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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B3589 - The moderating role of genetic propensity in the relationship between depression/anxiety and substance use during Covid-19 era - 11/08/2020

B number: 
B3589
Principal applicant name: 
Jueun Kim | Chungnam National University
Co-applicants: 
Title of project: 
The moderating role of genetic propensity in the relationship between depression/anxiety and substance use during Covid-19 era
Proposal summary: 

Previous studies have reported that addictive behaviors decrease when infectious disease first occurs but increase as the disease continues. It shows that especially among health workers, the addiction problems can get even more serious compared to the period when the infectious disease did not occur. This study wants to examine predictive factors that are associated with addictive behaviors before and after Covid-19.

Impact of research: 
Date proposal received: 
Wednesday, 5 August, 2020
Date proposal approved: 
Tuesday, 11 August, 2020
Keywords: 
Social Science, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc.

B3593 - Genetic impact on youth vaping extending known genetic risk factors in smoking to vaping - 11/08/2020

B number: 
B3593
Principal applicant name: 
Meghan Chenoweth | Centre for Addiction and Mental Health, and the University of Toronto (Canada)
Co-applicants: 
Dr. Rachel Tyndale, Dr. Marcus Munafo, Alaa Alsaafin, Ahmed El-Boraie
Title of project: 
Genetic impact on youth vaping: extending known genetic risk factors in smoking to vaping
Proposal summary: 

Adolescents who smoke cigarettes are more likely to start vaping, and the reverse is also true: vaping can lead to smoking. In former smokers, vaping can also increase the risk for relapse back to smoking. While some young people report vaping to help them quit smoking, most continue to smoke resulting in dual use. The high rate of dual use suggests that vaping could prolong smoking and increase harms in young people who would have otherwise quit. Biomarker data show that dual users are exposed to higher levels of harmful chemicals known to cause tobacco-related illnesses compared to those who only smoke.

Genetic variation influences cigarette smoking. People with gene variants that increase the rate at which nicotine is inactivated smoke more cigarettes, have a higher risk for tobacco-related illnesses, and are less likely to quit, compared to people with slow nicotine metabolism. In ALSPAC, we propose to study whether youth smokers with genetically faster nicotine metabolism have a higher risk for becoming a dual user and continuing smoking once they start vaping. In former smokers, we will test whether faster nicotine metabolism increases relapse back to smoking among vapers. As a secondary goal, we will also test whether other genes, for example those that alter the response to nicotine in the brain, also influence the risk for vaping.

The reasons underlying the popularity of vaping and dual use among youth are not well understood, and our work will show whether genetic factors play a role.

Impact of research: 
Our work will provide insight into the genetic contributions to vaping, allowing for the identification of vulnerable sub-groups. Due to the nature of the genes under study, our work will also identify potential mechanisms underlying the high rate of dual use, and thus the persistence of smoking, in youth vapers. Because CYP2A6 variation predicts smoking cessation outcomes and can be used to optimize treatment, our work may also facilitate tailored approaches to quitting vaping.
Date proposal received: 
Monday, 10 August, 2020
Date proposal approved: 
Tuesday, 11 August, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Statistical methods, Genetic epidemiology

B3591 - Exploring the progression of mental illness Identifying predictors of recovery - 11/08/2020

B number: 
B3591
Principal applicant name: 
Robyn Wootton | University of Bristol
Co-applicants: 
George Davey Smith, David Kessler, Marcus Munafo, Andy Skinner, Kate Tilling, Alexandra Havdahl, Anne-Siri Oyen
Title of project: 
Exploring the progression of mental illness: Identifying predictors of recovery
Proposal summary: 

Depression is the leading cause of global disability with over 300 million people suffering world-wide. Estimates suggest that up to two thirds of patients do not recover following their first antidepressant treatment and up to one third do not recover after multiple treatments. Therefore, it is critically important to identify factors that predict recovery and reduce risk of relapse. Current methods in genetic epidemiology focus on predictors of mental illness onset. While this is crucial to prevent new diagnoses, it does little to help individuals already suffering. Therefore, the Recover project aims to extend current genetic epidemiology methods to better understand recovery from depression. The methods developed here will begin with a focus on depression but can also be extended to other mental illnesses. First, we will develop trajectories of depression using continuous longitudinal measures in two critical time points, 1) adolescence and early adulthood and 2) during and post pregnancy. Second, using these trajectories as outcomes we will explore many modifiable predictors of recovery. Third, we will use cutting-edge causal inference techniques to test whether or not these predictors are causal. And finally, we will develop novel technologies to capture fine-grained fluctuations in mood. Taken together, this work will lead to better interventions and inform adjuncts to treatment having real impact for the growing number of individuals suffering from depression.

