Proposal summaries

These are research proposals that have been approved by the ALSPAC exec. The titles include a B number which identifies the proposal and the date on which the proposals received ALSPAC exec approval.

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B4639 - Understanding the role of epigenetic regulation of thyroid function using data from TWINS UK and ALSPAC cohorts - 11/06/2024

B number: 
B4639
Principal applicant name: 
Hannah Hickingbotham | Bristol Royal Hospital for Children University Hospitals Bristol & Weston Foundation Trust
Co-applicants: 
Dr Toby Candler, Dr Matt Silver
Title of project: 
Understanding the role of epigenetic regulation of thyroid function using data from TWINS UK and ALSPAC cohorts
Proposal summary: 

DNA methylation (chemical marks on the DNA code) can change the activity of genes and how our cells function. There is evidence that mother’s environment can influence her baby’s DNA methylation and have lasting health consequences.

Little is known about how DNA methylation affects the genes related to the thyroid gland but it could be an important factor in thyroid disease and health.

Using large established datasets (TWINS-UK, ALSPAC), we will explore how DNA methylation at important areas of the genetic code influences thyroid hormone production in children and how the mother’s environment may contribute to these DNA methylation changes.

Impact of research: 
The effect of epigenetic variation on thyroid development and function is an area with limited studies. Initial studies point to an environmental link between PAX8 methylation and thyroid phenotype. Studies have described seasonal variation in the incidence of congenital hypothyroidism and thus it is important to explore epigenetic causes and environmental influence. This study would provide insights into the relationship between PAX8 methylation and thyroid function across a large cohort and specifically in twins. It also provides the opportunity to explore periconceptual environmental factors. By understanding more about the impact of the periconceptual environment and the role of epigenetics in regulating thyroid function we can plan further studies to explore periconceptional interventions (e.g. nutritional) that may limit congenital hypothyroidism, which is especially important for those countries without screening. Understanding more about the epigenetic role in thyroid function would also support further work into the fundamental biology of thyroid regulation. We are liasing with the Costagliola lab in Brussels and the Pediatric Endocrinology Department at Universitatsmedizin, Berlin exploring future research opportunities using stem cells to investigate PAX8 methylation and thyroid function and hope that this research would support these collaborations. Establishing the link between maternal environment, DNA methylation and the impact on the thyroid through this research will provide the basis for a larger grant application for research at both a cellular level and across other datasets. We plan to disseminate our research through publications and conference presentations.
Date proposal received: 
Monday, 10 June, 2024
Date proposal approved: 
Tuesday, 11 June, 2024
Keywords: 
Epigenetic epidemiology , Thyroid disease Congenital hypothyroidism, Epigenome-wide association study Statistical methods, Epigenome-wide association Periconceptional and gestational factors Hormones - thyroid Statistical methods

B4637 - The Effects of Non and Pre- and Postnatal Exposure to Paternal Anxiety on their offs - 10/06/2024

B number: 
B4637
Principal applicant name: 
Peter J Lawrence | University of Southampton (UK) (England)
Co-applicants: 
James Swanton
Title of project: 
The Effects of Non and Pre- and Postnatal Exposure to Paternal Anxiety on their offs
Proposal summary: 

Anxiety disorders (AD) are the most prevalent
psychiatric condition in the general population worldwide, and it is estimated that
between 6.57 and 13.54% of new fathers suffer from an AD (Leiferman et al.,
2021), a considerably higher proportion than the prevalence for anxiety in men
generally estimated by the World Health Organization (World Health Organization,
2017; range between 2.2 − 3.8%). The mental health of children is robustly
associated with the mental health of their parents (Jami et al., 2021). In particular,
children whose parents suffer from ADs, compared to children whose parents do
not, have a higher risk of struggling with their mental health (e.g., Connell &
Goodman, 2002; Micco et al., 2009; Lawrence et al., 2019). However, the specific
role played by fathers in children's mental health difficulties has been underinvestigated, and the particular risk posed by paternal anxiety for offspring mental health difficulties is not well understood.

