Smoking is highly co-morbid with several psychiatric conditions, but understanding the causal nature of this relationship is complicated by well-described issues of confounding and reverse causality. Mendelian randomisation uses genetic variants associated with an exposure (e.g., smoking) to examine causal pathways between the exposure and outcomes. Previous genetic instruments for smoking have only captured discrete aspects (e.g., initiation, heaviness of smoking), limiting power and requiring individual level data on smoking status for analyses of heaviness of smoking. To overcome these issues, we are developing a novel genetic instrument for comprehensive smoking exposure, which takes into account duration of smoking, heaviness of smoking, time since cessation, and a simulated half-life constant to capture the exponentially decreasing effect of smoking on health over time. Our instrument includes both smokers and non-smokers, removing the need to stratify on smoking status.
We have begun work on this instrument by conducting a genome-wide association study (GWAS) of our comprehensive smoking measure in the UK Biobank (N=463,003) and identified 124 independent SNPs associated at the genome-wide level of significance. Our two-sample Mendelian randomisation validation analysis confirmed that smoking causes lung cancer and coronary heart disease. To further establish the validity of the instrument we need to check that it predicts smoking in an independent sample. Here we hope to use ALSPAC, checking whether a polygenic risk score for lifetime smoking exposure predicts actual smoking behaviour. Secondly, we need to check that the instrument is not spuriously associated with any traits other than smoking. We can do this by checking for associations with other outcomes in ALSPAC.
If the instrument predicts smoking in ALSPAC and is not associated with other unexpected traits, we hope to go onto use our novel genetic instrument to explore bi-directional effects between smoking and mental health, focusing on schizophrenia and major depressive disorder.

We want to quantify what the impact of genetics across the whole genome has on weight and risk of severe obesity from birth to middle adulthood.

The large increase in the prevalence of respiratory diseases over the last decades, in the West more particularly, cannot be explained by genetics only. It has been hypothesized that these increases are a consequence of changing environmental and/or lifestyle factors. Given the multifactorial aspect of these diseases, it is thus important to take into account the interrelations between these factors and respiratory health. The interrelations between body mass/body composition, physical activity, diet and lung function in childhood and adulthood have been incompletely addressed, likely because their time-dependent and bidirectional nature represent a methodologically challenging research question. Marginal structural models (MSMs) allow estimation of causal effects in observational studies by addressing time-dependent confounding (Robins JM et al. Epidemiology 2000). This approach has still limited application in respiratory epidemiology. We aim to investigate the joint and independent causal effects of body mass/body composition, physical activity and diet on lung function during childhood and early adulthood using MSMs in children from the ALSPAC study.

LifeCycle is a cross-cohort collaboration which brings together data from pregnancy and child cohorts from across Europe and also Australia to facilitate studies on the influence of early-life exposures on cardio-metabolic, respiratory and mental health outcomes. The end product of this collaboration is a sustainable data resource known as the EU Child Cohort Network.
In the proposed paper we provide a detailed description of the EU Child Cohort Network’s core variables; a set of basic variables, derivable by the majority of participating cohorts and frequently needed as covariates in life-course research. We firstly describe the process adopted to establish a list of core variables and the protocol developed to harmonise these core data, thus making them interoperable. This protocol also defines the harmonisation process adopted generally within LifeCycle. Secondly, we describe the catalogue developed to ensure that all EU Child Cohort Network data are both findable and reusable. Finally, we describe the core data themselves, including the proportion of variables harmonised by each cohort and the number of children with harmonised data.
We would also like to provide some summary statistics (N and % for categorical variables, and N, mean, standard deviation for continuous variables) on some key variables (namely, sex, maternal education at baseline, mother’s ethnic background, mother’s parity, mother’s smoking in pregnancy, size for gestational age, whether the index child was ever breastfed, age of the mother at birth, birth weight and gestational age). These variables have already been harmonised as part of the LifeCycle project. To obtain the requested summary statistics, we have prepared some R code for individual cohorts to run on their harmonised datasets.
The paper is already written and we hope to submit it to the Journal of Epidemiology in the summer.

