Proposal summaries
B4619 - Associations between adverse childhood experiences and cardiovascular risk factors in later life Exploring mechanisms and influ - 16/05/2024
Existing research has demonstrated that adverse childhood experiences (ACEs), such as exposure to violence or childhood abuse, may be associated with negative impacts upon health in later life - for example, increased risk of cardiovascular disease (CVD). However, within their 2017 scientific statement the American Heart Association made a call for further research which used data collected prospectively, i.e., following a population from childhood through to adulthood, to improve the reliability of ACEs measurement (as opposed to recalling ACEs at an adult age) and allow for measurement of possible mechanisms linking adversity exposures to health outcomes in later life. To achieve this, the present project aims to assess how ACEs, measured at 0-16 years of age, may be associated with the risk of CVD measured in early adulthood, from the ALSPAC dataset. We aim to build upon existing research by looking into how various factors, such as mental health status and behaviours posing a detrimental risk upon health during childhood and adolescence (i.e. smoking or low levels of physical activity) might help to explain these relationships. Further, we will also address potential physiological mechanisms, such as biomarkers of inflammation, that might contribute to the associations between ACEs and CVD. It is also important to consider how socio-demographic factors or environmental factors such as social class, economic status of the family, and sex of the child could alter the strength of associations between ACEs and CVD; thus, the impacts of these factors will also be measured within our analyses.
B4618 - Harnessing DNA methylation variation between populations to understand disease discordance across ancestries Diverse Epigenetic - 21/05/2024
DNA methylation (DNAm) is an epigenetic mechanism that plays a central role in gene regulation. It helps to define how cells respond to genetic and environmental signals and, ultimately, contributes to whole system health and disease status.
Levels of DNAm differ from one person to another. However, it is unclear how much of the variation in DNAm levels is caused by genetic or environmental factors and if such effects also relate to human phenotypes. Understanding the relationships between DNAm, genetics and environment is essential for both understanding pathways of health and disease and disease consequences.
Prior research has been limited to populations of European genetic ancestry, restricting understanding of DNAm variation to limited genetic and environmental contexts. This is a crucial knowledge gap because there are known genetic and environmental differences in drug response and disease risk factors across population groups worldwide which may be attributable to DNAm variation.
Evaluating DNA methylation variation in diverse population groups allows comparison across varying genetic and environmental exposure profiles. Identification of disease pathways common to all populations will represent mechanisms of health and disease that are common across all humans. This allows identification of drug targets that will be effective in any population group.
Identification of disease pathways restricted to specific genetic and/or environmental exposure profile will reflect adaptation to environmental and genetic context. This will allow identification of molecular mechanisms that underpin the disease discordance that we observe across global populations and highlight opportunities for targeted treatments.
This research builds a global partnership of teams to bring together genetic and epigenetic data collected from individuals worldwide. A key aspect of this study is building equitable partnerships between these teams. This is essential in order to build capacity for research in genetically diverse datasets and to provide internationally relevant research on cardiometabolic and child health phenotypes.
Identification of common and context specific mechanisms of health and disease mediated by DNA methylation is of high health impact because it will enable actions to reduce global health disparity and inequity via targeted interventions or treatments.
B4617 - Investigating the relationship between biological markers of adversity and chronic inflammation to psychiatric outcomes - 24/05/2024
A wealth of data implicates inflammation in the pathophysiology of psychiatric and many other disorders. Childhood adversity is a risk factor for later psychiatric disorder and it is associated chronic inflammation as measured by the soluble urokinase-type plasminogen activator receptor [suPAR]). We have shown that suPAR is elevated among ALSPAC participants who have psychotic experiences and psychotic disorder at age 24. We have also shown that the complement pathway in the blood, which contributes to inflammation, is upregulated in the blood 6 years prior to the identification of psychotic disorder (PMID 29036721). Similarly we have shown that people at clinical high risk for psychosis who later develop a psychotic disorder show increased baseline levels of markers of the complement pathway (PMID 32857162). Most recently we have shown (preliminary data) that the complement pathway is upregulated among those in the first episode of psychosis who respond well to antipsychotic drugs. These findings implicate the complement pathway in psychosis. Of the members of the complement pathway that have been shown to be dysregulated, C1r, has been most consistently and strongly altered and has been validated using ELISA (PMID 32857162; PMID 32857162). C1r is linked to the activation of C4A variant implicated so strongly in schizophrenia genomic studies (PMID: 26814963) and is associated with other medical diseases such SLE and Hereditary Angioedema.