Impact of research: 
This research will add to the existing literature on the father-specific contribution to the intergenerational transmission of psychopathology and will help disentangle direct (e.g., post-natal) from latent (e.g., pre-natal) effects of paternal anxiety on the development of their offspring.
Date proposal received: 
Saturday, 8 June, 2024
Date proposal approved: 
Monday, 10 June, 2024
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Parenting

B4632 - Effects of Socioeconomic Inequalities in Childhood Respiratory Tract Infections - 06/06/2024

B number: 
B4632
Principal applicant name: 
Demetris Avraam | Department of Public Health, University of Copenhagen, Copenhagen, Denmark
Co-applicants: 
Prof Anne-Marie Nybo Andersen
Title of project: 
Effects of Socioeconomic Inequalities in Childhood Respiratory Tract Infections
Proposal summary: 

Respiratory Tract Infections (RTIs) are the most common health problem in childhood, with children suffering on average 4-8 RTIs a year. Social determinants like parental education and household income, in addition to environmental and behavioural risk factors early in life, can influence susceptibility to RTI outcomes. Children living in disadvantaged socio-economic circumstances (SECs) are more likely to suffer from severe RTI outcomes, but the pathways leading to these inequalities are complex, inter-related and poorly understood. The overall objective of this project is to understand the burden of Upper and Lower Respiratory Tract Infections in children in Europe. Using federated analyses of data from the EU Child Cohort Network, the project aims to explore the social and geographic patterns and the pathways that relate social characteristics, early-life risk factors and childhood RTIs. Understanding these patterns and pathways is vital to inform preventative policy and help reduce the unfair child health differences through effective public health interventions.

Impact of research: 
Date proposal received: 
Tuesday, 4 June, 2024
Date proposal approved: 
Thursday, 6 June, 2024
Keywords: 
Epidemiology, Respiratory - asthma, Statistical methods, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B4634 - The Role of Epigenetics and Parenting in the Association Between Child Maltreatment and Depression - 06/06/2024

B number: 
B4634
Principal applicant name: 
Rosanna Breaux | Virginia Tech (United States)
Co-applicants: 
Jasmine Lewis, M.S.
Title of project: 
The Role of Epigenetics and Parenting in the Association Between Child Maltreatment and Depression
Proposal summary: 

Child maltreatment including traumatic experiences such as physical or sexual abuse is a consistent risk factor for depressive disorders. Depression often results from a combination of environmental, biological and psychological factors. Factors that explain this association between childhood trauma and depression are still being studied. Genetic factors could be a bridge between environmental stressors and the pathophysiology of depression. Research has already shown that parenting practices could be a protective factor for depression development; however, research is needed to explore the interaction between epigenetics and parenting in predicting depression symptoms in children. This study seeks to address these gaps in the literature.

Impact of research: 
Date proposal received: 
Tuesday, 4 June, 2024
Date proposal approved: 
Thursday, 6 June, 2024
Keywords: 
Clinical research/clinical practice, Mental health, DNA sequencing, Childhood - childcare, childhood adversity

B4627 - PRECISE Personalised Exposures and Responses for Equitable Policy Action - 29/05/2024

B number: 
B4627
Principal applicant name: 
Haneen Khreis | MRC Epidemiology Unit (United Kingdom)
Co-applicants: 
Title of project: 
PRECISE: Personalised Exposures and Responses for Equitable Policy Action
Proposal summary: 

