We will examine whether depression is related to the development of cancer by summing results of 18 large studies. We will examine whether depression predicts cancer only in some groups of individuals, for example males. In addition we will examine whether depressed individuals live less healthy, for example smoke more, and whether this is the reason they are more likely to develop cancer.

Most research on parental job loss has focused on the negative outcomes for the adults experiencing it, but much less is known about the effects on their children (Kalil, 2013). Emerging evidence suggests that parental job loss increases the likelihood of poor academic outcomes (e.g., school dropout, grade retention, Kertezi & Kezdi, 2007; Stevens & Schaller, 2011), but the mediating processes for these effects are not well characterized. Furthermore, we know little about the consequences of parental job loss for the offspring’s mental and physical health, or about factors that may promote resilience for youth exposed to this economic stressor. Our team combines expertise from psychology (Guyer, Hastings, Hostinar, Thompson), family sociology (Conger) and economics (Bitler, Page) to address these gaps by examining several questions regarding the effects of parental job loss on youth’s psychological and physical wellbeing. Our research questions are informed by the family stress model (Conger et al., 2010), which posits that adverse economic conditions can be stressful to families and that this stress can shape interactions within the family through parenting practices, parent-child interactions, and interactions between parents, which can lead to poorer health, achievement, and psychological adjustment for children. ALSPAC affords a unique opportunity to test this model through its longitudinal design, allowing us to simultaneously examine (a) associations between childhood exposure to parental job loss and psychological, physical and academic/cognitive outcomes across development, as well as (b) mediating pathways (e.g., altered parent-child interactions; children’s and parents’ stress physiology), and (c) moderators or protective factors (e.g., personality, peer relationships).

The link between childhood abuse and development of social problems and gastrointestinal disorders is well documented. However, some children exposed to abuse go on to lead relatively undisturbed lives, while others are totally devastated. This analysis will seek to understand whether risk and resilience to traumatic experiences may have an evolutionary foundation by using a framework provided by Polyvagal Theory, which outlines the biological link between neural circuits that regulate body states including gastrointestinal functions (and disorders of other subdiaphragmatic organs) and the regulation of social engagement behaviors (Porges, 2001; 2007; 2011). Within this framework, the function of neural systems that regulate body state during the perinatal period may determine individual differences in the long term consequences of severe childhood stressors and traumatic experiences. Thus, the goal of the proposed analyses is to examine whether perinatal variables, related to visceral regulation, will contribute to the risk for gastrointestinal disorders and social problems following childhood abuse.

The Eating Disorders (full and partial syndrome anorexia nervosa and bulimia nervosa and binge eating disorder) are life-threatening illnesses that start in adolescence and affect between one and two in ten adolescents and young adults. There is a lack in our understanding of why eating disorders develop, which affects our ability to develop treatment and adequately prevent eating disorders. This project builds on our preliminary data showing that metabolism and growth might play a role in the development of eating disorders; and aims to test the hypothesis that metabolic function, appetite and growth factors might precede onset of eating disorders. We also aim to explore whether these factors might be related to individuals’ genetic make up, using novel methodologies and based on novel genetic findings. This study will be fundamental in starting to understand new risk mechanisms for adolescent and young adult eating disorders that can be further investigated in larger and more detailed studies following this project.

Neurodevelopmental disorders (NDDs) are conditions involving perturbed brain development with manifestations ranging from specific to global impairment of developmental domains such as communication, social interaction, motor skills, cognition, activity and emotion. This includes autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), disorders of language, learning and motor functions, intellectual disabilities, schizophrenia and bipolar disorder. NDDs are highly prevalent in the population (~5% of children), typically emerge early in life, and are associated with substantial and long term disability.

The aim of this study to investigate the role of potentially modifiable risk factors for NDDs, using Mendelian Randomization (MR). Multiple pre-/perinatal risk factors are associated with NDDs, including nutritional deficiency (vitamin D deficiency, fatty acids), thyroid dysfunction, inflammation and autoimmune conditions, metabolic conditions, stress, smoking and low birth weight. However, results from epidemiological studies have been inconclusive and the causal role of these risk factors has not been established for most NDDs. Studies using methods that strengthen causal inference are important so that the role of these potentially modifiable risk factors can be determined.