Impact of research: 
With over 300 million people living with depression globally, it has been called a “mental illness epidemic”. Depression is the leading cause of disability worldwide, resulting in an estimated 800,000 suicides per year globally and 44 million lost years of productive life. Despite increased treatment provision, prevalence of depression has not decreased and up to a third of patients have still not responded after multiple treatments. Depression can bring immense suffering to both the individual afflicted and their family. Not responding to treatment can be both terrifying and frustrating. Given this significant burden that depression poses to both the individual and their families, strategies to promote recovery and prevent relapse are of upmost importance to public health. Therefore, it is critically important for patients that we identify factors that predict recovery and reduce the risk of relapse. Our proposed Recover project would have real impact for individuals with depression, their families and wider society.
Date proposal received: 
Thursday, 6 August, 2020
Date proposal approved: 
Tuesday, 11 August, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Genetic epidemiology

B3590 - Early signs and predictors of ADHD A population cohort study - 11/08/2020

B number: 
B3590
Principal applicant name: 
Esther Tobarra-Sanchez | Cardiff University (United Kingdom)
Co-applicants: 
Dr Anita Thapar, Clinical Professor, Child and Adolescent Psychiatry , Kate Langley, Senior Lecturer in Cardiff School of Psychology
Title of project: 
Early signs and predictors of ADHD. A population cohort study.
Proposal summary: 

Attention deficit Hyperactivity disorder (ADHD) is a disabling neurodevelopmental disorder that affects 5% of the population. There is emerging evidence that early detection and intervention improves neurodevelopmental disorders outcomes. This knowledge, coupled with clear evidence that the first signs and symptoms of developmental disorders may be evident for many children by 30 months of age, has led to increased early detection efforts. However, it is still uncertain how best to identify the very first signs of these disorders. For example, early speech, motor delay or global developmental delay, birth and neonatal complications may index future neurodevelopmental disorders. Investigations using prospective designs may be especially fruitful because they are less affected by retrospective recall biases.
In this project I propose to utilise data from a large, prospective population-based cohort, ALSPAC. The aim is to test the hypothesis that early developmental difficulties in the first year of life precede ADHD and other neurodevelopmental disorders emergence by ages 7 to 9 years.
This work will represent a step towards earlier detection of ADHD and other neurodevelopmental disorders prior to the onset of behavioural symptoms.

Impact of research: 
The findings of this study may bring more clarity towards a long-held suspicion that early differences underscore the multifaceted nature of ADHD. We aim to identify genetic risk factors of ADHD, as well as precursors and early signs reported in the first 3 years of life among children from general population that later develop ADHD. The findings of this study may have potential implications for the development of approaches to early population screening and intervention programmes. Early predictors of ASD have been broadly researched, but in comparison, this has not been extensively studied in ADHD. We therefore highlight the need of considering the developmental determinants of ADHD, as well as the genetic and environmental factors.
Date proposal received: 
Wednesday, 5 August, 2020
Date proposal approved: 
Friday, 7 August, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Developmental disorders - autism, Statistical methods, Genetics

B3583 - The course of autistic traits in the population from childhood to adolescence and educational attainment - 05/08/2020

B number: 
B3583
Principal applicant name: 
Pieter Hoekstra | University Medical Center Groningen
Co-applicants: 
Anne Smit, Annelies de Bildt, Jorien Vugteveen, Marieke Timmerman
Title of project: 
The course of autistic traits in the population from childhood to adolescence and educational attainment
Proposal summary: 

Children and young people with autism may do less well in school compared to others. This has a negative impact on their future. Even children with mild symptoms may have problems with school or finding a job when they are older. We want to find out how the development of autistic symptoms over time impacts future success in education.

Impact of research: 
Date proposal received: 
Tuesday, 4 August, 2020
Date proposal approved: 
Wednesday, 5 August, 2020
Keywords: 
Social Science, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Computer simulations/modelling/algorithms, Social science

B3582 - Understanding how patterns of glucose levels and variability relate to health exposures and outcomes - 05/08/2020

B number: 
B3582
Principal applicant name: 
Louise Millard | MRC IEU, Bristol Medical School
Co-applicants: 
Ms Ciarrah Barry, Professor Deborah Lawlor
Title of project: 
Understanding how patterns of glucose levels and variability relate to health exposures and outcomes
Proposal summary: 

Epidemiological and clinical studies interested in circulating glucose as a risk factor or outcome typically measure levels in the blood at a single or widely spaced time points (e.g. every few years). While these are important health indicators, there has been an increasing appreciation that glucose levels and variability in free-living conditions during both the day and night, may also provide important health measures in clinical (e.g. diabetic or obese) and ‘healthy’ populations.

Continuous glucose monitoring (CGM) systems measure interstitial glucose levels ‘continuously’ by implanting a sensor subcutaneously. This produces a sequence of measurements for each participant (e.g. the average glucose level every 5 minutes over several days), that can be used to assess how a person’s glucose levels vary over both the day and night. We have recently published a novel software package called GLU, for deriving a consistent set of summary variables from CGM data. The derived summary variables can be used in analyses to assess how different characteristics of glucose levels and variability relate to health exposures and outcomes.

