If we want to look at the impact of a given exposure on depression outcomes, we commonly require the assumption that the missingness in our depression indicator is "at random". "At random" is something of a misnomer here, and means "random conditional on measured covariates". In the instance that missingness is in fact not at random, i.e. depression itself affects participants likelihood to respond - then common analytical procedures to investigate the impact of exposures on depression may be biased.

We will develop a method to attempt to address this gap, using the effect of smoking on depression at 18 as a question to demonstrate our proposed approach, which will seek to provide testable conditions under which we can falsify the "missing not at random" assumption.

This proposal is part of LongITools (B3289) and LifeCycle projects.

There is inconsistent evidence of an association between prenatal exposure to air pollution and adiposity in childhood. Some studies suggest positive associations, possibly with stronger magnitude in boys, some find no association, and others find inverse associations between prenatal air pollution and adiposity in childhood. Most studies have been relatively small (<3,500 participants) and assess adiposity at a single time point.

The potential mechanisms linking air pollution to adiposity are still uncertain. Maternal exposure to air pollution may affect fetal growth, and intrauterine growth restriction will influence later-life adiposity. Inflammation is another hypothesised mechanism of the association between prenatal air pollution and offspring adiposity, and this might also be part of the fetal growth pathway.

Using data from three birth cohorts (ALSPAC, BiB and Generation R), this project will assess the association of different measures of air pollution (PM10, PM2.5, NO2 and NO) during pregnancy with fetal growth, trajectories of adiposity in childhood, and maternal and offspring inflammation. We will also explore possible sensitive windows by assessing trimester-specific associations, and whether associations differ by sex. If associations of air pollution with fetal growth, inflammation and childhood adiposity are evident, we will explore and quantify possible mediation by fetal growth and inflammation in the association between prenatal air pollution and childhood adiposity.

This proposal is part of LongITools project (B3289).

Blood pressure tracks from childhood to adulthood, and elevated blood pressure in childhood or adolescence is associated with several intermediate markers of cardiovascular disease (CVD) and with CVD events and mortality in adulthood. There is a growing body of evidence showing that ambient environmental exposures, such as air pollution, noise and many characteristics of the built environment are associated with high blood pressure/hypertension in adulthood, and some associations with blood pressure have also been observed in children.

Early-life, especially prenatal and early postnatal, is a period of rapid development and particularly vulnerable to environmental factors, and adverse exposures in this period could lead to long-term health effects, including higher risk of CVD. Some studies have shown associations between prenatal ambient environmental factors and blood pressure in children, including some measures of the built environment (e.g., facility density, facility richness and building density), noise, temperature, and air pollution. Investigating whether early-life ambient environmental factors are also associated with changes in blood pressure in different developmental periods will further contribute to the understanding of the importance of environmental exposures to the risk of hypertension across the life-course.

Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we aim to assess the association of a range of ambient environmental exposures in early-life with changes in systolic (SBP) and diastolic blood pressure (DBP) during three developmental periods: childhood, adolescence, and early adulthood. We will also seek to replicate the associations found in ALSPAC in other independent European cohorts part of the LongITools project (Generation R, EDEN, PANIC and NFBC 1986).

Individuals with attention deficit hyperactivity disorder (ADHD) may undergo different developmental trajectories throughout adolescence. Previous evidence has indicated that neural signatures and genetics could help to distinguish individuals with persistent ADHD symptoms from those remitted. However, little evidence has been provided to demonstrate whether environmental risk factors, such as substance use, could also affect the development of ADHD symptoms.

The aim of this project is to study self-harm and suicide attempts and ideation in adolescents and young adults (AYAs). We will use ALSPAC data to classify the cohort into different psychopathology groups (i.e. groups displaying similar psychiatric condtions like anxiety, depression etc.) and then to see which groups are at most risk of later self-harm or suicide. Furthermore, we will study how people transition between these different latent or hidden groups over time. Ultimately, we wish to examine the aetiology of, and then the trajectories to, self-harm and suicide in AYAs and get a clear picture as to the risk factors and life circumstances for those in the AYA group who later end up exhibiting this sort of behaviour. If this analysis is successful, we then hope to create a risk prediction model for self-harm and/or suicidal ideation and behaviour in AYAs so that implementation efforts can be put in place to prevent future self-harm and suicidal behaviour in AYAs.

The change in body weight from infancy to adulthood may impact later cardiometabolic health. In particular, early onset of excess weight gain and long duration of obesity in youth have been associated with an increased risk of cardiometabolic comorbidities in adulthood. High and low birth weight for gestational age, indicating abnormal fetal intrauterine growth, are also associated with an increased risk of cardiometabolic comorbidities in adulthood. There may be an interaction between birth weight and the change in body weight from infancy to adulthood, where the influence of weight gain on cardiometabolic health may depend on birth weight. In the present study, we aim to uncover the independent and combined effects of birth weight and the change in body weight from infancy to early adulthood, on cardiometabolic health in adulthood.

Information can be obtained from ALSPAC (B number folder) or the UK LLC on request

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 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.