Proposal summaries
B4110 - Genetic evidence for the causal relationship between 25OHD and bone fracture a non-linear Mendelian randomization analysis - 18/07/2022
While previous studies have demonstrated no clear effects of vitamin D upon risk of fracture and lowered BMD in the general population, it is clear that vitamin D deficiency causes increased risk of fracture and a reduction in BMD, as is seen in rickets. Further, RCTs of high dose vitamin D have shown a decrease in BMD after administration of vitamin D. This suggests that the effects of vitamin D upon BMD and perhaps fracture are non-linear.
We therefore propose non-linear MR studies of the effect of vitamin D (as measured by 25(OH)D) on BMD and fracture outcomes. Such findings could help to guide future RCTs and provide clinicians with some insights as to the utility of vitamin D administration in different segments of the population.
B4111 - Research methods in human epigenetics - 18/07/2022
This project looks at methods used in research on human epigenetics, particularly around uses of
sociological and psychological data in devising research questions.
All paperwork stored in relevant B number folder
B4107 - Fathers preconception smoking and offspring DNA methylation A population-based two generation study - 18/07/2022
Animal experiments suggest that exposure to toxins such as found in cigarette smoke may impact respiratory health across generations. Studies in humans are however limited. In this study, we ask if gene activity differs in children whose fathers smoked prior to them being conceived. Differences have been observed in participants of the RHINESSA study. Here we ask if similar differences are observed in ALSPAC participants.
B4101 - Sensitive periods for the effects of depression on suicide risk - 18/07/2022
Depression is one of the most important risk factors for suicide. Almost 60% of people who die by suicide experienced depression at some point in their life. Yet, it remains unclear why only certain people with depression eventually become suicidal. Recent evidence suggests there are sensitive periods in development when life experiences, such as depression, can have stronger effects on mental illness. It is also well documented that suicidality results from both life experiences and genetic risk.
However, most studies of genetic risk for suicide, depression, and subsequent suicidal suicidality focus on people measured at a single timepoint. This limitation prevents us from 1) identifying people who are at the highest risk for future suicidal behaviours and 2) developing timely and effective interventions that prevent suicide in people with depression. As such, this project will use longitudinal data from two birth studies to determine when and how genetic risk and experiences of depression during childhood and adolescence influence suicide risk in early adulthood.
First, we will identify the specific ages and patterns of depression during childhood and adolescence that most predispose young adults to suicide. These results will help us build and implement interventions that are positioned at the best possible time to prevent suicide risk among youth affected by depression.
Second, we will determine whether children and adolescents with increased genetic risk for suicide or mental illness are more likely to become suicidal after experiencing depression at specific ages. These findings will improve our ability to identify youth who are at greater risk for suicide and provide insight into the genetic pathways leading to suicide.
Third, we will identify biological mechanisms that explain the link between depression and suicide. We will focus on epigenetic changes, as they are linked to human health and are thought to reflect both life experiences and genetics. Thus, they may represent a biological pathway through which suicide risk can become “molecularly programmed”. Identifying epigenetic changes that link depression to suicide risk will help guide the development of biomarkers that will allow us to identify at-risk youth quickly and effectively.
In sum, this project will highlight key periods and biological targets that can be used to predict and prevent suicidality among childhood and adolescents who experience depression. These will ultimately catalyse better interventions that prevent suicide in young adults.
