This is part of an EU proposal which will be led by Olle Bygren at the Karolinska Institute in Stockholm. The over-arching aim of the study is to determine transgenerational effects of smoking, stress and famine on subsequent generations. We propose to undertake the following two work-packages using ALSPAC:

1. Transgenerational smoking studies:

Detailed information was collected from the parents during pregnancy concerning their own backgrounds, including their childhood. The details included the age at which the parents started to smoke, the maximum amount they had smoked in their lifetime, the duration in years that they had smoked,and the amounts they were smoking at three stages of the study pregnancy. There was also information on the preceding generation [including whether the parents' own parents were smokers, and whether the grandmother smoked when expecting the study parent]. Information on the study 'child' is now available concerning the age at which he/she started smoking, and the amount smoked in adolescence and will be available for the early 20s.

The data currently available allow detailed time-related data on active and passive smoke exposure of the grandparents, the parents and the child. Although we have carried out research projects on: (a) the association between paternal onset of regular smoking in the pre-puberty [slow growth] period, and (b) exploration of the effects of parental prenatal smoke exposure on the anthropometry of the study children, there is much still to be done.

The long-term effects across the generations of active and passive smoke exposure will be assessed for the first time in a human population. This work-package will determine whether there are other outcomes [we have already shown associations with height, fat and lean mass in the next generation to age 17; these observations will be extended in this work-package to age 24]. Candidate outcomes will include factors that have been linked with smoking in a single generation or with prenatal exposure, but not across generations. Possibilities include: markers of the metabolic syndrome such as insulin resistance, reproductive outcomes such as miscarriage and subfertility; myopia; hyperactivity; conduct disorder and criminal behaviour; neurocognitive and motor development.

2. Transgenerational stress studies:

Detailed information was collected from the parents during pregnancy concerning their own backgrounds, including their childhood. Information included traumatic events, such as separation, divorce or death of a parent, physical or emotional abuse and neglect, with a childhood traumatic life event scale of over 40 items. The parents also completed life event scales to cover the first half of pregnancy, and subsequent approximately annual periods for the first 10 years after delivery. In parallel a series of similar questions elicited traumatic events experienced by the study child at approximately annual periods.

The data currently available allow detailed time-related data on traumatic events to the parents and to the child. Ideally, the study would benefit from knowledge of traumas to the generation before. This work package will be used to make detailed enquiries of the parents in regard to the childhood of their own parents. This would particularly enquire about their experience of World War II - where were they, were they evacuated, were they bombed, did they lose family members as a consequence, etc.

Outcome variables that will be considered include neurocognitive development and motor abilities [we have already shown a strong association between maternal stress in mid-childhood and developmental coordination disorder in the child], as well as growth. We will look in particular at differences between the study offspring according to whether the maternal or paternal parents experienced the trauma, the ages at which it occurred, and the sex of the offspring.

Aims

This study has five specific aims

1. To describe the prevalence of psychotic and affective symptoms at age 18 years according to neighbourhood-level characteristics at 18-years old, 12-years old, 7 years old and birth using advanced spatial epidemiology

2. To conduct Hierarchical Bayesian Modelling (HBM) to investigate the extent to which psychotic and affective symptoms share a common risk component at the neighbourhood level at each period of the life course

3. To conduct multilevel logistic regression to examine whether duration of exposure to neighbourhood level social disadvantage is associated with the risk of psychotic symptoms at age 18.

4. To examine whether maternal and child-reported perceptions of neighbourhood safety and cohesion are associated with elevated levels of psychotic symptoms, depressive and anxiety symptoms and internalising and externalising disorders in chilhdood

5. To explore the pathways through which exposure to neighbourhood social disadvantage over the life course is associated with psychosis risk, with particularly interest in the mediating role of urban living on the association between individual-level early life adversity, childhood cognitive ability and psychotic symptoms at ages 12 and 18.

Aims

* To enhance ALSPAC to incorporate detailed annotation of epigenomic features and additional epigenomic profiling to provide an internationally leading, widely accessible, population-based reference resource.