Importance and need Ambient air pollution (AAP) causes 4.2 million premature deaths globally each year. It is a major contributor to non-communicable diseases, second only to cigarette smoking. In early-life, exposure to AAP influences the long-term risk of chronic disease development. Many diseases associated with AAP, such as respiratory illnesses , originate in childhood. Poor and ethnic minority children are disproportionately affected by AAP . Effective and equitable policy interventions targeting children are thus crucial. As a vulnerable group unable to control their exposures, children need to be considered and protected in policy transitions to clean air and net-zero.
Advancing current understandings and practice To tackle the inequitable health burden of AAP, we need to advance our understanding of where early-life exposures occur and how different children may be exposed differently and/or respond differently to the same exposures. This advanced understanding needs to be incorporated into decision-support tools, most notably health impact assessments (HIA), which can then assess equity impacts of clean air and net-zero transitions. I propose building a holistic program centred on the integration of multidisciplinary data, methods, tools, and networks. This integration will enable me to innovatively capture childhood exposure to AAP, estimate novel associations with chronic disease development, create and implement an equity oriented HIA, and foster enduring strategic coalitions and partnerships. The innovation in the exposure assessment can uncover fundamental insights into exposure disparities and health effects of AAP. The equity oriented HIA tool can have transformative impact on practice and policymaking. And creating a nucleus of diverse and engaged stakeholders can amplify the program’s impact. My approach will pave the way for addressing other complex and inequitable environmental health challenges.
Timeliness and trends I have been researching AAP and its health effects, primarily in children, over the past decade. The challenge of AAP is enduring. Whilst overall AAP levels have declined in some countries including the UK, levels are still considered too high to protect human health remaining above World Health Organisation (WHO) guidelines. Net-zero policies, such vehicles electrification, are expected to reduce AAP. However, these reductions will not be enough; tempered by a large, projected increase in future demand for transport leading to potential increases in non-exhaust emissions .
General AAP reductions also mask environmental injustice where there has been no progress in reducing the exposure gap between socioeconomic and racial groups . In the UK, the exposure gap between the poor and rich even increased in what has been cited as a failure of UK air quality policy . This failure is evident at locations important for children’s health. UK schools with high annual particulate matter less than 2.5 micrometres in diameter (PM2.5) levels (>12 μgm-3) had a significantly higher intake of pupils on free school meals (17.8%) and ethnic minorities (78.3%) compared to schools with low PM2.5 (<6 μgm-3, 6.5% on free school and 6.8% ethnic minorities) . Children spend about 30% of their time in schools . Commuting to school is another major contributor to exposure that is understudied. For example, AAP during commuting was 52% higher than exposures at school on average . Commuting mode and routes dictate exposures and vary between socioeconomic and racial groups complicating the understanding of equity impacts of e.g., transport policies targeting travel to school.
There is also sporadic evidence that the most exposed children might respond differently to their AAP exposures. This can be due to higher individual susceptibility or complex interactions with environmental, lifestyle and social characteristics. For example, despite controlling for a comprehensive set of confounders, I consistently observed larger associations between AAP and asthma and wheeze in children from families who struggled financially and children from Pakistani origins in Bradford, UK. So far, I do not have a satisfactory explanation of such differences but an indication of slightly higher exposure variability in the Pakistani but not the financially strained children. The question as to whether certain children respond differently to their exposures remains challenging to answer via traditional epidemiological studies which predominantly rely on a naïve assessment of exposure at the residential address only. Such studies are the norm and incapable of accurately representing exposure variability.
Impact Advancing current understandings of where exposures occur, how exposures vary across different children, and how different children might react differently to AAP has significant implications for policymaking. It can pinpoint which environments policies need to target to be most effective (e.g., at schools, on the route to school) and reveal any differential impact of policies on subgroups who may need more prioritization through a stratified approach to prevention (e.g., ethnic minorities).
But advancing understandings without a holistic approach to drive impact will not be enough. New knowledge needs translation into a new generation of equity oriented HIA, a key aspect of my program. I will use the HIA to test various clean air and net-zero policies solicited from and designed with stakeholders, focusing on climate policies which represent pathways in motion that can reduce both pollutant and greenhouse gas emissions. This focus strategically aligns with current national and global agendas on, and large investments in, net-zero and can reorient policy to better reduce inequities. As equity is also political and multi-sectoral, I acknowledge that my vision of reducing inequity extends well beyond the provision of new scientific information or adept decision-support tools. Actively engaging with policymakers and clustering influential partners to champion children’s health, prioritize equity and uptake novel science and tools is essential and at the heart of my program.