What is not known is:
1. what is the relationship of this marker of chronic inflammation [suPAR] and this plasma marker of the complement pathway, C1r, at age 24 to adversity in childhood and adolescence
2. what is the relationship between plasma suPAR and plasma C1r.
3. do measures of suPAR and C1r at age 24 mediate the relationship between adversity in childhood and adolescence and psychiatric outcomes at age 24.
We propose to answer these questions by quantifying these markers of chronic inflammation and complement activation in all young people who gave bloods in the ALSPAC clinics at age 24 to investigate the relationship to adversity and psychiatric outcomes at age 24.
We note that chronic inflammation and complement pathway function is an important contributing factor to many medical diseases and that this information can therefore be applied broadly and will find relevance far beyond the field of psychiatry.
B4117 - Demonstrating a casual role for adiponectin signalling in kidney disease at the population level using Mendelian randomisation - 14/05/2024
Adiponectin is a hormone produced by fat cells, which appears to protect blood vessels in diabetes and heart disease. In animal models of diabetes, adiponectin can protect from the development of diabetic kidney disease.
Blood vessels have a protective gel-like layer, the endothelial glycocalyx. This can be measured indirectly in humans using specialised microscopy imaging of blood vessels under the tongue, using a Glycocheck device. This has been shown to reflect changes to the endothelial glycocalyx on blood vessels elsewhere in the body, including the kidneys.Glycocheck parameters are being collected from individuals in ALSPAC (by Prof Abigail Fraser).
Damage to the endothelial glycocalyx in the filtering blood vessels of the kidney leads to protein, such as albumin, filtered into the urine (albuminuria), a hallmark of kidney disease. We have shown that adiponectin can protect the filtering blood vesssels in the kidney from glycocalyx damage and protect from the development of diabetic kidney disease.
We aim to show relevance to human disease by demonstrating that changes in adiponectin levels can cause albuminuria and kidney disease using Mendelian randomisation. We wish to use the ALSPAC data to explore the causal role of circulating levels of adiponectin and adiponectin receptor expression on glycocalyx depth (measured in ALSPAC- Glycocheck) and circulating levels of syndecan 4 (a marker of glycocalyx shedding). This will allow us to explore whether adiponectin signalling has a positive impact on kidney disease and function due to its effects on the glycocalyx.
B4608 - Translating the Lived Experience of Heatwaves into Policy Action - 14/05/2024
Climate change has increased how often we experience extreme weather events such as heatwaves. Being exposed to heatwaves can have a bad effect on our physical and mental health. People who live in cities will experience higher temperatures during a heatwave compared to those not living in a city. We will build on the work that we have already done in ALSPAC, where we asked participants about their experience of recent extreme weather events, to work with Bristol City Council to ask questions of people living in council housing about their experience in heatwaves. Using this combined data we will develop guidance to share with poeple living in council housing how to survive a heatwave.
B4611 - Running in the FAMILY - Understanding and predicting the intergenerational transmission of mental illness - 14/05/2024
A family history of mental illness is the most important known risk factor for the development of mental health problems. Up to 50% of children with a mentally-ill parent will develop a mental disorder in their life. In clinical practice, this intergenerational transmission of risk for mental illness is rarely taken into account, and in health care settings, family histories of mental illness are not adequately considered in diagnosis and care, leading to delays in diagnosis and missed time for protective measures and strengthening resilience. Furthermore, parents with mental illness are often unaware of the impact their condition can have on their children's well-being, are less able to reflect on their role and style as a parent, and rarely discuss this with health care professionals. This project aims to better understand the mechanisms of intergenerational transmission of mental illness. The ALSPAC data, together with data from other cohorts, will be used (i) to identify early risk and resilience factors, (ii) to predict who is likely to be diagnosed or develop symptoms of mental illness and (iii) to better define the role of genetics, epigenetics and brain metrics in the routes of transmission. This may lead to the development of new preventive strategies that can break the intergenerational cycle of mental illness and support the building of strength and resilience.