B4108 - Special collections Eating disorders in Britain 1980-2010 - 13/07/2022
I am interested in the ways in which eating disorders were being discussed (both popularly and amongst academics/practitioners) and researched in the late 20th/early 21st century. I’m especially interested in ALSPAC because of the specific interest in the impact on eating disorders on maternity (a relatively unusual approach at the time.) I am only interested in material on the eating disorder research components of ALSPAC
B4104 - UKLLC Multi-Longitudinal Cohort Study into occupational factors and COVID Risk as part of PROTECT National Core Study - 12/07/2022
Information can be obtained from ALSPAC (B number folder) or the UK LLC on request
B4105 - UKLLC Using metabolomics to better understand COVID-19 symptoms - 12/07/2022
Information can be obtained from ALSPAC (B number folder) or the UK LLC on request
B4106 - UKLLC Harmonised Core Socio-demographic Measures Dataset - 12/07/2022
Information can be obtained from ALSPAC (B number folder) or the UK LLC on request
B4094 - The relationship between maternal mental health and substance use in adolescence - 29/07/2022
Previous research has established the effects of maternal mental health on children and adolescents MH but there is limited evidence on the association between maternal mental health and risky behaviours in adolescence, such as substance use (Campbell et al., 2009; Pearson et al., 2013). Studies have demonstrated that depressed parents played a significant part in offspring’s MH and substance use in adolescence and adulthood (Weissman et al., 2006). These results have been replicated by Flouri and Ioakeimidi (2008) finding that adolescents, particularly male, engaged in more risky behaviours, including alcohol use, when their mothers had chronically high or increased depressive symptoms, compared to those that their mothers never experienced depression. Wickham and colleagues (2015) also showed that adolescents who were exposed to maternal depressive symptoms in middle childhood showed a stronger association with using common substances (alcohol, cigarettes, and marijuana) and earlier engagement in such behaviours, including hallucinogenic use. This project aims to extend the evidence and look at different maternal mental health conditions and their relationship with substance use in adolescence using the ALSPAC data.
B4091 - Cannabis use and mental health a genetically informed study - 11/07/2022
Cannabis use in youth is an important public health concern, especially as it often starts in young teens and in light of recent changes in Canadian legislation. The possible effects of cannabis (marijuana, weed, etc.) use on mental health are poorly understood. Cannabis is known to be associated with later psychosis. But what about more common mental health problems like depression, anxiety, and suicidal thoughts or attempts? Our first objective is to clarify the associations, if any, between cannabis use and later anxiety, depression, and suicidality, and whether they are causal or simply associative. Our second objective is to test the genetics-environment link – whether youth with pre-existing vulnerability to mental health problems are more at risk of depression, anxiety, and suicidality if they use cannabis, while the risk remains low for others. We will use data from the ALSPAC population-based longitudinal cohort. Participants had been asked at various times whether, how often, and when they started using, as well as questions on their mental health. Data will be analyzed by robust approaches to provide strong evidence in support (or not) of the links between cannabis use and later depression, anxiety, and suicidality. Clinically relevant patterns of cannabis use will be examined: a) ever used, b) age at onset, and c) intensity. Our findings will allow clinicians, researchers, and policymakers to develop better prevention and treatment programs to avoid mental health consequences of cannabis use in young people.
B4099 - Is sexual violence in early adulthood among women associated with subsequent alcohol misuse later in life - 11/07/2022
Within the United Kingdom the prevalence of women’s experience of sexual violence particularly in early adulthood is evidenced to be at an increasing rate (Borumandnia et al., 2020) and much higher than society displays. Reports to clinics of the consequential physical and psychological effects have led to an interest from researchers to further investigate the prominent consequential risks following an experience of sexual violence. Interest has risen around incidents of alcohol misuse over other substances following a woman’s experience of sexual violence, as a result of the accessibility and social acceptance accompanying the substance (Burnam et al., 1988). Additionally, consequent severe health risks have been linked to the misuse of alcohol which may lead to an endurance of health concerns for the individual as well as the subsequent pressure implemented onto the health services.
However, despite the prevalence of sexual violence and consequent health risks associated with alcohol misuse, a lack of consistent evidence dominates existing literature. A myriad of reasons as to why a lack of consistent evidence prevails, however consistent reference to the small sample sizes due to the diverse population, methodological complications and inadequate measures are the most prominent throughout existing literature. Furthermore, due to the ambiguous nature of both sexual violence and alcohol misuse, difficulties can arise when attempting to define the two concepts, particularly when portraying this to patients, which can influence accuracy of the data gathered. Nonetheless, a consistent effort is made to reduce these confounding factors to produce research that can reap both clinical and educational benefits from the knowledge gathered. This project aims to account for the issues that previous research has struggled to address, through focusing on the gap in the literature through the use of the large ALSPAC data set to investigate whether an association exists between women’s early adulthood experience of sexual violence in early adult hood at aged 16 and their subsequent alcohol use at ages 24.
