So far we have created a truly unique resource for sub-Saharan Africa supporting a wide range of robust and innovative study designs providing novel insights into the complexities of nutrition-disease interactions. Recent outputs have appeared in journals covering basic science (PLoSGenetics, Genome Biology, Human Molecular Genetics, Nature Communications, FASEBJ and Scientific Reports, with papers currently under review at Genome Biology and Cell), medicine (EBioMedicine, PLoSMedicine, Lancet, JAMA) and global public health (Lancet Global Health, PNAS) as well as in the core nutrition journals (AJCN, J Nutr). We summarise some of these experimental approaches and the insights they have yielded below. To date these outputs have all been driven by the local MRCG investigators with assistance from expert international collaborators as appropriate to each study. This approach has been very successful but is necessarily constrained by the intellectual bandwidth of the core investigators, the time available and by funding. The resource has ample spare capacity to be used more intensively.

Our challenge now is to capitalise on the existing legacy of the MRC’s, investigators’ and participants’ investment to maximise academic outputs with strong pathways to impact in global health. To achieve this we wish to partner with a large team of investigators based in Bristol around the trio of infrastructure between the Avon Longitudinal Study of Parents and Children (ALSPAC), the Bristol Bioresource Laboratory (BBL) and the MRC Integrative Epidemiology Unit (IEU). Together they have created a world leading system of cohort curation, resource storage and use which is exemplified, inter alia, by the fact that ALSPAC has just celebrated its 1500th publication and remains routinely used (for bioresources and data) by a large and active international collaborator group. We will work with the Bristol teams across a wide range of disciplines (legal and governance, human tissue biobanking, laboratory practices, genotyping and epigenotyping, data archiving and mining, bioinformatics and publicity) to ‘clone and adapt’ their existing procedures in order to professionalise and externalise what we will term the West African BioResource (WABR).

Skeletal health (bone shape/size/density/mass, and joint shape) is an important determinant of mid-life musculo-skeletal diseases including osteoporosis/fractures and osteoarthritis. Factors acting across the lifecourse from in-utero to older age influence skeletal health and our previous research suggests early-life skeletal loading may be important for healthy skeletal development. For example, we have shown that children who reach motor milestones, e.g. walking, jumping, at older ages than average have smaller, weaker bones and different joint shapes even in adolescence and old age. We postulate that this is due to both delayed early-life leg loading and because late walkers tend to be less active throughout life which also affects skeletal health.
Skeletal growth is quickest during the intrauterine period, when the skeleton is first assembled. However, there is little information on how skeletal loading during intrauterine development influences bone health. Objective assessment of fetal movements are difficult, but fetal position – breech or cephalic – will influence movements with these likely to be lower in breech infants as leg movement is constrained. Our research, and that of others supports this, showing that breech-born babies have smaller bones and different hip shape at birth compared to cephalic-born children. However, it is unclear whether these differences continue into later childhood, and whether they are explained by differences in activity post-birth. The aim of this study is to examine skeletal health in breech and cephalic-born children in adolescence, and to what extent any differences are explained by differences in physical activity and body composition between these two.

The Wellcome Trust Longitudinal Population Study (LPS, which includes studies like ALSPAC) Strategy states that research methods are needed to i) underpin efficient linkage of multiple datasets, ii) quantify potential biases resulting from linkage and how this impacts on results, and iii) to handle linkage error in data analyses. Our study aims to maximise the value of LPS by providing improved methods for linkage and analysis, building on previous work in these areas.

This is a simple look up request for basic association signals for BMo in ALSPAC by age. This is to help address reviewer comment for a paper being written by Dr Wheeler.

Low birth weight has been classified as a risk factor for cardiovascular disease by the World Health Organization (WHO).1 This strategy was supported by many observational studies since 1980s, showing lower birth weight was associated with higher blood pressure in later life.2-4 Some researchers explained this inverse association as a 'reverse paradox', which resulted from an over-adjustment for current weight status.5 A recent study of the 1958 British birth cohort used twin status as an instrumental variable, and reported no effect of birth weight on hypertension.6 Nevertheless, it remains unclear that to what extent the effects of birth weight on blood pressure are mediated by body mass index (BMI) throughout life.

Objectives: To assess what family socioeconomic attributes determine child educational achievement, and whether educational mobility affects cardiovascular disease (CVD) risk factors in young people. Design: A comparative study of two prospective birth cohorts.
Participants: 3,200 Chinese adolescents in Hong Kong’s “Children of 1997” birth cohort and 6,000 British adolescents in the Avon Longitudinal Study of Parents and Children.
Exposure: Parental socioeconomic position and parent-child educational mobility.
Outcomes: Educational attainment from public examination scores and CVD risk factors (body mass index, blood pressure, lipids and glycemic traits).
Expected results: Determinants of child educational achievement are culturally sensitive, but we expect them to be responsive to parental education and/or occupation in Hong Kong and the UK. Influence of educational mobility on CVD risk factors is universal, but stronger in migrant children.
Significance: These findings will inform strategies to promote social mobility in Hong Kong and will be highly relevant to the rest of China where educational opportunities are improving but challenges remain with mass internal migration.

