Disrupting Chemicals ◽  
Endocrine System ◽  
Current Understanding ◽  
Future Research ◽  
Developmental Origins ◽  
Research Needs ◽  
Important Class ◽  
Testing Strategies ◽  
Endocrine Disrupting ◽  
Health And Disease

Endocrine disrupting chemicals (EDCs) are exogenous chemicals which can disrupt any action of the endocrine system, and are an important class of substances which play a role in the Developmental Origins of Health and Disease (DOHaD) [...]

scholarly journals Toxicant effects on mammalian oocyte mitochondria†

2021 ◽  
Author(s):  
Kelli F Malott ◽  
Ulrike Luderer
Keyword(s):  
Assisted Reproductive Technologies ◽  
Primordial Germ Cells ◽  
Reproductive Technologies ◽  
Mature Oocyte ◽  
Developmental Origins ◽  
Founder Population ◽  
Mammalian Oocyte ◽  
Transport Chain ◽  
Polycyclic Aromatic ◽  
Health And Disease

Abstract Oocyte mitochondria are unique organelles that establish a founder population in primordial germ cells (PGCs). As the oocyte matures in the postnatal mammalian ovary during folliculogenesis it increases exponentially in volume, and the oocyte mitochondria population proliferates to about 100 000 mitochondria per healthy, mature murine oocyte. The health of the mature oocyte and subsequent embryo is highly dependent on the oocyte mitochondria. Mitochondria are especially sensitive to toxic insults, as they are a major source of reactive oxygen species (ROS), they contain their own DNA (mtDNA) that is unprotected by histone proteins, they contain the electron transport chain that uses electron donors, including oxygen, to generate ATP, and they are important sensors for overall cellular stress. Here we review the effects that toxic insults including chemotherapeutics, toxic metals, plasticizers, pesticides, polycyclic aromatic hydrocarbons (PAHs), and ionizing radiation can have on oocyte mitochondria. This is very clearly a burgeoning field, as our understanding of oocyte mitochondria and metabolism is still relatively new, and we contend much more research is needed to understand the detrimental impacts of exposure to toxicants on oocyte mitochondria. Developing this field further can benefit our understanding of assisted reproductive technologies and the developmental origins of health and disease (DOHaD).

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