B4100 - Validation of novel biomarkers in pre-diagnostic brain tumour bloods and potential correlation with tumour biomarkers - 29/07/2022
Around 60,000 patients in the UK are living with a brain tumour. Brain tumours are the most frequent solid tumour type in children and young adults, second only to leukaemias. Overall, less than 20% of brain tumour patients survive 5 years or more after diagnosis, and brain tumours are responsible for the most years of life lost of any cancer type. In the UK in 2013: 38 % of brain tumour patients visited their GP 5 times or more before referral to secondary care for diagnosis by imaging MRI/CT scan and neurosurgical biopsy because the symptoms such as headache are non-specific. There is an urgent need to develop new sensitive tests of brain tumours to help GPs in primary care.
A simple blood test performed by a GP in the clinic would aid decision-making and
early diagnosis. This would revolutionize care by speeding up diagnosis, reducing costs and anxiety of unnecessary scans and reducing the number of patients presenting with inoperable
large brain tumours. Moreover, this test could be used as an early monitor of brain tumour
recurrence.
B4098 - Heart failure with preserved ejection fraction during mid-life in women with previous hypertensive pregnancy - 08/07/2022
Women who develop high blood pressure during pregnancy are at substantial risk of future cardiovascular disorders, which emerge earlier in life than for women who have pregnancies without high blood pressure or complications related to this. Of particular concern, recent evidence highlights that high blood pressure during pregnancy doubles the risk of hospitalisation for heart failure, specifically, heart failure with preserved ejection fraction (HFpEF). Once established, changes in the heart underlying HFpEF are difficult to modify and prevention is considered a priority. However, we, and others, have shown changes in the heart consistent with early HFpEF are already evident following a pregnancy complicated by high blood pressure, before significant exposure to other known risk factors for HFpEF such as long-standing hypertension and diabetes.
Therefore, to understand whether there is a clinical rationale for pregnancy-related interventions to prevent later HFpEF we propose, firstly, to follow up the original maternal G0 cohort from the Avon Longitudinal Study of Parents and Children to determine whether high blood pressure during pregnancy remains independently associated with the presence of sub-clinical and clinical HFpEF in later life. Secondly, we will use cardiovascular magnetic resonance and echocardiography imaging techniques to characterise the changes and clinical features observed in the heart in this group. Finally, we will identify key biomarkers in the heart that are clinically relevant to the phenotype of HFpEF associated with high blood pressure during pregnancy. We will then study these biomarkers in other trials we currently have in progress that are using interventions earlier in life to try and prevent disease.
An additional anticipated feature of this project is the synergistic opportunity to link the imaging data we will collect in the maternal cohort of ALSPAC with our ongoing CLARITY study that is undertaking similar imaging of the ALSPAC G1 cohort of adults born to these pregnancies. We hope to link the imaging findings from the mothers and their children between cohorts to determine whether they share distinct familial patterns of cardiac remodelling.
B4097 - Investigating the impact of variation in BMI on the metabolome using multiple study designs - 29/06/2022
Obesity is known to have effects on cellular metabolism, which is reflected in a person’s circulating metabolome. Metabolomics, defined as the measurement and study of circulating small molecules that are the substrates and products of cellular metabolism, is increasingly used by epidemiologists to provide a functional read-out of bulk cellular activity and a proxy to individual current health. This approach also provides insight into biological pathways linking exposures and disease.
Measuring the metabolome of people with measured body mass index (BMI) allows us to look for ways in which BMI affects the metabolome. Metabolites found to be associated with BMI can then be further investigated and linked to cellular pathways – knowledge which will help us to understand the pathology of obesity. We have already begun to look at how bariatric surgery (within the By-Band-Sleeve trial (BBS), https://bristoltrialscentre.blogs.bristol.ac.uk/details-of-studies/by-ba...) and non-surgical weight loss interventions (within the DiRECT trial, https://www.directclinicaltrial.org.uk/) affect the metabolome, and we want to use the recall-by-genotype (RbG) Metabolon data in ALSPAC (https://onlinelibrary.wiley.com/doi/full/10.1002/oby.23441) to compare our results to population-level data. Bringing together data from these different study designs enables to unpick the metabolomic effects that are associated with BMI and their relevance to disease.