B4613 - Sex differences in physical activity across childhood adolescence and early adulthood - 14/05/2024
Men and women have different risks of getting heart disease during their lives. Differences in physical activity levels may be a contributing factor. The aim of this project is to examine physical activity levels of boys and girls from childhood through to early adulthood in the ALSPAC cohort.
B4612 - Biomarkers of accelerated aging and lung function trajectory a multi-omics study in a UK birth cohort - 18/05/2024
Chronic obstructive pulmonary disease (COPD) affects 212 million people globally and is responsible for 3 million premature deaths each year. Smoking causes most COPD, but it can also develop as a result of low lung function trajectory in childhood, adolescence and early adulthood. ALSPAC has been part of the effort to characterise such low lung function trajectories.
The mechanisms underlying low lung function trajectories remain unclear. One plausible mechanism is accelerated biological aging, which can be measured using epigenetic clocks based on DNA methylation data, or by measuring biomarkers of cellular senescence. Cellular senescence is an important pathological process in biological aging, in which cells stop dividing and secrete a variety of inflammatory mediators, leading to a state of chronic low-grade inflammation thought to be important in a variety of diseases, including COPD. The role of epigenetic aging and cellular senescence in low lung function trajectory and COPD is of interest because treatments which can arrest or reverse these processes are under investigation and could become COPD treatments in future.
This study will attempt to assess whether epigenetic age acceleration, calculated from DNA methylation data from blood samples collected from ALSPAC participants at age 7, is associated with belonging to a lower lung function (FEV1) trajectory. It will also assess for an association of plasma markers of cellular senescence (IL6, CXCL10, LAP TGF beta-1) with lung function trajectory. If observational associations are evident between epigenetic age acceleration or plasma markers of cellular senescence and lung function, multivariable mendelian randomisation analyses will be undertaken to assess whether they are likely to be causal.
B4614 - Investigating the effect of body size between menarche and first birth on breast cancer A lifecourse Mendelian randomization st - 13/05/2024
Nulliparity is associated with increased reproductive malignancies and early first full-term pregnancy has been found to reduce risk of breast cancer. There is also evidence that increased weight in childhood is protective against breast cancer. This research focuses on body size at different time points across the lifecourse and its effect on breast cancer risk, to understand the time frame in which undifferentiated nulligravid breast is most susceptible to carcinogenic insults. However, separating the effects of risk factors at different stages of the lifecourse is challenging due to confounding in conventional epidemiological settings. This is a key motivation behind using a Mendelian randomization (MR) approach. Conventionally, MR studies use a single measurement to estimate the effects of an exposure on an outcome. Effects obtained are therefore often interpreted as the lifetime effect of the genetically predicted exposure. This research will exploits the notion that genetic associations may arise from the direct effects of the same inherited variants at different stages throughout life. Our aim is to assess the effect of body size between menarche and first birth at different intervals across the lifecourse on breast cancer risk in later life.
B4607 - Cholesterol triglyceride and fatty acid trajectories throughout pregnancy and the association with pregnancy outcomes - 13/05/2024
In rich countries, over 30% of mums to be face problems when having a baby. These can be things like having a long labour, giving birth too early, getting dangerously high blood pressure called preeclampsia, or having diabetes during pregnancy. As so many women go through these pregnancy complications, it has become very important to find a way to see who might have problems during pregnancy before they happen. Right now, we do not fully know why these problems happen, but think it has something to do with certain types of fats in the body, called lipids.
We know that during pregnancy the lipids, cholesterol, triglycerides and fatty acids rise, reaching far higher levels than a non-pregnant women and return to normal following delivery. The rise in cholesterol, triglycerides and fatty acids occur to help support foetal growth and development but also help control the time at which the baby is delivered. Recently, imbalances in HDL, LDL, cholesterol, triglycerides, and free fatty acids during pregnancy have been shown to be linked to pregnancy complications including gestational diabetes, preeclampsia, premature birth and dysfunctional labour.
We know what levels of lipids are considered too high in non-pregnant women, but we know very little about what the normal lipid level changes are during pregnancy. We know lipids rise, but very few studies have investigated their trajectories to consider what would be considered too low or high. We also don’t know whether lipid changes outside the normal pregnancy range are related to common pregnancy complications.
