Polycystic ovarian syndrome (PCOS) is a major health concern that affects up to 10% of reproductive-aged women. This complex, heterogeneous condition is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction. Despite extensive physiologic and genetic studies, the treatment of PCOS remains limited by an incomplete understanding of the pathophysiology of the disorder. Identification of the genetic variants and pathways associated with PCOS susceptibility may provide insights into the pathogenesis of the condition and potential targeted treatments.

We propose to study phenotypes in children that may be associated with PCOS, including obesity, dyslipidemia, and premature adrenarche. Premature adrenarche is a pediatric condition characterized by early production of adrenal androgens such as DHEAS and androstenedione and has been proposed to be a precursor to PCOS in girls. We will calculate a polygenic risk score for PCOS in prepubertal children and test for associations with premature adrenarche and associated cardiometabolic and hyperandrogenic outcomes and biochemical and anthropometric traits. In addition, we will examine these outcomes during the pre-pubertal period in girls who later develop a diagnosis of PCOS in adolescence and young adulthood.

The extension of PCOS genetics to prepubertal children provides the unique opportunity to 1) classify the PCOS pathways into ovarian-dependent factors and nonovarian-dependent factors and 2) characterize the pediatric phenotypes associated with PCOS genetic risk factors, and 3) understand the pre-pubertal manifestations of a future PCOS diagnosis. Overall, investigations in prepubertal children have the potential to provide valuable insights into the mechanisms of pathogenesis and targets for treatment for PCOS.

Cleft of the lip and/or palate is a common birth defect worldwide and occurs at a rate of one in 650 live births in the UK. Being born with cleft places a significant burden on children, their families and the health system as they require surgery (multiple times depending on cleft type), and other interventions to improve appearance, speech, hearing, dentition and other adverse outcomes. They are also at increased risk of psychological, psychiatric and cognitive problems [1]. There are several possible mechanisms underlying these associations that may be operating alone or together. First, they may reflect the psychological, developmental and social impacts of clefting and its treatment. Second, they may reflect genetic factors either as pleiotropic outcomes of genetic susceptibility to clefting or as independently inherited genetic risk.
The aetiology of both cleft and of psychiatric disorders is complex, with common risk alleles [3] [4] of individually small effects as well as rare genetic mutations of large effect and environmental factors playing roles. One group of rare mutations of large effect are Copy Number Variants (CNVs), referring to deletion or duplication of a part of the genome leading to differences between individuals in the number of copies of genes within the affected region. CNVs are known to increase risk of neurodevelopmental disorders (ND-CNVs), such as ADHD and autism, as well as mental health disorders but the presence and the impact of CNVs have not been studied in cleft [5].

The PhD project will provide the first detailed description of neurodevelopmental and mental health outcomes in children with cleft and examine the contributions of genetic and environmental factors. For this we will use two unique genetically informative clinical cohorts of children; the Bristol University Cleft Collective and the Cardiff University longitudinal ExperiencCes of people witH cOpy number variants (ECHO) study. Control samples will consist of the Avon Longitudinal Study of Parents and Children (ALPSAC) and the Millennium cohort which are deeply-phenotyped cohorts of typically developing children.

Socioeconomic disadvantage and stress are associated with adverse pregnancy and child health outcomes. There is some evidence to suggest that these associations may be mediated by changes in placental development and function. However, studies of the placenta are often small or limited to pathologic samples, which may not be representative. ALSPAC routinely collected placentas of participants, including term deliveries, and ALSPAC has rich parental sociodemographic information and longitudinal follow-up on child health and development. This presents a unique opportunity to estimate associations between socioeconomic disadvantage and child development and to examine the mediating role of placental pathology in a well-characterized, representative sample.

Pain which lasts for more than 3 months is termed "Chronic Pain". It often occurs in the absence of obvious injury. It can be very difficult to treat.
We believe that the body may produce antibodies (part of the natural defence against infections) that can activate "pain" nerves. This may contribute to Chronic Pain.
Antibodies, produced by the body are known to sometimes interfere with the nerves in diseases such as Myaesthenia Gravis.
If we can demonstrate that these antibodies can cause chronic pain, we will be able to treat patient with chronic pain much more effectively.

Recent data show young adults (age 16-30) experiencing extreme loneliness. Loneliness has a detrimental impact on health and wellbeing, however existing studies largely focus on older adults, meaning the full impact in young adults is unclear. Of particular concern is the likely adoption of negative health behaviours (including addictions), the harmful overuse or underuse of NHS services, and potential for self-harm or suicide in young adults experiencing loneliness. Also, of concern is the negative impact on milestones such as finishing school, further education and getting a first job, which contribute to household wealth and wellbeing. This research aims at using the ALSPAC data to assess the impact and cost of young adult loneliness in the UK with respect to health status, over or under use of health care resources, education attainment and unemployment. Regression analysis will identify correlations between variables, while causal relationships will be investigated through instrumental variable analysis and propensity score matching. Results will be used to update existing costs estimates that have focused only on older adults. Analysis will be conducted on data before, during and after COVID-19 to consider the prevalence and impact of young adult loneliness through COVID-19, given the likely exacerbation of loneliness in the context of social distancing. This research will develop understanding and inspire greater consideration of loneliness in young adults promoting cross-sector involvement and improved support.