To exploit the unique scientific opportunities afforded by ALSPAC to identify epigenetic signatures of exposure, track their persistence over time, across generations and evaluate their relationship with development and disease.

To assess the genetic contribution to DNA methylation variation through leadership of a Genome-Wide Association Study Consortium

To develop a "statistical tool-kit" to facilitate the analysis of population-based epigenetic data

Aims:

In this secondary analysis of the ALSPAC study, we have five aims.

First, we aim to establish what constitutes paternal involvement with the child in the perinatal period. We will be evaluating aspects of the father-infant relationship antenatally, as well as postnatally in terms of attitudes towards parenting, attachment with the child, infant temperament, father's mood and feelings, among others. Second, we will study those aspects of early father involvement that are associated with positive outcomes for the child in terms of scores on the SDQ (*others?). Third, we are interested to know whether the mental health of fathers provides a protective effect to the mental health and wellbeing of the mother. Fourth, we are interested to establish how the quality of the father-mother relationship effects the healthy emotional and behavioural development of the child. Finally, we are looking to identify those early factors involved in positive child outcomes in the father-infant relationship that are amenable to intervention.

AIMS

We propose repeating the detailed MRI examinations on 125 participants from ALSPAC who were scanned at 18 years as controls for a study of psychotic symptoms (MRC, PLIKS) in order to test the hypothesis that differences in brain structure and dysregulation in function are associated with AU. Thus:-

1. We will compare MR imaging data from their first imaging session (age 18) to the second (age 24) to assess the cumulative impact of drinking alcohol during the intervening years on:

i) brain tissue macrostructure, grey and white matter, using voxel based morphometry (VBM) and cortical thickness measurements

ii) white matter microstructure, including standard diffusion tensor MRI measures (FA, mean diffusivity) and 'hindrance modulated orientational anisotropy', using diffusion MRI (dMRI), and multi-component relaxometry (mcR) to assess putative markers of myelin along specific pathways(52)

iii) activation of prefrontal cortex (PFC) during a task of working memory (n-back).

2. We will investigate whether MR imaging data (VBM, dMRI, mcR, fMRI as above) from the 1st session predicts use of alcohol during the intervening years.

Specifically we hypothesise that compared with those with limited or no drinking, those with greater cumulative alcohol consumption and those predominantly with a binge pattern during the intervening years will show: i) greater reduction in hippocampal, prefrontal, cerebellar volumes; ii) altered WM microstructure in those white matter tracts maturing later (PFC connections eg cingulum, superior longitudinal fasciculus (SLF)) compared with those maturing earlier (eg posterior limb of internal capsule; iii) greater activation during n-back task with unimpaired performance, in their 1st session and when comparing 1st and 2nd sessions.

3. We will investigate the relationship between current and cumulative alcohol consumption with MR imaging data (VBM, dMRI, mcR, fMRI as above) and from ICCAM protocol at the 2nd session, activation of PFC during inhibitory task (go-nogo(53)), activation of ventral striatum during reward task (MIDT(54)), activation of amygdala during stress (stressful images).

Aims: To identify association between the available variables and the measured metabolites in order to facilitate hypothesis generation.

In genomics there are lots of non-variable base positions, because if a mutation were to occur there it would be deleterious. But of course there are many polymorphic sites that are deleterious too, and a large number that are potentially selectively neutral or functionally neutral.

An old idea for which GWAS data is now providing new evidence is that complex traits follow the infinitesimal model - where an infinite number sites each with an infinitesimally small effect exist. Of course this is not to be taken literally but the point is, is it the case that a very large number of methylation sites influence complex traits, each with a small effect?

Aims: The proposed project aims at investigating the potential mediating role of DNA methylation in the relationship between breastfeeding and children's cognition.

AIMS

To assess whether children who have undergone LASER training suffered less accident and injury over time than a comparable group of children who had not experienced this training. To investigate two specific hypotheses:

1. If long-term accident rates differ by attendence at a LASER risk training intervention?

2. If long-term use of safety precaution measures differ by attendence at a LASER risk training intervention?