Impact of research: 
Beneficiaries The program will provide valuable insights to the scientific community in epidemiology and HIA, revealing exposure and response differences, alongside developing scalable methods for assessing time-activity patterns, exposures, and population health impacts. The program will be a hub for the multidisciplinary training of junior staff. It will engage with and benefit healthcare professionals who were found to underestimate the presence and urgency of AAP, due to incomplete understanding of health effects, feelings of insufficient evidence, and a rosy view on AAP , thus filling a gap where two thirds of people with lung conditions want healthcare guidance to manage the impact of AAP . The HIA models will support emerging initiatives in the NHS that are seeking solutions to AAP, including the UK's first air pollution clinic for children at the Royal London Hospital. Respiratory patients and their caretakers will receive information about activity-based exposures, AAP risks, and factors which heighten the risks, from patient organizations. This information will empower them and patient organizations to lobby for policy action, especially in communities with inequities. HIA models will provide new foundation to the equitable design, testing and implementation of policies, aiding policymakers in tackling AAP's impacts and inequities on the route to net-zero. My approach and partners correspond to these beneficiaries guaranteeing a tangible path to wider benefits (see Letters of Support).
Date proposal received: 
Tuesday, 28 May, 2024
Date proposal approved: 
Wednesday, 29 May, 2024
Keywords: 
Epidemiology, Respiratory - asthma, Qualitative study, Statistical methods, Childhood - childcare, childhood adversity, Sex differences, Statistical methods

B4625 - Maternal postnatal stress and epigenetic pathways to childhood growth - 29/05/2024

B number: 
B4625
Principal applicant name: 
Elizabeth Holdsworth | The Ohio State University (United States)
Co-applicants: 
Title of project: 
Maternal postnatal stress and epigenetic pathways to childhood growth
Proposal summary: 

A consensus of research has demonstrated that stress and adversity can become embodied and transmitted across generations, creating pathways by which social and economic inequality can affect human biology and health for decades. Most research has identified fetal development as a sensitive period for this transmission of stress from mother to child, with considerably less research on the postnatal period. Maternal postnatal stress has been found to shape infant stress response development, potentially creating a pathway by which maternal stress can become embodied in the next generation and influence how the next generation responds to and handles stressors. However, it is not clear how these effects on the stress response become embodied and whether these changes persist through childhood. This study proposes to test whether maternal postnatal stress in her child’s infancy and toddlerhood is related to the child’s methylation of stress-response related genes at age 7.

Similarly, previous research has demonstrated a relationship between psychosocial stress and childhood growth in weight and height. However, this relationship has been inconsistently demonstrated and the pathways by which stress affects growth are not clear. While the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in this relationship, results have been inconsistent. This research project proposes to test the relationship between growth velocity throughout childhood and methylation of HPA-axis related genes at age 7, in order to determine whether alterations to stress response physiology are a mechanism by which stress can affect growth.

Impact of research: 
This research will significantly advance knowledge of how stress can be transmitted transgenerationally in ways that may influence health and physiology throughout life. It will also significantly advance knowledge of the mechanisms by which psychosocial stress can influence childhood growth. This work will be published in peer-reviewed journals in public health and anthropology.
Date proposal received: 
Monday, 27 May, 2024
Date proposal approved: 
Wednesday, 29 May, 2024
Keywords: 
Anthropology, Mental health, Obesity, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Physical growth and development, Statistical methods, BMI, Bones (and joints), Childhood - childcare, childhood adversity, Development, Epigenetics, Hormones - cortisol, IGF, thyroid

B4445 - Sex differences in the longitudinal impact of birth weight phenotype-genotype mismatch in behaviour - 28/05/2024

B number: 
B4445
Principal applicant name: 
Craig Pennell | University of Newcastle (Australia)
Co-applicants: 
Ms Carol Wang, Dr
Title of project: 
Sex differences in the longitudinal impact of birth weight phenotype-genotype mismatch in behaviour
Proposal summary: 

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.