We will answer these questions using the ALSPAC cohort. The results will be extremely important for pregnant populations, as we will determine the lipid changes that occur during pregnancy but also lipid patterns that may predict pregnancy or childbirth complications.
B4609 - The role of meaning and purpose in mental health outcomes - 13/05/2024
Previous research has examined the importance of having a sense of meaning and purpose in life. However, there are limitations with these studies. We want to examine the association between meaning and purpose, and how it relates to mental health outcomes.
B4610 - The longitudinal association between early parenting and psychotic experiences in adolescence - 13/05/2024
Psychosis is an incredibly debilitating condition, the symptoms of which include hallucinations, delusions, and disordered thinking/speaking. Experiences early in life can contribute to psychotic experiences later in life. It has been well researched that parenting and parent-child interaction can affect children’s outcomes across a range of domains. It is possible that parent-child interaction also influences future outcomes for psychotic experiences. If we find factors in parent-child interaction that appear to increase the risk of (or protect from) psychotic experiences this could open the door for future research and have implications for prevention.
B4606 - Special Educational Needs and Youth Offending - 14/05/2024
Young people with special educational needs (SENs) are disproportionately represented in the criminal justice system. Eighty seven percent of all violent youth offences in England are committed by those with an identified SEN (DfE, 2022). Understanding the link between youth offending and SEN will help to identify ways in which young people with SENs can be diverted away from the criminal justice system.
B4604 - Genetic determinants of perinatal depression and its long-term impact on the family unit - 14/05/2024
Depression is one of the most common medical complications in the perinatal period. Previous studies have suggested long-term consequences on infant, child and future offspring development. However, few studies have investigated the relationship between perinatal depression, offspring and partner outcomes in a multi-generational large scale longitudinal study. Furthermore, in order to fully understand the impact of perinatal depression, more research is needed to understand the genetics of perinatal depression.
B4605 - Placental accelerated villous maturation a potential screening target for premature somatic aging - 08/05/2024
Humans live longer than ever. Although women live longer than men, they experience poorer age-matched health. Early identification of women at risk for premature aging could lead to tremendous personal, societal, and health care benefits. Therefore, a leading health challenge is to understand the causes of premature aging and use this to promote heathy aging in women. Pregnancy is a multi-systemic stress test, offering a sex-specific opportunity to understand healthy vs premature aging. Placental accelerated villous maturation (AVM), characterized by hypermature terminal villi for gestational age, reflects premature aging of the placenta. We will test the novel hypothesis that AVM is an early adulthood marker of premature aging. We will determine whether AVM predicts premature aging in mid-life across multiple systems (endocrine, neurocognitive, musculoskeletal, reproductive, respiratory, cardiovascular, and renal), and identify genetic and environmental AVM risk factors. We will leverage three globally unique cohorts: the US Magee Obstetric Maternal and Infant study, the UK Avon Longitudinal Study of Parents and Children and the Dutch PEARLS cohort; and establish a global multidisciplinary collaboration linking placental aging to lifespan aging to provide novel insights into mechanisms underlying women’s somatic aging, potentially identifying strategies to enable women to live longer and healthier lives.
B4598 - Disentangling the associations between community engagement inequalities and youth anxiety and depression - 29/04/2024
This project will investigate whether community engagement is a modifiable health behaviour that can prevent and reduce youth anxiety and depression. Although community engagement (e.g., arts, culture, heritage, volunteering, community groups) is associated with reduced anxiety and depression, previous research is limited by not accounting for inequalities in mental health and community engagement, reliance on small studies with short follow-ups, and little evidence specifically in young people.
We will establish whether community engagement can reduce youth anxiety and depression, assess its equality of distribution internationally, and test whether individual- and society-level community engagement interventions can reduce youth anxiety and depression. We will use population-level longitudinal data from the UK, US, Australia, Japan, Egypt, and Norway. We will triangulate evidence from novel statistical methods for causal inference. These approaches have not yet been used in this field but are vital to examine associations independent of inequalities in mental health and community engagement. Cutting-edge cross-country evidence will demonstrate whether community engagement could be a public health intervention that reduces anxiety and depression. This project will facilitate further innovative research, inform population health policy and funding, and support development of large-scale interventions to reduce youth anxiety and depression globally.