Risk towards poor mental health is impacted by a number of biological, psychological, and social factors that work together throughout the lifespan and across generations. A large body of research supports the influence of the prenatal environment on children’s developmental and mental health outcomes. For example, prenatal depression has been linked to later risk of depression in children, and prenatal depression, prenatal anxiety, and stressful life events during pregnancy have all been associated with risk of anxiety disorders in children. There is also growing interest in understanding the potential biological causes that may drive these relationships. In particular, inflammation has been suggested as a potential factor that may influence these associations, due to its role in the onset of depression and other mental and physical health disorders. However, few studies to date have examined the role of inflammation in relationships between prenatal maternal stress and child and adolescent mental health outcomes, calling for continued research in this area.

In addition, although the relationships between prenatal stress and child and adolescent mental health outcomes are well-established, children continue to be exposed to a number of influences, both positive and negative, after birth. For example, research suggests that the relationships between prenatal stress and child outcomes may differ depending on how mothers are able to cope with the stress they experience, including their degree of partner and social support, and availability of psychological resources including higher self-esteem and self-efficacy. Furthermore, a growing number of studies suggest that parenting behaviours may play an important role in these associations. For example, children exposed to parental warmth and positive relationships with their mothers and fathers may be buffered to the impacts of early adversity; conversely, children exposed to maltreatment or harsh parenting may exhibit increased vulnerability. Considering how both maternal coping resources and parenting further increase or reduce the risk towards chronic inflammation and later mental health outcomes in children exposed to prenatal stress, however, is an area that requires further investigation. In addition, the influence of many coping resources and parenting behaviours on later inflammation is an understudied area.

There is variation in when and how children develop speech in early childhood. Some children experience difficulties in the process but many of these have speech which is well developed by the time they start school. Some children have persistent problems which continue into early childhood. These problems can be associated with problems with educational attainment in older childhood as well as having difficulties in making themselves understood. Some of these children will have problems with their speech as a result of subtle problems with the coordination of the movements required for speech while others will have difficulties associated with the cognitive skills involved in developing speech. Some will have problems with both.
Genes have been identified which are associated with some types of speech and language difficulties but it is not yet clear what part genes may play in persistent speech sound disorder. The analysis outlined in this proposal will enable us to determine to what extent children's problems with speech after they have started school may be associated with genetic factors rather than environmental factors. This information will help us identify how best to help children who present with these difficulties to speech and language therapists and in school.

The work is an effort to collect serological data on past infection status within the population based cohorts of the UK – in particular a set of cohorts which have been selected to report on 4 important axes of variation – ethnicity, age, socio-economic status and geography. The key thing for us is that we are able to move swiftly to capture the signature of infection and that we are able to exercise the cohorts (and all they bring re. retrospective data and new sample and data collection capacity) whilst being complementary to the efforts of existing studies – importantly REACT 2 and UKBB. We have been focusing on LFT and talking to those testing and developing kits. We have been pursuing the Orient gene kit as a strong option here – given performance, testing and our aim to use this as an epidemiological tool rather than an individually relevant test solution. Paul Elliott has been extremely generous with time and details re. the REACT 2 study and we are now proceeding with Orient gene as a viable option (home-based lateral flow antibody testing). We have been able to work with Peter Diggle (Lancaster) to develop the structure of our sampling frame across the 6 cohorts and now are primed to get approval locally (a process already started re. the PPI around these tests) in order to deliver kits to participants.

Stark inequalities in health already exist in the UK, with people from lower socioeconomic backgrounds suffering from greater levels of ill health across multiple domains. The covid-19 pandemic potentially threatens to worsen these health inequalities. The ‘lockdown’ changed people’s behaviour radically, but the socioeconomic differences in these experiences are not well understood. Some groups of society may have increased health-promoting behaviours – for example, engaging in more physical activity and preparing more food within the home. Other groups may have experienced adverse changes in health-related behaviours – for example, smoking more or consuming more alcohol in response to the stress and anxiety induced by the pandemic. It is possible these differences are socioeconomically patterned, and could therefore worsen pre-existing inequalities. Another key factor likely to influence patterns of behaviour change during the pandemic is household/family structure. For example, parents with children and individuals shielding or living with a household member who was shielding may have been less able to engage with health-promoting behaviours.

Data from the Office for National Statistics demonstrate that between 23rd March and 5th April 2020, 27% of the UK workforce were furloughed due to the COVID-19 lockdown. Many others lost jobs, or had working hours and income reduced. The adverse financial and employment consequences of the covid-19 lockdown are concentrated in already vulnerable groups of society – they are more likely to be experienced by people in insecure or low-paid jobs. The young adults in ALSPAC are in the age groups most likely to have been affected by furlough, job losses, and loss of pay or hours (https://www.resolutionfoundation.org/publications/young-workers-in-the-c...). Detailed pre-pandemic data from the ALSPAC cohort offers the opportunity to better understand which groups of society were more likely to be impacted financially by the lockdown. We will explore whether SEP, adverse childhood experiences, pre-existing mental health problems, obesity, smoking, alcohol use, shielding or living with a household member who was shielding, and family structure are associated with greater likelihood of adverse financial changes during covid-19, and hence whether the lockdown is likely to exacerbate health challenges for these groups.