B4096 - Center for Causal Data Science for Child Maltreatment Prevention - 27/06/2022
Maltreatment by caregivers is associated with devastating consequences; include poor school performance, mental disorders, substance abuse, violence and suicide, and chronic health problems. Despite decades of research to acquire the scientific knowledge to prevent maltreatment exposures (ME’s) and maltreatment-related outcomes (MRO’s); only a small proportion of those children at risk have benefited. Complex etiology entails several requirements for scientific knowledge to achieve preventative results for a large proportion of children at risk: (1) etiology must be accurately determined (at the approximate level of its’ complexity), because intervention targeting non-etiological/non-causal factors cannot result in reduced risk, (2) valid models of complex etiology must be used to enable unbiased estimates of quantitative causal effect, (3) intervention targets must be identified from those factors with largest causal effect, and (4) personalized and precise intervention strategies must be determined from those intervention targets. We propose to address these considerable barriers to progress, by establishing the Center on Causal Data Science for Child and Adolescent Maltreatment Prevention (The CHAMP Center), to (1) discover the scientific knowledge on the complex etiology of the ME’s and MRO’s, by applying state-of-the -art methods of Causal Data Science to several large, and highly relevant existing data sets; (2) translate this knowledge into specific Decision Support Tools for those practitioners, whose decisions – when supported by these tools – can result in large-scale prevention, and (3) validate this knowledge in the field, in trials using the developed Decision Support Tools, with those practitioners, and the children and families whom they serve.
B4095 - Understanding predictors of study participation amongst individuals with mental health difficulties in established cohorts - 18/07/2022
This project aims to understand better the factors which affect participation in research, both academic and NHS service evaluation. This will involve a mix of quantitative bias analyses using electronic health records from the NHS Mental Health Partnership for Avon and Wiltshire Partnership, as well as a qualitative component aiming to understand better the reasons why continued participants (ALSPAC) and non-participants (recruited through AWP) perceive that individuals might participate or not participate in health research.
B4081 - Identifying master regulators of gene expression in human immune cells - 16/06/2022
Common genetic variants that differ between individuals in a population lead to millions of ‘natural experiments’ that can be used to gain insight into the principles of how our immune system works. However, most published studies relying on this information have been too small take full advantage of these natural experiments. In this project, we plan to assemble genetic variation and gene expression data from up 10-15 individual studies that have all profiled multiple cell types of our immune system. We expect that joint analysis of these data will help us to identify master regulators gene expression - genes that control the activity patterns of other genes - and help us understand how these genes contribute to complex immune-mediated disorders.
B4093 - Measuring steroid hormones in ALSPAC hair samples - pilot study - 11/07/2022
In response to a stressful situation, whether psychological or physical, the human body activates processes that aim to increase chance of survival. This “fight-flight-freeze” response could include making you feel more alert, giving the body energy and making you feel less pain. One key hormone involved in this response is cortisol.
Although the release of cortisol in response to stress is initially beneficial, it is thought that experiencing severe or ongoing stressful events can lead to a maladaptive stress response which can result in harmful effects on the body[1]. As such, the stress response system has been implicated in a range of adverse outcomes including obesity, cancer, heart disease, susceptibility to infection, and psychiatric disorder[2].
Commonly, cortisol is measured from saliva samples two or three times daily. However, as cortisol is secreted in a pulsatile fashion throughout the day, these measures are difficult to interpret and compare as it is uncertain whether samples are taken at the same time point along a pulse. Furthermore, saliva measures provide limited information about long-term cortisol secretion.
In contrast, hair cortisol concentration can provide a non-invasive, alternative assessment method capturing information about cortisol levels over the course of several months, thus overcoming the difficulties of single timepoint measures. Validation studies strongly support the assumption that hair cortisol concentration provides a valid index of long-term cortisol concentrations[3]. As such, given its advantage of providing information on the mean stress levels during a chosen extended period, hair cortisol analysis is increasingly being applied in many studies of physical and mental health[4-6].
