Mendelian randomisation studies have not yet clarified the direction of causality between heavy cannabis use and Schizophrenia. Thus, while cannabis use remains the most preventable risk factor for psychotic disorders, it is still unclear what makes some heavy users more susceptible to develop clinical psychosis. This is a question of global relevance with the spreading of laws legalising cannabis use for medicinal and/or recreational purposes.

Recently, epigenetic processes that regulate where our DNA is expressed, have been implicated in both psychotic disorder and substance use. Indeed, genome wide DNA methylation (DNAm) studies (EWAS), which measures where the DNA is switched on or off, have become a tool to look at the biological effects of environmental exposures.
This proposal, nested within a larger MRC Senior Fellowship project, focuses on the development of a genome wide DNAm score associated with regular cannabis use, taking into account both genetic factors and other environmental exposures. These analyses will run in parallel to mouse model experiment of exposure to both THC and CBD (cannabidiol), the most studied ingredient of cannabis. Finally, we plan to examine overlaps in the effect of cannabis compounds on the brain of mice with the effect in human blood tissue, to begin to understand a) the neurobiology of psychosis in the context of heavy cannabis use and b) to build epigenetic and genetic scores that might help distinguish those cannabis users that come to no harm from those who develop a) sub-clinical psychotic experiences paranoia and b) frank clinical psychosis.

Children who experience adverse childhood experiences (ACEs) are at greater risk for psychiatric disorders, chronic health diseases, and poor educational and social outcomes. Experiencing ACEs such as abuse, neglect or bullying in childhood increases vulnerability to poor developmental outcomes, yet not all children who experience such adversity go on to develop adjustment difficulties. Sources of resilience exist on multiple levels: individual characteristics including biological predisposition and psychological coping styles; physical, economic and social capital offered to children and caregivers; psychosocial interventions by mental health, social welfare, and education providers; and government policies that prioritise or neglect maltreated children. This project will integrate methods from social epidemiology and developmental psychology to understand the trajectories of risk and resilience amongst children who experienced ACEs, by using longitudinal analysis and advanced statistical methods to examine risk and protective factors at the individual, family, school and community level. Findings will inform intervention strategies and policies aimed at promoting resilience amongst vulnerable children.

The smoking score was developed in the Raine Study (partner: University of Western Australia/Telethon Kids Institute, Perth, Western Australia) and the Northern Finland Birth Cohorts 1986 and 1966 (partner: University of Oulu, Oulu, Finland). For the score development, DNA methylation data measured with the Illumina HumanMethylation450 BeadChip array was utilized, together with a binary variable, indicating if the study participant’s mother was smoking during pregnancy.

Our hypothesis is that the smoking score captures and quantifies latent information on early life exposure. We also hypothesize that it quantifies the persistent changes that occur systemically in the offspring with maternal smoking exposure in utero.

The last decade has seen a dramatic improvement in our understanding of how our genes affect our height, body mass index (BMI), mental health, cancer risk, and many other traits. This has been facilitated by technological developments which allow us to measure a persons’ epigenetic data accurately and economically. Almost all epigenetic studies investigate traits collected at a single timepoint (e.g. adult height), and the epigenetic sites associated with these traits are then found using an epigenome wide association study (EWAS). However, some traits such as BMI change over time, and the epigenetics of these repeatedly measured traits remain poorly understood. This project will apply new approaches for epigenetic analysis of longitudinal traits - in particular BMI measured repeatedly from birth to adulthood and depressive symptoms from later childhood through adolescence.

Adolescence is marked by rapid social and biological change and a sharp rise in the incidence of depression and some forms of anxiety. Youth anxiety and depression are typically foreshadowed by earlier childhood difficulties and exposure to multiple adversities; additionally, there are far-reaching consequences for outcomes in adulthood – for education and employment, relationships with others, and physical and mental health. Young people today are also more likely to experience anxiety and depression than previous generations.

There is substantial variability in the developmental course of depression and anxiety, with our own research showing distinct developmental pathways leading to depression, and differences in outcomes. For example, some children show chronic or escalating mental health difficulties; others (even those at high risk) do not develop anxiety and depression. Understanding when, how and in whom to intervene to reduce risk is important to prevent anxiety and depression and to improve outcomes. We aim to identify early predictors of risk (social, clinical and genetic), consider protective mechanisms that build mental health resilience and optimise outcomes, and test the causal role of identified risk and protective factors.

Through comparison with other cohorts, we will test the extent to which findings generalise, and what the reasons are for increases in youth depression and anxiety in more recent generations of young people.

There is limited evidence for the role of parental religious beliefs in offspring mental health, with the existing literature predominantly concerned with American samples, and a limited number of mental health outcomes. This project seeks to examine the role of parental religious beliefs, and how they may predict offspring mental health in childhood and adolescence. This will be done using a broad range of mental health measures, and possible confounding, mediating, or moderating variables.

Children with idiopathic short stature (ISS) are defined by height below 2 standard deviations (SD) of the mean for age and sex without any endocrine, metabolic or other disease explaining the short stature. Recently the US Food and Drug Administration has approved Vosoritide for individuals with extreme short stature which is caused by a single gene mutation.

However, there are causes of extreme short stature that are not due a single gene mutation. These include polygenic predisposition to disease. We have recently generated a polygenic risk score that can reliably predict adult height, and this was tested in the ALSPAC cohort. We hypothesize that children who are extremely short due to a polygenic cause may also benefit from Vosoritide therapy.

Therefore, we posit that a polygenic risk score can help to identify children at extreme short stature. It could also help to predict if Vosoritide therapy could be helpful, by assessing if genetic changes in the biological pathway that is influenced by Vosoritide influences height. Last, we can use this polygenic risk score to better understand if extreme short stature is associated with other diseases and medically-relevant traits.

This PhD project aims to study the underlying relationship between eating architecture (initially understood as size, timing and frequency of eating, but intended to be expanded to other aspects of nutrition such as dietary patterns, macronutrients and food preference) and adiposity-related traits in the population.

Exploring the determinants of nutrition-related behaviours, especially related to obesity – currently one of the major public health problems of the westernized world – may contribute to the understanding of the complex interactions between genetics, physiology, environment surrounding people’s eating behaviours.

Advanced parental age has been associated with adverse offspring health outcomes, but the biological mechanisms underlying these associations remain unclear. Research suggests that epigenetics may play a role, especially since advanced parental age has been associated with lower levels of offspring DNA methylation, which in turn, have been associated with adverse offspring outcomes. Nevertheless, the association between advanced parental age and epigenetics has only been explored in two studies with relatively small sample sizes. Larger epigenome-wide association studies are required to identify more CpG sites and improve our understanding of epigenetic mechanisms underlying the observed associations between advanced parental age and adverse offspring health outcomes.

References:
1. Adkins RM, Thomas F, Tylavsky FA, Krushkal J. Parental ages and levels of DNA methylation in the newborn are correlated. BMC Med Genet. 2011;12:47.
2. Markunas CA, Wilcox AJ, Xu Z, et al. Maternal Age at Delivery Is Associated with an Epigenetic Signature in Both Newborns and Adults. PLoS One. 2016;11(7):e0156361.
3. Pinheiro RL, Areia AL, Mota Pinto A, Donato H. Advanced Maternal Age: Adverse Outcomes of Pregnancy, A Meta-Analysis. Acta Med Port. 2019;32(3):219-226.
4. Ryer EJ, Ronning KE, Erdman R, et al. The potential role of DNA methylation in abdominal aortic aneurysms. Int J Mol Sci. 2015;16(5):11259-11275.