Epigenetic Modifications at the Center of the Barker Hypothesis and Their Transgenerational Implications

Embryo/fetal nutrition and the environment in the reproductive tract influence the subsequent risk of developing adult diseases and disorders, as formulated in the Barker hypothesis. Metabolic syndrome, obesity, heart disease, and hypertension in adulthood have all been linked to unwanted epigenetic programing in embryos and fetuses. Multiple studies support the conclusion that environmental challenges, such as a maternal low-protein diet, can change one-carbon amino acid metabolism and, thus, alter histone and DNA epigenetic modifications. Since histones influence gene expression and the program of embryo development, these epigenetic changes likely contribute to the risk of adult disease onset not just in the directly affected offspring, but for multiple generations to come. In this paper, we hypothesize that the effects of parental nutritional status on fetal epigenetic programming are transgenerational and warrant further investigation. Numerous studies supporting this hypothesis are reviewed, and potential research techniques to study these transgenerational epigenetic effects are offered.

FETAL ORIGIN OF ADULT DISEASE

“Fetal origins of adult disease”, often called the “Barker hypothesis” after a large proportion data of Barker and colleagues in Southampton over the last decade, that adverse influences early in development, and particularly during intrauterine life, can result in permanent changes in structure, physiology, metabolism, which result in increased disease risk in adulthood. Many further studies have provided evidence for the hypothesis that size at birth is related to the risk of developing disease in later life. In particular, links are well established between reduced birthweight and increased risk of coronary heart disease, diabetes, hypertension and stroke in adulthood. The most widely accepted mechanisms thought to underlie these relationship are those of altered fetal nutrition, genetic–epigenetic links, fetal programming and fetal excess glucocorticoid exposure. It is suggested that the fetus makes physiological adaption in response to changes in its environment to prepare itself for posnatal life. The “Fetal origin of adult disease” hypothesis is attractive. It suggests that these diseases could be prevented by improving maternal health and fetal development

A cautionary note on using Mendelian randomization to examine the Barker hypothesis and Developmental Origins of Health and Disease (DOHaD)

Recent studies have used Mendelian randomization (MR) to investigate the observational association between low birth weight (BW) and increased risk of cardiometabolic outcomes, specifically cardiovascular disease, glycemic traits, and type 2 diabetes (T2D), and inform on the validity of the Barker hypothesis. We used simulations to assess the validity of these previous MR studies, and to determine whether a better formulated model can be used in this context. Genetic and phenotypic data were simulated under a model of no direct causal effect of offspring BW on cardiometabolic outcomes and no effect of maternal genotype on offspring cardiometabolic risk through intrauterine mechanisms; where the observational relationship between BW and cardiometabolic risk was driven entirely by horizontal genetic pleiotropy in the offspring (i.e. offspring genetic variants affecting both BW and cardiometabolic disease simultaneously rather than a mechanism consistent with the Barker hypothesis). We investigated the performance of four commonly used MR analysis methods (weighted allele score MR (WAS-MR), inverse variance weighted MR (IVW-MR), weighted median MR (WM-MR), and MR-Egger) and a new approach, which tests the association between maternal genotypes related to offspring BW and offspring cardiometabolic risk after conditioning on offspring genotype at the same loci. We caution against using traditional MR analyses, which do not take into account the relationship between maternal and offspring genotypes, to assess the validity of the Barker hypothesis, as results are biased in favor of a causal relationship. In contrast, we recommend the aforementioned conditional analysis framework utilizing maternal and offspring genotypes as a valid test of not only the Barker hypothesis, but also to investigate hypotheses relating to the Developmental Origins of Health and Disease more broadly.

David James Purslove Barker. 29 June 1938—27 August 2013

Professor David James Purslove Barker was a physician and one of the most influential medical scientists of our time. His fetal programming hypothesis (known as the Barker Hypothesis) transformed thinking about what causes chronic diseases that are the scourge of modern society: cancer, cardiovascular disease and diabetes. The Barker Hypothesis proposed that the environment of the fetus and infant determined by maternal nutrition and exposure to infection subsequently predisposes the pathologies of later life. He challenged the idea that chronic diseases result from a combination of bad genes and unhealthy adult lifestyle. The environment of the fetus and infant, he suggested, permanently set or ‘programmed’ the body's metabolism and growth, and thereby pathologies of old age. His initially controversial, but now widely accepted, ideas have produced an explosion of research worldwide into the complex processes of nutrition and growth during intrauterine and early post-natal life and how these cause adult diseases. His discoveries created a new field of research, developmental origins of health and disease (DOHaD), influencing global scientific thinking. David believed that ‘the poorer health of people in lower socio-economic groups or living in impoverished places was linked to past and present neglect of the welfare of mothers and babies’. Tackling the epidemics of diabetes and heart disease in the Western world and in developing countries would require, he said, a shift in focus to prioritize the health and nutrition of adolescent girls, pregnant women and infants. This focus has subsequently been enshrined in global health policies and priorities.

