Proposal summaries
B3926 - What is the relationaship between biological markers of adversity and chronic inflammation to psychiatric outcomes at age 24 - 29/11/2021
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.
B3878 - Play and Child Development Role of Parent and Child Genes and the Environment - 12/11/2021
To better understand the function of play, its origin, and purpose in child development; developmental psychology, and behavioural genetics methodologies are uniquely combined in an original approach to studying children's play. Variables related to children, their parents, and the genetic propensities of both will be combined to explore linkages between home environments, play, and children’s social/cognitive outcomes, in a cross-cohort-longitudinal approach. Data from three UK longitudinal studies will be used in a holistic attempt to tap into the construct of play given it is a multidimensional construct. The study addresses the call for novel approaches to studying how play relates to child development.
B3879 - Gene-environment interactions in mental health trajectories of youth - 12/11/2021
This work aims to improving our understanding of the emergence of mental health problems across childhood, adolescence and young adulthood. We will investigate how different biological and environmental factors interact to drive or prevent the onset of mental ill-health.
B3925 - Networks of Adversity in Childhood and Adolescence and their Relationship to Adult Mental Health - 17/11/2021
Adverse events before the age of eighteen are common and include diverse experiences ranging from sexual abuse to parental divorce. These stressful events have been linked to physical and mental health issues. Previous research has focused mainly on childhood adversity and adverse experiences in the family environment, and little consideration has been given to what types of adversity may be particularly harmful in adolescence.
B3924 - Novel diagnostic and therapeutic pathways and improved exacerbation prediction in asthma and COPD - 19/11/2021
Respiratory disease, the third largest cause of death in England, affects one in five people. Hospital admissions for lung diseases drive NHS winter pressures, costing £11billion annually. Reducing the impact of respiratory disease and associated health inequalities is a UK Government priority (UK Life Sciences Vision 2021).
In collaboration with ALSPAC we will focus on
• Workstream 2: Asthma and chronic obstructive pulmonary disease (COPD)
B3921 - Sugar Sweetened Beverages and adiposity - 04/11/2021
It has been repeated suggested that drinking sugar sweetened drinks is a major risk factor for obesity. The role of pure fruit is controversial as although it contains natural sugar it also provides beneficial polyphenosl and vitamin C. The project will compare the drinking sugar sweetened drinks, sugar sweetened fruit containing drinks and pure fruit juice by the mother during pregnancy and during the firts year of age. The effects on the weight gain during the first ten years of life will be examined.
B3920 - The connectomics of Alzheimers risk characterising brain temporal network dynamics in young adults - 04/11/2021
Using advanced imaging and novel mathematical approaches, we will identify spatio-temporal brain networks that show altered dynamics in young adults with genetic risk for Alzheimer's disease. The PhD will provide grounding in network neuroscience — an evolving field using network theories to study the brain across multiple scales and modalities.
B3899 - Developmentally-induced DNA methylation changes in response to maternal tobacco and cannabis use during pregnancy - 03/11/2021
Substance use during pregnancy is a large driver of health inequalities in exposed children, and despite the known impacts on infant health that accompany its use, tobacco use during pregnancy is still prevalent. Additionally, cannabis use in pregnant women is increasing. Tobacco use during pregnancy is associated with low birth weight, respiratory distress, and an increased risk of neurodevelopmental disorders and Irritable Bowel Disease (IBD) in exposed offspring. Developmentally-induced health inequalities are often driven by environmentally-induced genetic change, and our recent research has shown a link between DNA methylation and neurodevelopmental disorders. Interestingly, exposure to cannabis during development shows similar phenotypic patterns to tobacco, however, the molecular links between exposure and phenotype have not yet been explored.
Thus, in addition to data derived from our current cohorts (the Christchurch Health and Development Study [CHDS], Southampton Trio Cohort of the UK & Ireland Paediatric IBD Genetics Group) which both have well documented maternal tobacco and cannabis exposure measures, and manifestations of disease in the offspring, we seek to include DNA methylation data from ALSPAC to determine whether maternal tobacco and cannabis use impacts the genome of exposed offspring at genes involved in neurodevelopment and immune regulation, which may help explain the observed link between developmental exposure and offspring outcomes.