Treatment for mental illness often focuses on changing cognitive patterns (for example, cognitive behavioural therapy). There is much evidence to suggest that cognition is different in those with mental illness but whether change in cognition is a causal risk factor has not yet been established. Classic observational studies of cognitive patterns and mental illness do not get around the problems of reverse causation and residual confounding. That is to say that the change in cognition might instead emerge as a result of the mental illness, or both might be the result of other unmeasured factors.

One way to get around this is using Mendelian randomisation. Here we take genetic variants associated with the trait of interest: cognition and use them to naturally randomise individuals to levels of the exposure. Therefore, analogous to a randomised control trial, we can make conclusions about whether or not the relationship is causal. In this study, we will be looking at the cognitive traits of emotion recognition, working memory, cognitive styles and impulsivity. This research could inform the development of cognitive training tasks as interventions for mental illness.

Socioeconomic disparities in health across the life-course are well-documented, long-standing, and consequential. Research suggests that a significant proportion of the social gradient in health is due to SES differences in health-risk behaviors. Scholarship investigating the underlying mechanisms whereby lower SES increases health-risk behavior points to the mediating role of risk-increasing (or ‘riskogenic’) psychosocial schemas. Specifically, evidence suggests that social context and experiences in development, which are patterned by one’s social position, calibrate psychosocial orientations, including impulsivity or self-control, sensation seeking, and hostile views of relationships, which influence health-risk behaviors and health outcomes. Although the past decade has seen a spate of published GE-health research, few studies have focused on the role of G-E interplay in shaping psychosocial schemas as mechanisms through which SES adversity shapes health disparities. This project will investigate the effects of SES adversity on changes in psychosocial schemas, conceived as socially-calibrated and genetically-influenced endophenotypes which link SES adversity to increased health risk-behaviors. Additionally, although we know that social experiences “get under the skin” to have enduring effects on health outcomes, we lack knowledge on the biological pathways through which such effects persist. Thus, second, and more innovatively, we will engage with the nascent field of social epigenetics to examine DNA methylation (DNAm) as a biological mechanism through which SES-adversity calibrates psychosocial schemas. In this project, we will investigate the DNAm patterns underlying psychosocial adaptations to SES adversity that increase health-risk behaviors, building on work that identifies DNAm as an important molecular underpinning of experience-dependent changes in cognitions, decision-making, and behavior.

This study aims at exploring the possible influence of genetic and epigenetic variants in the newborn brain on neurologic and mental traits and outcomes. This project aims to combine research from the Bristol Neonatal Gene Study and from ALSPAC. This will represent an interesting opportunity to study in detail the effect of specific genetic and epigenetic variants both in newborns and in childhood. We specifically aim to study the main candidate pathways involved in perinatal brain injuries (glutamate signalling and inflammation) and long-term motor, cognitive and behavioural outcomes. We have produced interesting preliminary findings within the Bristol Neonatal Gene Study, which support the involvement of candidate genetic variants in the glutamate signalling and inflammation pathways. The ALSPAC cohort provides a unique opportunity to validate and add to these findings in a large sample with genetic, epigenetic and phenotypic data collected longitudinally from birth to childhood. With the availability of maternal data, it also offers the opportunity to expand the analysis to maternal-neonatal gene-gene and gene-environment interactions. We have the appropriate expertise in genetic and epigenetic research required for this project. In addition, we are coupling this approach with in vivo work on animal models of newborn brain injuries, exploring the (dys)regulation of key genes involved in glutamate transport and inflammation during perinatal insults.

27 SEPT 08 Update from Robyn - The data collection for this project is complete. A number of manuscripts are under various stages of completion.

Peer victimization is a widespread phenomenon with many harmful and persistent consequences, such as anxiety, depression, and even suicidal ideation. However, consequences of can vary widely in presentation and severity, which hinders development of appropriate interventions targeted at alleviating the effects of peer victimization. This may in part stem from the fact that little is known about the biological mechanism through which bullying affects children's psychological development and wellbeing. Therefore, we aim to study how peer victimization is related to epigenetic development and explore to what extent epigenetics mediate the association between peer victimization and negative outcomes in children. We will do this by combining data of two large comparable cohorts, ALSPAC in England and Generation R in Holland.