Specific aims are:

1. To study associations of abuse in childhood including sexual, parental physical and emotional abuse with cardiometabolic health in middle age (Framingham CVD risk score, atherosclerosis (cIMT, arterial distensibility), pulse wave velocity, adiposity, blood pressure, lipids, insulin, glucose, inflammatory markers).

2. To study associations of abuse in childhood including sexual, parental physical and emotional abuse with women's reproductive health across the lifecourse (age at menarche, menstrual regularity, time to conception, seeing a physician for possible infertility, pregnancy outcomes: pregnancy losses, preterm delivery, mode of delivery, birth weight, parity, age at menopause).

3. To describe longitudinal patterns of intimate partner physical and emotional cruelty throughout the life course, and of physical and emotional abuse of offspring, in men and women.

4. To compare maternal and paternal reports of IPV.

5. To examine patterns of IPV across two generations in the same families.

6. To examine associations of longitudinal patterns of intimate partner physical and emotional cruelty with cardiometabolic (men and women) and reproductive health (women).

7. To examine whether any associations identified in aims 1, 2 and 6 are mediated by established cardiometabolic risk factors such as smoking, alcohol consumption, eating disorders, adiposity, and mental health.

8. To examine whether any associations identified in aims 1, 2 and 6 are mediated by differential DNA methylation.

Foods are generally consumed in combination; therefore dietary recommendations should consider diet as a whole, rather than individual foods or nutrients. We know that dietary intake throughout the life course is involved in the development of lifestyle diseases, including cardiovascular disease (CVD) and obesity which are currently endemic in the UK. This project aims to provide an insight into nutritional life course exposures and the potential of these exposures to affect markers of CVD.

Studies have previously linked childhood obesity with CVD in adulthood (Lloyd et al., 2010) and therefore asfood behaviours established in childhood/adolescence may ultimately go on to affect adult cardiovascular health it is important to adopt a healthy lifestyle early in life in order to decrease later disease risk. Observing dietary patterns throughout the life course should be beneficial in calculating the time point at which nutritional intake may be most important and also whether tracking one type of dietary pattern over a period of time or changing to a different diet pattern renders an individual more/less likely to be at risk of disease. Dietary patterns are primarily derived via two statistical methods: cluster analysis (CA) and principal component analysis (PCA). Both of these methods have been found to give similar results in the ALSPAC study at 7 years of age (Smith et al., 2011).

Tracking over time is easier to quantify for patterns that have been derived using cluster analysis as this method assigns an individual to one category only at each timepoint. Change in category can then easily be determined. In comparison, PCA results in a score for each individual for each pattern obtained. We will therefore examined patterns obtained from CA in the first instance.Four clusters have been observed in ALSPAC using food diary data at 7, 10 and 13 years of age (Northstone et al., 2013). We will use this information to investigate whether dietary patterns and their tracking have any implication upon known risk factors for CVD (fat mass, blood pressure, CIMT and blood lipids) observed in the cohort at 15 and 17 years of age. Socioeconomic status is a major confounder for dietary intake (Northstone et al., 2012 & 2005). It is hypothesised that there will be a correlation between dietary patterns and measured risk factors for CVD, such that a more healthy pattern will infer decreased risk and that any associations may strengthen with pattern tracking (e.g. where an individual is consistently assigned to the same pattern over time).

Aim 1. To determine the relationship between early life adversity and cardiometabolic health and cognitive function in mid-life.

Study design: We will estimate the association between each of several measures of early life adversity (SEP measured by parental education and occupation; major life events such as parental divorce, death or illness; parental mental health and addiction; warmth, affection and satisfaction with parent-child relationships; perception of happiness of childhood; parental physical or emotional cruelty; sexual abuse; mobility of family indexed by number of schools attended) and 1) trajectories of cardiometabolic health in the ALSPAC mothers or 2) the single measures of cardiometabolic health in the ALSPAC fathers. In both the ALSPAC mothers and their partners, we will also assess the extent of clustering of dimensions of early life adversity, and whether these dimensions have effects on health that are greater or less than would be predicted from their independent associations.

Aim 2. To clarify the role of adult adversity in the association between early life adversity and cardiometabolic health and cognitive function in mid-life.