Impact of research: 
If our initial findings are reproduced it will do two things: 1) It will cement that sex-differences in psychiatry stem from (among other things) early life programming in line with the theories of fast/slow life history. 2) It will demonstrate in an unbiased fashion that a crude focus on birthweight is to simplistic, but rather needs to account for the varying determinants of birthweight (genetic and environmental) and that deviations from the genetic birthweight potential at both the high and low end of the birthweight spectrum determines mental health in childhood and adolescence.
Date proposal received: 
Monday, 27 May, 2024
Date proposal approved: 
Tuesday, 28 May, 2024
Keywords: 
Developmental biology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Computer simulations/modelling/algorithms, Genetic epidemiology, Sex differences

B4626 - Social Mechanisms of Genetic Effects - 31/05/2024

B number: 
B4626
Principal applicant name: 
Asta Breinholt | Roskilde University (Denmark)
Co-applicants: 
Dr. Marii Paskov, Gaia Ghirardi
Title of project: 
Social Mechanisms of Genetic Effects
Proposal summary: 

Today, it is widely accepted that most traits are both genetically heritable and affected by the environment. In the social sciences, the previous nature-nurture debate has been replaced by a new paradigm analyzing the interplay between genetics and the social environment (e.g., in sociology: Breinholt and Conley 2023; in economics: Houmark, Ronda, and Rosholm 2024; in psychology: Wertz et al. 2020). Rooted in sociology, this project analyzes how social mechanisms of genetic effects play out in three realms affecting childhood educational performance: family, daycare, and school peers, and asks how knowledge on these social mechanisms of genetic effects changes theories of justice on social stratification. The project thereby advances knowledge on the complex interplay between the social environment and genetics and addresses ethical questions re-actualized by the integration of molecular genetics in the social sciences. Addressing these issues will promote well-being of children.

Impact of research: 
The project will show how social mechanisms of genetic effects play out in three realms affecting childhood educational performance – the family, the daycare, and the school peers – thereby expanding our understanding of the complex interplay between environment and genotype. Taking the starting points that genetics are part of the circumstances beyond the control of the individual (Roemer 2001), and that it is unethical to intervene on genotypes, the empirical results will feed into theoretical work on models of theory of justice. Popularizing this knowledge will the impact the way we think about the relationship between genetics and the environment moving away from reductionist nature vs. nurture accounts, which in the long run will help promote the well-being of children.
Date proposal received: 
Monday, 27 May, 2024
Date proposal approved: 
Tuesday, 28 May, 2024
Keywords: 
Social Science, Mental health, Childhood - childcare, childhood adversity

B4624 - Investigating the effects of maternal physical activity on pregnancy and perinatal outcomes an integration of multiple lines of - 24/05/2024

B number: 
B4624
Principal applicant name: 
Grace Power | MRC Integrative Epidemiology Unit
Co-applicants: 
Deborah Lawlor, Carolina Borges, Gunn-Helen Moen
Title of project: 
Investigating the effects of maternal physical activity on pregnancy and perinatal outcomes: an integration of multiple lines of
Proposal summary: 

• 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.

Impact of research: 
Date proposal received: 
Thursday, 23 May, 2024
Date proposal approved: 
Friday, 24 May, 2024
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., GWAS, Statistical methods, Genetic epidemiology, Mendelian randomisation, Mothers - maternal age, menopause, obstetrics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Offspring, Physical - activity, fitness, function

B4623 - Early years telomere dynamics - 31/05/2024

B number: 
B4623
Principal applicant name: 
Duncan Baird | Cardiff University (United Kingdom)
Co-applicants: 
Dr Veryan Codd, Dr Susan Ring
Title of project: 
Early years telomere dynamics
Proposal summary: 

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.