This research addresses the knowledge gaps around the association of maternal substance use and health outcomes in children, clarifying the potential risks of substance use, particularly maternal cannabis use, and indicate what this might mean for the health outcomes of exposed children.
B3915 - Smoking induced newborn DNA methylation and early childhood caries experience - 01/11/2021
Dental caries a complex chronic disease of multifactorial etiology that affects a children worldwide. Its risk factors include a susceptible tooth, fermentable sugars and caries bacteria. Certain upstream factors have also been implicated in the etiology of dental caries and they are those that promote a favorable oral environment for dental caries susceptibility and progression. One of such upstream factors is prenatal smoking. The prenatal period is a sensitive time for fetal growth and development, including the development of the primary tooth germ that commences at the end of the 5th week of gestation. Exposure to prenatal smoking during this critical period not only affects the health and wellbeing of the developing fetus but also the quality of the developing tooth. Previous studies that have found an association between prenatal smoking and dental caries in the child relied on self-reported smoking during pregnancy, and thus, susceptible misreporting and recall bias of actual smoking status. This current study utilizes an objective measure of exposure to smoking in-utero in the form of newborn DNA methylation (DNAm) measured in cord blood collected at birth.
B3918 - Modelling longitudinal trajectories of lung function using UNICORN cohorts - 28/10/2021
Introduction: Several studies have reported that lung function in early adulthood is a significant predictor of mortality and COPD and that childhood events in part determine lung function in adult life. Multiple birth cohort’s studies support these findings; these studies have shown different lung function growth trajectories in the population. Most of the studies reported parallel lung function trajectories with two to four trajectories, except Tasmanian longitudinal health study. Tasmanian longitudinal health study identifies six trajectories, besides persistently high, average, below average, persistently low they also reported trajectories with early below average, accelerated decline and early low, accelerated growth, normal decline, the reason for this may be due to long follow-up time (up to age 53 years).
Hypothesis: We hypothesised that besides the parallel trajectories already reported in the literature, there are trajectories with both declining and increasing trends. We have already found some interesting findings to support our initial hypothesis using the MAAS and IOW data, which need validation using a similar cohort but larger sample size. Furthermore, using MASS and IOW, we are modelling other spirometry patterns derived from actual spirometry measures; these new derived markers are more clinically relevant and easily interpretable.
Methods: We will use a latent process mixed model for multivariate markers and latent transition analysis to support our hypothesis. After deriving the trajectories, we will identify early-life predictors for these trajectories; we will also use the genotyping data to see whether these trajectories have genetic bases. To Validate our findings from MAAS and IOW, we need a larger cohort, and ALSPAC is vital for this validation due to its larger sample size.
B3919 - Investigating the mechanisms underlying sleep problems and links to mental ill health in autistic children and adolescents - 01/11/2021
Disordered sleep is commonly reported in autism from a young age, as are symptoms of mental illness. Mental health and sleep are known to influence each other in a bidirectional manner within the general population, but the nature of the association between sleep and mental health problems in autism is poorly understood. Moreover, the underlying causes of sleep problems in autism are unknown. Thus, current treatments for sleep problems are largely ineffective in autistic people, and they also face severe consequences of mental ill health, such as high rates of suicidality and in-patient care. We aim to characterise the relationship between sleep problems and mental ill health, and identify factors underpinning the sleep problems in autism and in people with autistic traits. We will focus specifically on childhood and adolescence as this comprises the typical age-range of onset for problems in both sleep and mental health. Our approach to answering these questions will involve statistical modelling of longitudinal data on sleep and mental health in ALSPAC.