In this project we plan to use MR analysis, whereby genetic variants robustly associated with the risk factors above are used as instrumental variables (IV) to examine whether they have a causal effect on NDDs (categorical disorders and dimensional traits). We will use two-sample MR in which the IV-risk factor and IV-outcome associations are obtained from non-overlapping samples (Burgess et al., 2015). First, published GWAS studies will be used to identify genetic variants robustly associated with the risk factors. Second, these genetic variants will be used to calculate a genetic score for each risk factor in an independent target sample (ALSPAC). Standard linear and logistic regression models will be used to estimate the effect of each risk factor on the NDD trait of interest in the ALSPAC target sample, using the genetic scores as an instrument.

We will also employ additional methods such as positive and negative control designs to strengthen causal inference (Lawlor, Tilling & Davey Smith, 2017).

References

Burgess S, Scott RA, Timpson NJ, Davey Smith G, Thompson SG, Consortium E-I (2015). Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. European Journal of Epidemiology 30, 543–552.

Lawlor DA, Tilling K, Davey Smith G (2017). Triangulation in aetiological epidemiology. International journal of epidemiology. [Epub ahead of print]

Cannabis is the most commonly used illicit drug with particularly high rates of use among young people. The question of whether cannabis is harmful remains the subject of heated debate. The rapidly changing attitudes towards the legalization of cannabis for medical and recreational purposes add urgency to the need for scientific answers. Adolescence is of particular concern because use in this period has been associated with altered brain development, long-term health effects, and dramatically higher odds for meeting DSM-IV criteria for cannabis use dependence.

Two particular factors limit inferences from current research on the health effects of adolescent cannabis use. First, as most findings involve cross-sectional studies, it is unclear whether reported associations reflect the effect of cannabis or preexisting differences between users and nonusers. Thus, we need prospective, longitudinal studies that begin in adolescence and continue into adulthood, and where cannabis use data has been collected before and after initiation. Second, current markers for cannabis exposure in peripheral tissues only indicate whether it has recently been used. Instead, there is a need for biomarkers that reflect its biological impact and can predict the risk for cannabis dependence and negative health outcomes. Methylation marks are ideal for this purpose as they involve the stable methyl-cytosine bond that can be measured cost-effectively in easy to collect genomic (histone-free) DNA.

To better understand cannabis use and its health effects, we propose the use of already collected samples from the Great Smoky Mountains Study (GSMS). The GSMS started 25 years ago with children aged 9 to 13 and is still ongoing. Both cannabis use information and blood samples were obtained at two-year intervals for the same subjects. Using data and blood samples from before and after initiation, this allows us to control for preexisting differences between user groups and link cannabis induced biological changes to health outcomes later in life. To develop new biomarkers, we will first assay the methylation status of all 28 million common CpGs and study the impact of regular cannabis use on the methylome. Next, we will use the methylation data to predict cannabis use trajectories as well as effects of cannabis on short and long-term health outcomes. The most promising methylation sites will be followed up using a targeted assay in samples from the Avon Longitudinal Study of Children and Parents (ALSPAC).

Successful completion of this research will yield replicable methylation signatures of regular cannabis use as well as biomarkers that predict risk of dependence and health outcomes. Our results will inform public health policies and become part of algorithms that can be used to improve prognosis, diagnosis, and treatment.

The inclusion and achievement of boys in the school setting is of significant concern, especially for those whose challenging behaviour is so severe that it disrupts the learning and wellbeing of others. With a reduction in specialist places for boys with behavioural, emotional and social difficulties (BESD), schools are expected to use devolved funding to establish support mechanisms ‘in-house’. If this includes exclusion to a behavioural unit, the socio-economic outcomes for individuals is often dire involving educational underachievement, youth unemployment, crime and substance dependence. My proposed study aims to explore factors associated with the challenging behaviour of boys with BESD in the school setting with the aim of informing possible interventions and strategies to positively support their behaviour and inclusion. These include biological factors associated with puberty and psychological factors such as social skills and cognition.

Both genetic and environmental factors play a role in the etiology of aggression and conduct problems. However, it is unclear which and to what extent genes contribute to aggressive traits and what the relative contribution is of the environment and possible interactions between genetic makeup and environmental exposure. Also the neural and molecular pathways which underlie the aforementioned effects are still unclear.
Therefore, our goals are to identify genes that contribute to the onset and course of aggresion and conduct problems, to assess the effect of the pre- and perinatal environment on the onset and course of aggression and conduct problems and to identify gene-environment interactions between susceptibility genes on one hand, and pre- and perinatal environmental events on the other hand.

To better understand the causal role of lipoproteins and lipid components in cardiovascular and metabolic disease.