Fetal Origins of Mental Disorders? An Answer Based on Mendelian Randomization

The Barker hypothesis states that low birth weight (BW) is associated with higher risk of adult onset diseases, including mental disorders like schizophrenia, major depressive disorder (MDD), and attention deficit hyperactivity disorder (ADHD). The main criticism of this hypothesis is that evidence for it comes from observational studies. Specifically, observational evidence does not suffice for inferring causality, because the associations might reflect the effects of confounders. Mendelian randomization (MR) — a novel method that tests causality on the basis of genetic data — creates the unprecedented opportunity to probe the causality in the association between BW and mental disorders in observation studies. We used MR and summary statistics from recent large genome-wide association studies to test whether the association between BW and MDD, schizophrenia and ADHD is causal. We employed the inverse variance weighted (IVW) method in conjunction with several other approaches that are robust to possible assumption violations. MR-Egger was used to rule out horizontal pleiotropy. IVW showed that the association between BW and MDD, schizophrenia and ADHD is not causal (all p > .05). The results of all the other MR methods were similar and highly consistent. MR-Egger provided no evidence for pleiotropic effects biasing the estimates of the effects of BW on MDD (intercept = -0.004, SE = 0.005, p = .372), schizophrenia (intercept = 0.003, SE = 0.01, p = .769), or ADHD (intercept = 0.009, SE = 0.01, p = .357). Based on the current evidence, we refute the Barker hypothesis concerning the fetal origins of adult mental disorders. The discrepancy between our results and the results from observational studies may be explained by the effects of confounders in the observational studies, or by the existence of a small causal effect not detected in our study due to weak instruments. Our power analyses suggested that the upper bound for a potential causal effect of BW on mental disorders would likely not exceed an odds ratio of 1.2.

“Extension of the “Fetal Origin Hypothesis of Barker” towards the “Fetal Origin Hypothesis of Mental Diseases”

In this editorial we will first describe most common information about the intriguing “traditional” fetal origin hypothesis of Barker for physiological, endocrine and cardiovascular diseases (CVDs). The ‘developmental origins of adult disease’ hypothesis, often called the ‘Barker hypothesis’, states that adverse influences early in development, and particularly during intrauterine life, can result in permanent changes in physiology and metabolism, which result in increased disease risk in adulthood.

Birthweight, Type 2 Diabetes and Cardiovascular Disease: Addressing the Barker Hypothesis with Mendelian randomization

BackgroundLow birthweight (BW) has been associated with a higher risk of hypertension, type 2 diabetes (T2D) and cardiovascular disease (CVD) in epidemiological studies. The Barker hypothesis posits that intrauterine growth restriction resulting in lower BW is causal for these diseases, but causality and mechanisms are difficult to infer from observational studies. Mendelian randomization (MR) is a new tool to address this important question.MethodsWe performed regression analyses to assess associations of self-reported BW with CVD and T2D in 237,631 individuals from the UK Biobank, a large population-based cohort study aged 40-69 years recruited across UK in 2006-2010. Further, we assessed the causal relationship of such associations using the two- sample MR approach, estimating the causal effect by contrasting the SNP effects on the exposure with the SNP effects on the outcome using independent publicly available genome-wide association datasets.ResultsIn the observational analyses, BW showed strong inverse associations with systolic and diastolic blood pressure (β, −0.83 and −0.26; per raw unit in outcomes and SD change in BW; 95% CI, −0.90, −0.75 and −0.31, −0.22, respectively), T2D (odds ratio [OR], 0.83; 95% CI, 0.79, 0.87), lipid-lowering treatment (OR, 0.84; 95% CI, 0.81, 0.86) and CAD (hazard ratio [HR] 0.85; 95% CI, 0.78, 0.94); while the associations with adult body mass index (BMI) and body fat (β, 0.04 and 0.02; per SD change in outcomes and BW; 95% CI, 0.03, 0.04 and 0.01, 0.02, respectively) were positive. The MR analyses indicated inverse causal associations of BW with low density lipoprotein cholesterol, 2-hour glucose, CAD and T2D, and positive causal association with BMI; but no associations with blood pressure. Sensitivity analyses and robust MR methods provided consistent results and indicated no horizontal pleiotropy.ConclusionOur study indicates that lower BW is causally and directly related with increased susceptibility to CAD and T2D in adulthood. This causal relationship is not mediated by adult obesity or hypertension.