B3909 - The tempo of childhood growth and physical and neurocognitive development - 27/10/2021
In our research and clinical experience, we have found that children with delayed puberty often have delays in other aspects of childhood growth and development, including later emergence of adult teeth (secondary tooth eruption), slower growth in childhood, and delayed appearance of changes driven by hormones from the adrenal glands, such as pubic hair, underarm hair, and body odor. These observations suggest that some "master" mechanism (currently unknown) dictates the tempo of childhood growth and development.
This master mechanism may also affect aspects of neurocognitive development, as we have observed high rates of attention-deficit/hyperactivity disorder in children with delayed puberty - over 35%, compared to 5% to 10% in the general population. Alternatively, it has been proposed that ADHD medications may affect the timing of puberty (perhaps through suppression of appetite, or by stimulating production of the hormone cortisol), though studies that have formally examined this possibility have not found evidence for this.
Our above studies focused on children with delayed puberty. In this project, we seek to examine relationships between these childhood milestones in a more general population. We also seek to identify the genetic factors that control the tempo of childhood growth and development.
B3793 - Clusters of exposome components and their association with lung function evolution during the youth - REMEDIA project - 19/11/2021
The concept of exposome refers to the totality of the environmental exposures (diet, lifestyle, occupational and environmental factors, …) from conception onwards, including its external and internal components. Among non-communicable respiratory diseases, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are two highly debilitating diseases that are of particular interest to consider in parallel in a human exposome study. The overall objective of the REMEDIA project is to determine how and to what extent the exposome affects the severity and morbidity of COPD and CF throughout the progression of disease, thus providing key elements to design more tailored prevention and care programs. We assess exposome and health data from several cohorts and population registers to determine, at various times of life, whether specific exposome(s) is(are) associated with particular phenotypes of COPD/CF in terms of severity, morbidity, exacerbations and co-morbidities. Yet, lung function development starts in utero and continue up to early adulthood, when a maximal lung function is reached. It is therefore of crucial importance to understand the impact of exposome on this key determinant of adult pulmonary health.
We hypothesize that lung diseases occurrence and lung function development during the youth is both influenced directly by individual/contextual components of the exposome and indirectly (mediated) via more complex pathways. Human research on this topic has generally focused on single exposure–health effect relationships. Our objective is to consider a broader definition to the exposome accounting for its multiple facets at the individual/contextual levels, also taking into account the potential clustering of exposures which may often be observed in combination (e.g. air pollution, socioeconomic indicators and individual health-related behaviours).
Consequently, the specific objective to be addressed using the ALPSAC cohort is to investigate whether there are specific exposome components, in isolation and/or in combination (clusters), linked to lung function trajectories and maximal achieved lung function at early adulthood, taken as an early determinant of COPD and CF outcome.
B3908 - Longitudinal associations of DNA methylation and sleep in children - 26/10/2021
Sleep is important for healthy functioning in children. However, the biological factors underlying sleep development in childhood remain unclear. Epigenetic processes may serve as a biological mechanism that underlie differences in child sleep characteristics.
B3916 - Physical and mental health multimorbidity across the lifespan LIfespaN multimorbidity research Collaborative LINC - 19/11/2021
Multimorbidity (MM) happens when two or more different diseases are present at the same time in an individual. This is
common between physical and psychiatric diseases with almost half of people with a psychiatric disease also having a
physical disease. As well as about a third of people with a physical disease also having a psychiatric disease. These
patients have worse quality of life than those with a single disease, they often struggle to get the best care and are at risk of
living less long. A common and serious type of MM is between internalizing diseases (depression and anxiety) and
cardiovascular disease (ICV-MM). Still, very little is understood as to how ICV-MM develops and why it happens. We do
know however that both internalizing disease and cardiovascular risk (e.g., obesity, cholesterol) tend to begin before
adulthood.
To really understand how ICV-MM risk develops, we need large studies of people of all ages whose health has been followed
over time. Studies of children are crucial because they can tell us about early risks for development of ICV-MM later in life.
This is important for developing better plans to prevent at-risk children developing ICV-MM.