Study design: We will determine the extent to which social mobility (change in SEP between early life and adulthood), adult relationships, social support and neighbourhood factors mediate or modify the association between early life adversity and trajectories of cardiometabolic health and cognitive function. Within ALSPAC, we will examine male-female differences in the health consequences of early life adversity, using data from male-female partners (using couples who have been together throughout the period of the ALSPAC cohort, as identified by Yoav Ben-Schlomo and Alison Teyhan); these couples are matched at least partially for adult SEP and other life circumstances, but not necessarily for early life adversity.

Aim 3. To examine which factors mitigate or exacerbate the association between early life adversity and cardiometabolic health and cognitive function in mid-life.

Study design: We will examine the roles of trajectories of smoking, alcohol use, depression, and of DNA methylation as mediators or moderators of the association between early life adversity and cardiometabolic health/cognitive function.

Aim 1. Does poor prenatal nutrition (i.e., macronutrients, micronutrients and/or omega 3 fatty acids) impact with DNA methylation at birth, and does continued poor nutrition impact DNA methylation in childhood?

Aim 2. Is the relationship between prenatal poor nutrition and early onset conduct problems greater for those children whose mothers were stressed and depressed?

Aim 3. Is the relationship between nutrition, the key risk factors and an early onset of conduct problems partially explained by DNA methylation?

Aim 4. Use of whole genome-wide epigenetic approaches to identify developmental inter-relationships beween maternal depression and unhealthy nutrition in the prenatal and postnatal periods.

Aim 5. Use of conventional Mendelian Randomization to assess causal relationships between nutrition factors (prenatal and postnatal) and the early onset of conduct problems.

Aim: The aim of this study was to determine whether genetic risk from common genetic risk variants for schizophrenia and ADHD, based on large, case-control genome-wide association studies could predict non-return of questionnaire data by children and parents, as well as non-attendance at clinic for data collection.

Objectives:

1) To detect genetic variants reliably associated with depression in adolescents via genome-wide association approaches in the ALSPAC and TEDS cohorts

2) To identify observational associations between depression and modifiable risk factors using the Mendelian randomization approach

3) To investigate the association between depression and patterns in DNA methylation

Given the paucity of significant findings concerning depression, our first aim will be to investigate the genetic architecture of, and potentially identify genetic variants reliably associated with, depression in adolescents via a combination of genome-wide approaches within both the ALSPAC and TEDS cohorts.

The second aim will be to use genetic instruments to investigate causality in associations between modifiable or environmental risk factors and depression. First, literature searches will be used to identify important observational or proposed environmental exposures for depression. Several of these, such as vitamin D, glycaemic traits, inflammation and physical activity, are available in ALSPAC. Observational associations will be calculated and, for those modifiable risk factors with suitable genetic instruments, MR will be applied to determine whether the association is causal. The ARIES data will be used to investigate associations between exposure to maternal depression and patterns of methylation throughout early development. In particular, we aim to investigate whether early life stress events, such as antenatal and postnatal depression, have an effect on methylation patterns in the offspring. Independent associations between adolescent depression and both antenatal and postnatal depression have previously been shown, which appear to involve different mechanisms. We propose to explore whether this is mediated through DNA methylation.

Aim:

1) identify novel parent of origin variants in relation to DNA methylation in ALSPAC;

2) investigate the effects of known/established parent of origin variants (related to common disease) in relation to DNA methylation in ALSPAC;

3) Investigate the relationship between genotype, methylation and phenotype to better understand parent-of-origin effects on phenotype.

Aims:

1. To detect genetic variants (using GWAS) associated with one-carbon pathway metabolite measures.

2. Investigate how pathway measures are associated with downstream molecular phenotypes (e.g. Epigenetic and metabolic profiles) in the selected subset of individuals.

Aims

To perform Mendelian randomization analyses to investigate the causal effect of maternal pre-pregnancy BMI on a number of pregnancy outcomes using genetic variants combined in a weighted allelic score. Other related exposures including maternal waist-hip ratio, maternal glycaemia and fatty acid profile will also be considered in an Mendelian randomization framework.