The management of reproductive and perinatal care has never been so advanced. However, a high proportion of pregnancies still have adverse outcomes. These can range from hypertensive disorders of pregnancy to preterm or stillbirth.

Gestational diabetes mellitus (GDM) affects between 1 and 14% of pregnant women, depending on the sample and criteria used. Due to overnutrition and underactivity in the developing world, this number is expected to rise. In GDM, there are extensive complications for both mother and offspring. Postnatal complications for the mother include type 2 diabetes, obesity and cardiovascular dysfunction. The offspring of mothers born with GDM have nearly double the risk of being obese and hyperglycaemic, both have been linked to long-term health complications.

Many interventions are in place to reduce the prevalence and severity of GDM. However, there is a need for GDM to be diagnosed earlier during the pregnancy and treated accordingly. DNA methylation is a mechanism by which certain environmental exposures affect gene expression without altering DNA sequence and has been used as a biomarker for diseases including a variety of cancers. In this project, we aim to use longitudinal birth cohorts to investigate the relationship between DNA methylation, GDM and related factors such as body mass index, smoking, maternal age and parity.

We hope that these investigations will improve our understanding of the mechanisms underlying GDM and possibly lead to the development of a tool that uses DNA methylation in pregnant mothers for early detection of GDM. Ultimately, we hope to identify effective strategies for the prevention and management of GDM.

A long literature in psychology and sociology attempts to measure the relative contributions of “nurture” and “nature” to individuals’ life outcomes. Nature is characterized as principally consisting of a person’s genetic makeup, while nurture is treated as the social environment in which a person is born and raised, which includes parental investment in their children’s development. The relative emphasis on nurture or nature in scholarly argumentation is largely the product of disciplinary differences; increasingly, multidisciplinary work, spanning the social, biological and psychological sciences, emphasizes their complex interaction in producing outcomes. In this project, we hope to contribute to this burgeoning multidisciplinary endeavor by broadening the scope of how scientists conceive “nature” and “nurture”.

We plan to do this in two ways. First, we plan to examine the extent to which the genetic material a child receives at birth is, in fact, related to prenatal “nurture”, which includes the health, behaviors and the environment of the parents prior to, and over the course of the pregnancy. Although offspring receive exactly 50% of their genes from each parent, little is known about the survival of the fertilized egg. Depending on the genetic material of the zygote – the fertilized egg – the womb environment of the mother, or the sperm quality of the father, genetically different zygotes may survive past their initial fertilization. We can use a number of different factors, such as parental age and other stress factors, all of which are thought to result in harsher womb conditions, to study how zygote genetic makeup interacts with prenatal environment to predict zygote survival till birth. This would be evidence of “nurture before birth”, and would affect the distribution of “natures” in the population, complicating the dichotomy of nurture versus nature arguments in human development and life outcomes.

Second, we hope to compare prenatal environmental effects, if established by the first analyses, with the more traditional measures of the social environment in childhood development. In this stage of the research too, we hope to complicate how nurture and nature are defined. We will empirically examine the idea that parental choices are independent of their own genes. Studies have shown that the genes of parents, even when not transmitted to the offspring, have an effect on their outcomes later in life. The main pathway through which these un-transmitted genes affect children’s outcomes is via parental “nurturing practices”, which may or may not be influenced by parents’ genes. Further, a nurturing parent confronts a child, who has his or her own nature, personality and behavior, allowing for a possible interaction between a parents’ genes and nurturing behavior and a child’s genotype. Conceiving of parental behaviors as inelastic to and independent from the child’s own genetically-influenced interests, behaviors, and tendencies has been challenged by developmental psychologists. Parents may well adapt their parenting practices in response to children's interests and behaviors. For example, the extent to which a parent can adopt nurturing practices to a child’s antisocial behavior may be constrained by their genotype. We will examine the complex interactions in relation to educational outcomes of the child and cognitively stimulating parenting, since educational outcomes are of immense sociological interest, and they are among the most well-measured outcomes. We specifically consider (1) whether children's genetic makeup affects socio-emotional and cognitive skills, (2) whether children's genetic makeup evokes cognitively stimulating parenting, and (3) whether cognitively stimulating parenting moderates the relationship between children's genetic makeup and socio-emotional and cognitive skills.

There is increasing concern that the non-random sampling of participants into major cohort studies may lead to spurious GWAS and Mendelian randomisation results.
The UK Biobank, ALSPAC and the 1958 cohort sampled individuals in different ways. The UK Biobank invited around 9 million individuals to attend a clinic, and around 0.5 million responded. These individuals are not a random sample of those invited to take part, for example they are more educated. Whereas ALSPAC sampled all mothers who gave birth within the Avon area. The 1958 cohort sampled all people born within a specific week in 1958.

This project will investigate whether there are any systematic genetic differences between the participants of the three studies.