We know that genes influence risk of both internalizing and cardiovascular disease and that some people are at high
genetic risk. We also know that certain conditions that start early in life (neurodevelopmental conditions) such as
intellectual disability, autism and ADHD increase risk of developing ICV MM later. Children's environments can also
increase this risk, for example, stressful experiences such as poverty and physical or sexual abuse. But how exactly genes,
neurodevelopmental conditions and early environmental risks influence the development of ICV-MM over the lifespan is still
not understood.
Certain groups are known to be at increased risk of ICV-MM, such as people of South Asian heritage and women, but we
don't know why this is. Better understanding of how ICV-MM develops in different groups in society will help doctors give
patients care that is matched to their specific needs. It will also help doctors, governments and schools prevent ICV-MM in
at-risk children in ways that work best for them.
To really understand the complexities of ICV-MM development, a team of researchers with a wide range of expertise is
needed who together understand physical and psychiatric diseases as well as how genetics, neurodevelopmental
conditions and the environments people live in influence them throughout their lives.
Our LIfespaN multimorbidity research Collaborative (LINC) combines wide-ranging medical and research expertise in
physical and psychiatric diseases. We have brought together five very large studies in which the health of many people has
been followed over time. Rich medical data is available, including from medical records. Genetic information is also
available for these people. Other important information has also been collected such as on people's living environments,
life events and lifestyles.
These studies follow the health over time of children, adolescents and adults. We can therefore study how internalizing and
cardiovascular disease happen together in adulthood. Importantly we can then also study early risk factors in the children
before they develop these conditions. Because our child and adult samples differ in ethnicity and economic situation, we
can also study how the development of ICV-MM differs for different groups in society. Finally, because we have genetic
data, we can study how genes influence ICV-MM development in people at risk.
Our study will help us understand how ICV-MM develops and which circumstances influence this. What we learn will be
important for the prevention of ICV-MM in children who are at risk because of genetics, their sex, or ethnic or economic reasons. We will work with patients, doctors and charities to develop specific health advice in order to reduce ICV-MM in at
risk groups in the future.
B3912 - Measurement of Genic Constraint via Reproductive Success - 01/11/2021
New genetic variants arise in the germline due to mutation. While the majority are genetically neutral and have no effect on organismal phenotype, some variants confer either an advantage and proceed towards fixation via positive selection, or a disadvantage and are removed from the gene pool by negative selection. The context of where a given variant arises in the genome strongly predicts whether it is eliminated or becomes fixed, with the function of the gene impacted perhaps the most predictive for coding variation. Genes that are depleted of deleterious genetic variation (DGV) due to negative selection are said to be “constrained”. Why most genes are under significant constraint remains a mystery, but in recent work using data from the UK Biobank we identified a link between DGV burden within constrained genes and increased childlessness.
We also found that a combination of having a partner at home and presence of various mental health disorders played a significant role in the relationship between DGV and childlessness. We hypothesized that DGV burden is associated with behaviours attributable to mental health disorders that in turn decrease the likelihood of finding a reproductive partner. However, we were unable to test this hypothesis due to limitations in the phenotyping of our original data. Using the rich, longitudinal phenotyping and genetic data provided by ALSPAC, we now wish to explore how individual feelings about having children, mental health disorders, and behaviours interact to create selective pressure on DGV within constrained genes.
B3903 - Does Fetal Alcohol Spectrum Disorders FASD classification predict engagement in adolescent Multiple Risk Behaviours MRBs - 26/10/2021
To explore the associations between fetal alcohol spectrum disorder (FASD) / Prenatal alcohol exposure (PAE) and adolescent multiple risk behaviours (MRBs). We are interested in exploring the prospective associations between prenatal alcohol exposure and MRBs, such as self-harm, drug use, tobacco smoking and alcohol consumption which are known to increase through adolescence and may persist into adulthood leading to multiple and composite adverse health outcomes. Identifying at risk adolescents could be used to aid the development of interventions and preventative policy.