Impact of research: 
For this pilot study the outcome will be whether it is possible to make the measurement within the larger cohort and provide preliminary data for a grant funding application. As HT-STELA is currently used by the NHS for the diagnostic work up of patients with telomere biology disorders, an additional benefit will be to refine the normal length range as defined with HT-STELA for diagnostic purposes.
Date proposal received: 
Monday, 20 May, 2024
Date proposal approved: 
Monday, 20 May, 2024
Keywords: 
Epidemiology, Cancer, cardiovascular , Genomics structural variants, Ageing, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Cardiovascular, Genetics, Genomics, Telomere

B4622 - Identification of rare genetic variants associated with lung function using whole-exome and whole-genome sequencing data - 20/05/2024

B number: 
B4622
Principal applicant name: 
Marisa Canadas Garre | University of Bristol (United Kingdom)
Co-applicants: 
Professor Nicholas Timpson, Dr Laura Corbin, Dr Laurie Fabian
Title of project: 
Identification of rare genetic variants associated with lung function using whole-exome and whole-genome sequencing data
Proposal summary: 

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.

Impact of research: 
Greater understanding of the aetiology of COPD and especially lung function. This study will help identify novel genetic variants involved in lung function and may reveal not only causative markers but also potential targets for therapy and drug development.
Date proposal received: 
Monday, 20 May, 2024
Date proposal approved: 
Monday, 20 May, 2024
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), • Lung Function • Chronic Obstructive Pulmonary Disease (COPD) , Computer simulations/modelling/algorithms, DNA sequencing, Gene mapping, GWAS, Microarrays, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Whole genome sequencing, BMI, Fathers, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Sex differences, Statistical methods

B4620 - Effects of Maternal Genetic Risk Factors for Polycystic Ovary Syndrome on Birth and Childhood Outcomes in Offspring - 17/05/2024

B number: 
B4620
Principal applicant name: 
Jia Zhu | Boston Children's Hospital, Harvard Medical School (USA)
Co-applicants: 
Dr. Joel N. Hirschhorn, Dr. Yee-Ming Chan
Title of project: 
Effects of Maternal Genetic Risk Factors for Polycystic Ovary Syndrome on Birth and Childhood Outcomes in Offspring
Proposal summary: 

*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.

Impact of research: 
Our project will provide insights into the interplay between PCOS genetics and intrauterine environment and the resulting adverse effects on maternal and child health, and thereby, pave the way for a targeted approach to the preventative treatment of PCOS, and its associated conditions in mothers and children.
Date proposal received: 
Friday, 17 May, 2024
Date proposal approved: 
Friday, 17 May, 2024
Keywords: 
Endocrinology, Diabetes, Fertility/infertility, Obesity, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Computer simulations/modelling/algorithms, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Birth outcomes, BMI, Cardiovascular, Genetics, Genomics, Offspring, Sex differences

B4616 - Adverse childhood experiences and oral health - 16/05/2024

B number: 
B4616
Principal applicant name: 
Eduardo Bernabe | Queen Mary University of London (England)
Co-applicants: 
Dr Ali Glokari
Title of project: 
Adverse childhood experiences and oral health
Proposal summary: 

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.

Impact of research: 
There will be academic and non-academic outputs coming out of this proposal. Academic outputs are the PhD degree for the supervised student, multiple papers in peer-reviewed journals and conference presentations (posters and oral). In addition, these outputs will assist our research group to advocate with national and international organizations for family interventions to reduce the negative impacts of adversities on health in general and oral health in particular.
Date proposal received: 
Tuesday, 14 May, 2024
Date proposal approved: 
Thursday, 16 May, 2024
Keywords: 
Dentistry, Oral health, including childhood dental caries, dental trauma, tooth loss, mouth ulcers and oral health behaviours, Statistical methods, Childhood - childcare, childhood adversity, Dental

B4615 - Whole-exome sequencing as a tool to reveal rare genetic architecture of diabetes - 16/05/2024

B number: 
B4615
Principal applicant name: 
Marisa Canadas Garre | University of Bristol (United Kingdom)
Co-applicants: 
Professor Nicholas Timpson, Dr Laura Corbin, Dr Laurie Fabian
Title of project: 
Whole-exome sequencing as a tool to reveal rare genetic architecture of diabetes
Proposal summary: 

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.