We propose to conduct a pilot study in ALSPAC (n= 10-20 hair samples, collected at age 15years) to determine the feasibility of measuring steroid hormone concentrations from adolescent hair samples using liquid chromatography tandem mass spectrometry (LC-MS/MS)[7]. If successful, these results will be used in a funding proposal to extend measurement to a larger number of ALSPAC hair samples.
Within the funding proposal, we aim to use measures to investigate the associations between hair cortisol concentrations and subsequent mental health, and to perform a genome-wide association study (GWAS) of hair cortisol concentrations. GWAS results will be meta-analysed with 9 other cohorts within the CORtisol NETwork (CORNET) to provide the first GWAS to date of hair cortisol concentrations.
References
1. Charmandari, E., et al., Endocrinology of the stress response. Annual Review of Physiology, 2005. 67: p. 259-84.
2. Adam, E.K., et al., Diurnal cortisol slopes and mental and physical health outcomes: a systematic review and meta-analysis. Psychoneuroendocrinology, 2017. 83: p. 25-41.
3. Stalder, T., et al., Analysis of cortisol in hair--state of the art and future directions. Brain, Behavior, and Immunity, 2012. 26(7): p. 1019-29.
4. Iob, E., et al., Cardiovascular Disease and Hair Cortisol: a Novel Biomarker of Chronic Stress. Current Cardiology Reports, 2019. 21(10): p. 116.
5. Ling, J., et al., Body mass index, waist circumference and body fat are positively correlated with hair cortisol in children: A systematic review and meta-analysis. Obesity Reviews, 2020. 21(10): p. e13050.
6. Koumantarou Malisiova, E., et al., Hair cortisol concentrations in mental disorders: a systematic review. Physiology & Behavior, 2021. 229: p. 113244.
7. Gao, W., et al., Quantitative analysis of steroid hormones in human hair using a column-switching LC–APCI–MS/MS assay. Journal of Chromatography B, 2013. 928: p. 1-8.
B4047 - Assessing the association between a DNA methylation-based exposure score for maternal smoking during pregnancy and neurodevelopm - 14/06/2022
Maternal smoking during pregnancy has been related to lower child neurodevelopment and higher behavioural problems. However, there is a need to replicate such analyses in a consortium of several European cohorts, using machine learning-based DNA methylation smoking scores. The harmonization of mental health problems in several population-based birth cohorts will allow us to perform trajectory analyses with specific mental health domains.
B4090 - Early Psychedelic Use and Brain Structure in Young Adults - 13/06/2022
There has been a dramatic reemergence of research into the therapeutic effects of psychedelic substances over the past decades (Nutt & Carhart-Harris, 2021). For example, a recent randomized controlled trial investigated the effects of psilocybin on depressive symptoms among patients with moderate-to-severe major depressive disorder. The results showed that the psilocybin condition was at least as effective as a leading antidepressant (escilatopram) in reducing depressive symptoms (Carhart-Harris et al., 2021). Although previous research has found associations between long-term use of ayahuasca (20 ayahuasca users versus 20 matched controls) and brain structure (Bouso et al., 2015), relatively little is known about the potential effects of other psychedelics such as psilocybin (‘magic mushrooms’) and lysergic acid diethylamide (LSD) on brain structure, especially in adolescence. This research project therefore aims to investigate associations between early use of psychedelics (i.e., psilocybin, LSD) and brain structure.
References
Bouso, J. C., Palhano-Fontes, F., Rodríguez-Fornells, A., Ribeiro, S., Sanches, R., Crippa, J. A. S., ... & Riba, J. (2015). Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans. European Neuropsychopharmacology, 25(4), 483-492.
Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., ... & Nutt, D. J. (2021). Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine, 384(15), 1402-1411.
Nutt, D., & Carhart-Harris, R. (2021). The current status of psychedelics in psychiatry. JAMA psychiatry, 78(2), 121-122.