B3913 - The causal role of the human gut microbiome in cancer aetiology - 26/10/2021
The human gut microbiome, home to a range of bacteria and various other microorganisms, is a diverse and complex feature of human homeostasis. Its specific composition varies between individuals due to pre-determined characteristics, i.e. our genetics, and modifiable factors including diet, lifestyle and probiotic consumption. The differences between individuals have highlighted its role in mediating a range of pathologies including obesity, metabolic syndrome, inflammatory disorders, and alterations in stress responses and behaviour. More recently, a relationship to cancer has been highlighted, where variations in the metabolites produced from these microorganisms is likely to have differential risk to cancer aetiology between individuals. The bacteria within the microbiome therefore has the potential for pharmaceutical intervention (through pro/prebiotics), if specific metabolites produced from these microbes are robustly associated to cancer outcomes.
Observational epidemiological studies have tried to quantify this relationship; however, they will often lack in overall certainty of causal inference and further be prone to biases, confounding and reverse causation. Mendelian randomisation (MR) has therefore been used as a tool within the field to improve the weakness pertinent to observational studies. The aim of the methodology is to utilise genetic polymorphisms, with well-characterised biological functions, as a proxy measurement for environmental exposures to provide evidence for causation. These germ line variants are independently and randomly assorted, allow for objective measurements to the degree of exposure and show a lack of association to behavioural, social or physiological factors, therefore allowing MR to be comparable to that of a randomised controlled trial (RCT) within the hierarchy of evidence – if done correctly.
Whilst MR may improve causality within this field, it is however prone to its own limitations. Specifically in the context of the microbiome, whereby, identifying variants to proxy for our trait of interest becomes increasingly more difficult. The project will therefore aim to test the relationship between the microbiome and cancer outcomes, through triangulating finding from both observational and genetic evidence. It will focus specifically on cancer outcomes that have not previously been robustly studied within this context, including (but not limited to) lung cancer.
B3898 - ASSOCIATIONS BETWEEN CERTAINTY OF COVID-19 INFECTION STATUS AND REPORTING OF LONG COVID SYMPTOMS THE ROLE OF NOCEBO - 25/10/2021
Some people experience symptoms caused by COVID that last longer than the original infection and these can be severe or disabling (COVID Symptom Study, 2020). This study aims to better understand why some people develop ‘long COVID’ – symptoms lasting longer than four weeks (National Institute for Health and Care Excellence, 2020) – and others do not. We will be comparing long COVID symptoms between those who have had COVID confirmed by a test, and those who believe they have had COVID but have not had a positive test. We will then explore whether this relationship is different between men and women, and between those who reported anxiety and those who didn’t. We hope that this research will help us to understand better whether psychological mechanisms contribute to the development of long COVID.
B3904 - Comparison of blood pressure measures for assessing risk of adverse outcomes in pregnancy - 25/10/2021
Blood pressure is routinely measured during pregnancy and is important for determining the risk of experiencing adverse pregnancy outcomes including pre-eclampsia, gestational hypertension, preterm birth, having a small for gestational age baby, and gestational diabetes. There is evidence that measurement early in pregnancy of integrative measures of systolic and diastolic blood pressure may be more important than individual blood pressure measures for predicting which women may go on to experience hypertensive disorders of pregnancy (preeclampsia and gestational hypertension). For example, mean arterial pressure (MAP) calculated as (systolic blood pressure + 2 x diastolic blood pressure)/3 has been shown to be a better predictor of pre-eclampsia than systolic blood pressure (SBP) or diastolic blood pressure (DBP). However, to our knowledge, there have been no direct comparisons of a range of different measures of blood pressure (SBP, DBP, MAP, pulse pressure (PP), mid blood pressure) on all of these adverse pregnancy outcome (APO) subtypes at a the same timepoint early in pregnancy. This research aims to look at which measures/derived measures of blood pressure best predict pre-eclampsia, gestational hypertension, preterm birth, small for gestational age (SGA) and gestational diabetes.