Impact of research: 
Greater understanding of the aetiology of diabetes and especially insulin resistance. This study will help identify novel genetic variants involved insulin resistance and may reveal potential targets for therapy and drug development.
Date proposal received: 
Monday, 13 May, 2024
Date proposal approved: 
Thursday, 16 May, 2024
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Diabetes, Obesity, Computer simulations/modelling/algorithms, DNA sequencing, Gene mapping, GWAS, Metabolomics, Statistical methods, Ageing, Biological samples -e.g. blood, cell lines, saliva, etc., Whole genome sequencing, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., BMI, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Metabolic - metabolism, Statistical methods, Whole Exome Sequencing

B4619 - Associations between adverse childhood experiences and cardiovascular risk factors in later life Exploring mechanisms and influ - 16/05/2024

B number: 
B4619
Principal applicant name: 
Alan Barker | Children’s Health and Exercise Research Centre, University of Exeter (UK)
Co-applicants: 
Laura Macro, Prof. Sarah Halligan, Dr Lisa Price
Title of project: 
Associations between adverse childhood experiences and cardiovascular risk factors in later life: Exploring mechanisms and influ
Proposal summary: 

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.

Impact of research: 
Assessing the contribution of psychological, environmental and lifestyle risk factors to CVD simultaneously provides a novel, interdisciplinary, and comprehensive view of approaches which may be beneficial to improving the health and wellbeing of current and future generations across their lifespan. Furthermore, consideration of differences between societal groups may identify populations who are particularly vulnerable to mental health issues or adversity in childhood or those who may suffer greater impacts on cardiovascular health in adulthood. I would aim to share information beyond my organisation through publication in a peer-reviewed scientific journal and through presentation of results at relevant conferences. Sharing the most important findings with local schools or mental health charities where possible would further build upon the impact of this research. Crucially, current governmental approaches towards tackling CVD focusing on diet and exercise may not be a successful long-term plan to reach proposed targets, based on evidence illustrating high rates of non-compliance to studies promoting physical activity and dietary interventions. As a result, the present research, which aims to assess the combined influence of psychological, environmental and lifestyle factors on cardiovascular health, could play a pivotal role in the future prevention of CVD.
Date proposal received: 
Thursday, 16 May, 2024
Date proposal approved: 
Thursday, 16 May, 2024
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Blood pressure, Statistical methods, BMI, Cardiovascular, Childhood - childcare, childhood adversity, Physical - activity, fitness, function, Puberty, Sex differences, Siblings, Social science

B4618 - Harnessing DNA methylation variation between populations to understand disease discordance across ancestries Diverse Epigenetic - 21/05/2024

B number: 
B4618
Principal applicant name: 
Hannah Elliott | University of Bristol (United Kingdom)
Co-applicants: 
Dr Josine Min, Dr Sarah Watkins
Title of project: 
Harnessing DNA methylation variation between populations to understand disease discordance across ancestries (Diverse Epigenetic
Proposal summary: 

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.

Impact of research: 
DEEP research will uncover common and novel pathways of health and disease across populations. This will translate to identify the causes of differential disease risk observed across populations, identify appropriate treatment and interventions and reduce global health disparity.
Date proposal received: 
Wednesday, 15 May, 2024
Date proposal approved: 
Thursday, 16 May, 2024
Keywords: 
Epidemiology, Diabetes, Obesity, GWAS, EWAS, BMI, Cardiovascular, Epigenetics, Genetic epidemiology, Genome wide association study, Mendelian randomisation

B4617 - Investigating the relationship between biological markers of adversity and chronic inflammation to psychiatric outcomes - 24/05/2024

B number: 
B4617
Principal applicant name: 
David Cotter | RCSI (Ireland)
Co-applicants: 
Joshua Gilheany, Dr Subash Susai
Title of project: 
Investigating the relationship between biological markers of adversity and chronic inflammation to psychiatric outcomes
Proposal summary: 

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.

