Depression is the leading cause of global disability with over 300 million people suffering world-wide. Estimates suggest that up to two thirds of patients do not recover following their first antidepressant treatment and up to one third do not recover after multiple treatments. Therefore, it is critically important to identify factors that predict recovery and reduce risk of relapse. Current methods in genetic epidemiology focus on predictors of mental illness onset. While this is crucial to prevent new diagnoses, it does little to help individuals already suffering. Therefore, the Recover project aims to extend current genetic epidemiology methods to better understand recovery from depression. The methods developed here will begin with a focus on depression but can also be extended to other mental illnesses. First, we will develop trajectories of depression using continuous longitudinal measures in two critical time points, 1) adolescence and early adulthood and 2) during and post pregnancy. Second, using these trajectories as outcomes we will explore many modifiable predictors of recovery. Third, we will use cutting-edge causal inference techniques to test whether or not these predictors are causal. And finally, we will develop novel technologies to capture fine-grained fluctuations in mood. Taken together, this work will lead to better interventions and inform adjuncts to treatment having real impact for the growing number of individuals suffering from depression.

Previous research has indicated that individuals with ADHD have an increased likelihood of developing mental health problems such as depression, anxiety and antisocial behavior. Despite mental health problems being increased in individuals with ADHD, not all children go on to develop poor mental health outcomes. Research has indicated that resilience is a dynamic process that arises from normal adaptive mechanisms and can be influenced by many factors. However, why some individuals with ADHD show higher levels of resilience and better outcomes compared to others is not yet well understood. One way of defining resilience is better-than-expected long-term mental health outcome than predicted by initial severity of childhood ADHD. Therefore, the current research project will focus on first identifying risk mechanisms which increase the likelihood of individuals with childhood ADHD developing adult mental health problems, and then will aim to identify potentially modifiable protective factors that could be the focus of prevention and intervention programs.

Epidemiological and clinical studies interested in circulating glucose as a risk factor or outcome typically measure levels in the blood at a single or widely spaced time points (e.g. every few years). While these are important health indicators, there has been an increasing appreciation that glucose levels and variability in free-living conditions during both the day and night, may also provide important health measures in clinical (e.g. diabetic or obese) and ‘healthy’ populations.

Continuous glucose monitoring (CGM) systems measure interstitial glucose levels ‘continuously’ by implanting a sensor subcutaneously. This produces a sequence of measurements for each participant (e.g. the average glucose level every 5 minutes over several days), that can be used to assess how a person’s glucose levels vary over both the day and night. We have recently published a novel software package called GLU, for deriving a consistent set of summary variables from CGM data. The derived summary variables can be used in analyses to assess how different characteristics of glucose levels and variability relate to health exposures and outcomes.

Individuals with Attention Deficit Hyperactivity Disorder (ADHD) have difficulties with sustaining attention, being overactive and being impulsive. It is one of the most common childhood disorders and causes difficulties in school, and with family relationships and friendships, whilst those with ADHD are also at higher risk of other difficulties such as anxiety and depression both in childhood and later life. Not all individuals with ADHD have the same problems though, so it is important to understand who is at greatest risk of them. Difficulties with attention or hyperactivity are present across many people whilst only some have sufficient problems to be diagnosed with ADHD. International guidelines indicate where the dividing line between having a diagnosis or not is set, but we know that individuals who do not meet this diagnostic threshold can still have difficulties due to their ADHD symptoms whilst even in those with a diagnosis, the specific constellation of problem behaviours differs between individuals. This project aims to examine how differences in the symptom presentation and impairments in children are linked to other difficulties they have in childhood and as they grow into adulthood. It will also look at how genetic risks for ADHD and other disorders are related to these different presentations. This will be examined in both the general population (the ALSPAC cohort) and a clinical sample of children with ADHD, with additional replication in other international cohorts.

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.

