Proposal summaries
B4445 - Sex differences in the longitudinal impact of birth weight phenotype-genotype mismatch in behaviour - 28/05/2024
Fetal growth and biological sex are thought to affect behaviour in childhood and adolescence. Fetal growth is often estimated with birthweight, however, birthweight can vary both as a consequence of genetic and environmental factors and furthermore a large literature has suggested that the effects of fetal growth may differ between males and females. We want to test how measured birthweight and birthweight-genetics influence lasting behaviour in males and females and if a mismatch between an individuals potential for birthweight - i.e. their genetically determined birthweight - and their actual birthweight, produces lasting behavioral changes throughout their childhood and adolescence. Finally, we will test if the effects of such a mismatch differs between males and females.
B4624 - Investigating the effects of maternal physical activity on pregnancy and perinatal outcomes an integration of multiple lines of - 24/05/2024
• The experience of pregnancy is associated with physiological and psychological change that is shown to promote sedentary behaviour and/or lower levels of physical activity (PA).
• PA in pregnancy has historically been deemed a risk factor for miscarriage, though this may result from reverse causality. Those feeling well enough to stay active early in pregnancy might already be in the early stages of miscarriage and thus experience fewer symptoms like nausea and fatigue. The perception of Pa as a risk may have led to the promotion of sedentary behaviour and reduced PA during pregnancy by clinicians and medical professionals in fear of causing harm.
• The majority of epidemiological analyses to-date, however, have reported that higher PA and reduced sedentary time are associated with improved health outcomes for pregnant people and their offspring. Furthermore, guidelines in several countries encourage safe levels of activity and exercise during pregnancy.
• Since PA in pregnancy may have benefits for the mother and/or offspring, it is important to better understand its effects in pregnancy on a range of pregnancy and perinatal outcomes.
• When conducting conventional multivariable regression analyses, sources of bias induced by confounding factors, including confounding by undiagnosed existing disease (reverse causation), present challenges when inferring causality.
• Mendelian randomisation (MR) exploits the random distribution of genetic variants from parents to offspring, independent of the influence from other traits, to reduce susceptibility to these confounding factors. However, MR may be biased by weak instruments or horizontal pleiotropy.
• Negative control designs, which use paternal exposures as the negative control, can reveal bias in associations of maternal exposures with adverse pregnancy and perinatal outcomes. The paternal exposure is unlikely to affect these outcomes but may be associated with unmeasured confounders in a similar way to the maternal exposure.
• Employing a triangulation approach using multivariable regression, Mendelian randomisation, and a paternal negative control design, this investigation seeks to explore the causal effects of PA in pregnancy on pregnancy and perinatal outcomes.
B4622 - Identification of rare genetic variants associated with lung function using whole-exome and whole-genome sequencing data - 20/05/2024
Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. Recently, over a thousand variants in over 500 genes were associated with lung function. Those variants were involved in different cell functions, providing information that brings us closer to understanding the mechanisms underlying lung function and COPD.
In this study, we will investigate a more comprehensive number of variants in genes, with a focus on those that are not that frequent in the population (frequency under 1%), to help identifying variants responsible for lung function impairment.
B4623 - Early years telomere dynamics - 31/05/2024
elomeres are structures at the ends of chromosomes, as cells divide, and as people age, they become progressively shorter. The length of telomeres is associated with a range of diseases including cardiovascular and cancer. People start adulthood with a broad range of telomere lengths and this length variation contributes to people’s individual risk of disease. Telomere length variation is partly genetically determined but may also be influenced by early life. We want to utilise the ALSPAC cohort to examine the dynamics of telomeres during life, by undertaking serial telomere length analysis of individuals from birth to 17 years old. We will use a method called HT-STELA that combines a low error rate with high throughput and is provided as a clinically validated diagnostic service for the NHS by TeloNostiX Ltd.
The purpose of this pilot study is to test the utility of HT-STELA in analysing genomic DNA samples from the ALSPAC cohort that have been extracted with different methodologies. By analysing a panel of serial samples, we aim to generate preliminary data that will be used in a funding application to undertake a larger study. An additional aspect of this pilot project is that the data generated will be useful to define the normal telomere length range in the younger population to improve the use of HT-STELA in clinical diagnostics.