Impact of research: 
This study will provide unique and clinically important data on the longitudinal pattern of markers of chronic inflammation and complement activation within all available plasma EDTA samples of the ALPAC cohort at age 24. Thus, while our own focus is the relationship between these markers and psychiatric outcomes at age 24, this data will be equally relevant to the very many general medical disorders of which inflammation is a part. The impact will be significant.
Date proposal received: 
Tuesday, 14 May, 2024
Date proposal approved: 
Wednesday, 15 May, 2024
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Proteomics, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc.

B4117 - Demonstrating a casual role for adiponectin signalling in kidney disease at the population level using Mendelian randomisation - 14/05/2024

B number: 
B4117
Principal applicant name: 
Rebecca Foster | University of Bristol (UK)
Co-applicants: 
Simon Satchell, Emma Vincent, Prof Abigail Fraser
Title of project: 
Demonstrating a casual role for adiponectin signalling in kidney disease at the population level using Mendelian randomisation
Proposal summary: 

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.

Impact of research: 
This will be the first time we can show a causal effect of adiponectin and its receptors on human kidney disease and albuminuria, using measures of endothelial glycocalyx to demonstrate mechanism.
Date proposal received: 
Monday, 25 July, 2022
Date proposal approved: 
Tuesday, 14 May, 2024
Keywords: 
Physiology, Diabetes, GWAS, Cardiovascular

B4608 - Translating the Lived Experience of Heatwaves into Policy Action - 14/05/2024

B number: 
B4608
Principal applicant name: 
Ulrika Maude | UoB
Co-applicants: 
Dr Eunice Lo, Professor Kate Northstone, Professor Nic Timpson, Dr Jo Godwin
Title of project: 
Translating the Lived Experience of Heatwaves into Policy Action
Proposal summary: 

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.

Impact of research: 
Date proposal received: 
Friday, 3 May, 2024
Date proposal approved: 
Tuesday, 14 May, 2024
Keywords: 
Environment - enviromental exposure, pollution

B4611 - Running in the FAMILY - Understanding and predicting the intergenerational transmission of mental illness - 14/05/2024

B number: 
B4611
Principal applicant name: 
Alexander Neumann | Erasmus University Medical Center Rotterdam (Netherlands)
Co-applicants: 
Charlotte Cecil, Ryan Muetzel, Fin van Uum, Raffael Kalisch, Greta Mikneviciute, Elena Isaevska, Nicole Creasy, Mina Shahisavandi, Mannan Luo
Title of project: 
Running in the FAMILY - Understanding and predicting the intergenerational transmission of mental illness
Proposal summary: 

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.

Impact of research: 
The results of this project can help researchers, healthcare professionals and policy makers to better understand how genetic, epigenetic, metabolomic and environmental risk and resilience factors interact to determine risk of mental illness over the life course. Greater awareness and knowledge about the transmission of risk from parent to offspring will support vulnerable families in taking an active role in managing their own health. Developing and implementing family-based risk prediction tools in clinical settings can lead to better prediction of future mental health, and it can facilitate the design of low-threshold, preventive actions by eliminating risk factors or strengthening resilience. Such evidence-based programs can thus empower vulnerable families and support mental health professionals in providing better care.
Date proposal received: 
Tuesday, 7 May, 2024
Date proposal approved: 
Tuesday, 14 May, 2024
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Eating disorders - anorexia, bulimia, Mental health, GWAS, Medical imaging, Microarrays, Statistical methods, Development, Equipment - MRI, Epigenetics, Genetic epidemiology, Genetics, Parenting, Psychology - personality, Sex differences, Sleep, Statistical methods

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