Adverse childhood experiences (ACEs) such as abuse, bullying or family disruption are increasingly recognised as one of the most potent determinants of later mental health problems. Estimates suggest that mental health problems, including depression and self-harm are at least double among those who have been exposed to ACEs. Despite the recognised importance of ACEs to later mental health outcomes, relatively little is known about the characteristics of ACE’s that have the greatest impact. Firstly, many studies have relied on cumulative scores, whereby ACE’s are simply dichotomised and summed. This approach assumes that each ACE contributes equitably to the outcome of interest and that they operate via the same mechanisms. Other research has focused on the relationship between individual ACEs’ and mental health. Although such studies have provided useful insights, it is known that ACE’s often co-occur and most have failed to take account of this clustering. Person centred approaches such as Latent Class Analysis (LCA) could be used to identify variability in ACE profiles between individuals and investigate potential differential associations with mental health, demographic factors, and mechanisms. Secondly, little attention has been paid to the role of timing, chronicity, or recency of exposure in relation to mental health, and findings from existing studies have been inconclusive. Disentangling these effects is challenging as it may be that those who have been exposed earlier in childhood have also been exposed for longer. This PhD will address these limitations and generate valuable new insights into the relationship between ACEs and two mental health outcomes – depression and self-harm.

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.

Attachment theory explains social, relationship and personality development across the lifespan (Bowlby 1969) and has been shown to provide a psychological framework for understanding mental ill health (Mikulincer & Shaver, 2007). The basic postulation is that very early childhood social interactions with primary caregivers are internalised to create and maintain conscious and unconscious mental representations of the self and others. These form the basis of ‘attachment styles’, which have an impact on close relationships and ability to regulate emotions. There is extensive evidence that attachment style is a predictor of coping strategies, adjustment in response to stressors and therefore a vulnerability to mental health problems (see Mikulincer & Shaver 2012 for a review). Research has widely demonstrated an association between secure attachment style and well-being and positive mental health, whilst both insecure attachment styles (anxious and avoidant) have been associated with poor relationship quality, psychological vulnerability and maladjustment, and mental health difficulties (e.g. Sroufe et al., 1999; Hankin et al., 2005; Mikulincer & Shaver 2007; Groh 2016; Spruit 2019). However, the direction of causality is less well established as most studies rely on cross-sectional design and measure attachment style as a discrete variable at a single point in adulthood.

By using a large prospective birth cohort, we will be able to (a) investigate the prospective relationship and (b) use latent variable modelling of repeated measures of attachment to create a more robust and detailed measure of attachment style. This will aid more nuanced explanations of how and when insecure attachment style may lead to mental ill health, such that the association can be interrogated to identify possible intervention targets.

This proposal has implications for healthcare provision and public health policies around childhood and parental interventions to support research to address the growing number of mental health difficulties in later adolescence.

Multiple Sclerosis (MS) is a disorder of the brain and spinal cord which affects about 1 in 1000 people worldwide. In people with MS (pwMS), the immune system attacks the lining of nerve (myelin), leading to ‘attacks’ of disability which can last days-months, and a gradual accumulation of disability over time. Although there are many effective treatments for MS, there is still no cure. MS was previously thought to mainly affect White people, but recent evidence suggests this is untrue: in the USA, the number of newly-diagnosed people with MS is now higher among African American individuals than individuals of White European ancestry.

Most of our understanding of what causes MS comes from studies of European individuals. The largest genetic association study to date revealed over 200 sites in the genome associated with MS, but it remains unclear whether these insights - from an exclusively European cohort - apply to individuals from different ethnic backgrounds.

In this study, we attempt to perform the largest genetic association study of MS among Black, Asian, and Minority Ethnic (BAME) individuals to date in the UK. We will collect genetic data from people with MS and healthy controls from BAME backgrounds, and we will systematically search for genetic variants more common in the pwMS. We anticipate that this research will advance our understanding of what causes MS in BAME individuals, and may have important implications for our understanding of the causes of MS more broadly.