B4602 - Data note on diet in pregnancy in a UK longitudinal birth cohort The Avon Longitudinal Study of Parents and Children ALSPAC - 29/04/2024
Information on diet in ALSPAC has been collected regularly in parents and children, starting with the the mother's diet in pregnancy using a postal questionnaire. This information has been used many times to look at how the mother's diet affects the health and development of her child, as well as her own health. This information has been made available to many researchers, but we'd like to write a summary for researchers detailing exactly what is available, how we have processed the information in various ways to make it useful for different types of research studies, and how to access it.
B4600 - Prenatal alcohol exposure PAE and the development of multiple risk behaviours at adolescence an ALSPAC birth cohort study - 29/04/2024
Pre-natal alcohol exposure (PAE) can lead to the development of fetal alcohol spectrum disorders (FASD). Individuals with FASD have a range of neurodevelopmental impairments including learning difficulties, social impairment and difficulties in regulating behaviours. This study aims to understand how different levels and types of maternal alcohol consumption impact the development of multiple risk behaviours at adolescence. Multiple risk behaviours (MRBs) are typically harmful behaviours such as alcohol consumption that tend to accumulate in adolescence and may have lasting impacts on the health and wellbeing of the individual. This project is a continuation of a Public Health Masters study (B3903), to apply statistical methods to evaluate and address the impact of missing data.
B4601 - Interrogating the age-dependent genetic architecture of childhood BMI using a novel longitudinal GWAS framework - 08/05/2024
Understanding how the influence of genes on BMI changes over the course of childhood holds important implications for understanding why BMI differs between children of different ages, and, ultimately, for understanding the biological basis of some adult diseases. We have recently developed an approach for interrogating longitudinal data along with genetic data to glean insights into genetic effects on health trajectories. In this project, we seek to understand whether the approach we have developed can help to clarify the age-varying effects of genes on BMI in childhood.
B4595 - The role of rare genetic variants in dyslexia - 23/04/2024
It's estimated that approximately one in ten children struggle with learning to read, a condition known as dyslexia. Dyslexia can have lasting effects on many aspects of life, including academic achievement, job opportunities, self-esteem, social interactions, and overall life satisfaction. These challenges are particularly significant when dyslexia goes undiagnosed, depriving individuals of much-needed support. Undetected dyslexia also contributes to societal costs, such as employment difficulties and mental health issues. Despite these challenges, individuals with dyslexia often possess unique problem-solving skills, yet barriers can limit their contributions to innovation and creativity.
Genetics is the primary known cause of dyslexia. Recently, collaborative research efforts have identified dozens of common genetic risk factors associated with dyslexia for the first time. This discovery underscores the complex nature of dyslexia and parallels findings in other neurodevelopmental disorders. Genetic research for other conditions such as autism, has progressed more rapidly thanks to the availability of large samples. This work has highlighted a crucial role for very rare genetic mutations. We anticipate that such rare variants also play a role in dyslexia. Detecting these rare variants requires genome sequencing technology in large samples.
We're embarking on the largest sequencing project ever conducted for dyslexia, utilizing a unique collection of samples amassed over decades and characterized with high-quality data by multiple research teams with a proven collaborative track record. Our cohort is enriched for severe cases and includes families with multiple affected members.
Our research will deepen our understanding of the genetic risk factors for dyslexia and illuminate the biological pathways involved in dyslexia and brain development. By comparing data with other conditions, we aim to identify genes specifically associated with dyslexia. In the long term, our findings may contribute to the development of early diagnostic strategies. We will share our results with the broader research community, creating a valuable resource for future dyslexia studies and related conditions, such as language disorders, dyscalculia, and attention deficit hyperactivity disorder.
Our project offers a unique opportunity to engage with the public and discuss the neurobiological determinants of dyslexia. The Specific Learning Difficulties Network, an initiative we launched in 2022, will provide a platform to engage with different stakeholders, including individuals with lived experiences of dyslexia, teachers, clinicians, and policymakers. Our findings will provide evidence to explain the role of genetics, reduce stigma around dyslexia, and increase awareness.