B4621 - Lifecourse predictors of mental health and obesity stigma data collection and analysis - 20/06/2024
This data collection and analysis in ALSPAC will form part of a larger project on health-related stigma. Following a process of expert consultation to identify the best available measurement tools and explore development of new ones, new data will be collected in ALSPAC measuring different types of stigma related to health. This will support analysis providing new insights on how these can be intervened on.
B4620 - Effects of Maternal Genetic Risk Factors for Polycystic Ovary Syndrome on Birth and Childhood Outcomes in Offspring - 17/05/2024
*Please note this new proposal will re-use the dataset that has been provided for the previous project ID B3581.*
Polycystic ovary syndrome (PCOS) is a major health concern that affects up to 10% of reproductive-aged women and is the leading cause of female infertility. This complex, heterogenous condition is characterized by ovulatory dysfunction and hyperandrogenism and is often associated with metabolic dysregulation and increased risk for adverse birth outcomes. Existing evidence suggests that the androgenic and metabolic features of PCOS can be passed down from mothers to their offspring, but the relative contributions of maternal genetics and intrauterine environmental factors to these features in offspring are not known.
Our original project ID B3581 studies metabolic and growth and developmental phenotypes in children that may be associated with PCOS. We have recently identified that a higher polygenic risk score (PRS) for PCOS is associated with higher BMI, fat-mass index, and risk of obesity in childhood and earlier age at pubarche and younger age at peak height velocity. These associations persisted after controlling for the maternal PCOS polygenic risk score, indicating that genetic risk for PCOS has direct effects in offspring. In addition, genetic risk for PCOS could also have indirect effects in children through direct effects on the intrauterine environment in their mothers. For example, mothers with PCOS have an increased risk of preterm delivery, attributed to metabolic perinatal complications, such as pre-eclampsia.
I hypothesize that maternal PCOS genetic factors and associated intrauterine environmental factors play an integral role in the development of adverse birth outcomes and childhood androgenic and metabolic features of PCOS in offspring.
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.
B4616 - Adverse childhood experiences and oral health - 16/05/2024
Oral health inequalities start early in life. Previous studies have looked at childhood socioeconomic circumstances, the early family environment and parental behaviours in relation to child oral health. This project will focus on another important social determinant of health. Adverse childhood experiences (ACEs), such as physical abuse, emotional neglect, parental separation or imprisonment, can increase the risk of psychological problems and behavioural problems, respiratory diseases, diabetes, cardiovascular diseases and gastrointestinal diseases among children and adults.
Previous studies in dentistry have shown that ACEs are associated with childhood tooth decay, poor child oral health and lower oral health-related quality of life. ACEs have also been related to fewer dental visits and more tooth extractions in adults as well as poor oral health and greater tooth loss in older adults. Common limitations of previous studies are the use of cross-sectional data and the retrospective assessment of ACEs that introduces measurement bias. In addition, in most studies, different ACEs were combined into broad categories, thereby making it difficult to evaluate the effects of individual ACEs. Identifying which ACEs are more relevant to child oral health, their specific timing and potential underlying mechanisms can inform relevant policy and interventions at family level. Evidence from longitudinal studies will shed some lights on this important research area.
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.
B4615 - Whole-exome sequencing as a tool to reveal rare genetic architecture of diabetes - 16/05/2024
People with diabetes taking insulin sometimes present resistance or failure to this therapy. Investigating the genetic factors influencing the resistance to insulin in people with diabetes may lead to biological insights into the causes of failure to this therapy and help improving their long-term health.
We will look into the DNA of ALSPAC participants that codes the proteins, to identify rare variants (those with a frequency <0.1%) that have a high impact on the structure and/or function of the protein. Then we will investigate if those variants have an influence on the risk of diabetes, and if they have an impact on the levels of diabetes-related traits, as insulin, glucose, etc.
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.
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.
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.
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.