Impact of research: 
Understanding which aspects of activity relate to glucose levels and glucose variability, and which aspects of glucose levels and glucose variability may impact offspring outcomes in early life.
Date proposal received: 
Friday, 24 July, 2020
Date proposal approved: 
Wednesday, 5 August, 2020
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Birth outcomes, Physical - activity, fitness, function

B3587 - Optimizing Adult Mental Health Outcomes in Children with Neurodevelopmental Problems Interplay of Social and Genetic Factors - 05/08/2020

B number: 
B3587
Principal applicant name: 
Stephan Collishaw | Cardiff University (Wales, UK)
Co-applicants: 
Lorna Ushaw, Dr Kate Langley, Dr Jon Heron, Dr Gemma Hammerton
Title of project: 
Optimizing Adult Mental Health Outcomes in Children with Neurodevelopmental Problems: Interplay of Social and Genetic Factors
Proposal summary: 

Previous research has indicated that individuals with ADHD have an increased likelihood of developing mental health problems such as depression, anxiety and antisocial behavior. Despite mental health problems being increased in individuals with ADHD, not all children go on to develop poor mental health outcomes. Research has indicated that resilience is a dynamic process that arises from normal adaptive mechanisms and can be influenced by many factors. However, why some individuals with ADHD show higher levels of resilience and better outcomes compared to others is not yet well understood. One way of defining resilience is better-than-expected long-term mental health outcome than predicted by initial severity of childhood ADHD. Therefore, the current research project will focus on first identifying risk mechanisms which increase the likelihood of individuals with childhood ADHD developing adult mental health problems, and then will aim to identify potentially modifiable protective factors that could be the focus of prevention and intervention programs.

Impact of research: 
Treatment of ADHD typically focuses on alleviation of core symptoms. However, it is also important to consider how best to prevent and treat co-occurring mental health problems such as anxiety and depression. Development of effective preventative intervention however requires a good understanding of likely modifiable risk and protective factors that could be targeted in interventions in children and young people with ADHD. The project has potential to impact in two ways: i) by helping identify those children with ADHD problems who are at highest risk of later mental health problems and who are therefore a priority for early support and preventative intervention; and ii) by identifying potentially modifiable protective factors of relevance in this group that could be a focus for interventions that aim to optimize long-term mental health outcomes. The supervisory team have experience of developing impact work and forging links with educators and other stakeholders. Furthermore, the research team works closely with ADHD support groups, trains mental health practitioners, and also has strong links and experience of working with other stake holders such as schools, education authorities and Welsh Government.
Date proposal received: 
Friday, 31 July, 2020
Date proposal approved: 
Wednesday, 5 August, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Development, Parenting, Statistical methods

B3586 - Super Cohort for COVID Research - 07/08/2020

B number: 
B3586
Principal applicant name: 
Andy Boyd | University of Bristol
Co-applicants: 
Prof. Jonathan Sterne, Prof. John Macleod, Prof. Nic Timpson, Dr Kate Northstone
Title of project: 
Super Cohort for COVID Research
Proposal summary: 

We propose that a ‘Super Cohort’ - comprising of multiple existing UK Longitudinal Population Studies (LPS), including ALSPAC/Children of the 90s – is formed. The data from ALSPAC participants will be linked to whole population NHS and subsequently administrative records and rapidly used for COVID-19 (COVID) research. This work is part of UK government strategy for COVID pandemic research developed by the NHS, government officials and academic health and social science research community. The Super Cohort envisages centralised (by UK nation) sets of key NHS records which are minimised to the purpose, joined together and regularly refreshed during the COVID pandemic. All records will be stored, processed and used for research in a 'Trusted Research Environment'. This is a high security research server which is de-identified and allows researchers to access individuals (including ALSPAC participants) records without revealing individual identities. No data is allowed to exit the server, only anonymous statistical research findings can be exported. These findings will contribute to government policy development and the international understanding of COVID as a disease and the impacts of social distancing and other protective measures.

Impact of research: 
The ability for longitudinal studies - including ALSPAC - to rapidly answer priority government policy questions using linked study and routine health and social and environmental data.
Date proposal received: 
Thursday, 30 July, 2020
Date proposal approved: 
Friday, 31 July, 2020
Keywords: 
Epidemiology, COVID-19, Data Linkage

B3584 - Understanding the health implications of using different definitions of attention deficit hyperactivity disorder - 06/08/2020

B number: 
B3584
Principal applicant name: 
Kate Langley | Cardiff University (primary site) and University of Bristol (United Kingdom)
Co-applicants: 
Dr Joanna Martin, Dr Evie Stergiakouli
Title of project: 
Understanding the health implications of using different definitions of attention deficit hyperactivity disorder
Proposal summary: 

Individuals with Attention Deficit Hyperactivity Disorder (ADHD) have difficulties with sustaining attention, being overactive and being impulsive. It is one of the most common childhood disorders and causes difficulties in school, and with family relationships and friendships, whilst those with ADHD are also at higher risk of other difficulties such as anxiety and depression both in childhood and later life. Not all individuals with ADHD have the same problems though, so it is important to understand who is at greatest risk of them. Difficulties with attention or hyperactivity are present across many people whilst only some have sufficient problems to be diagnosed with ADHD. International guidelines indicate where the dividing line between having a diagnosis or not is set, but we know that individuals who do not meet this diagnostic threshold can still have difficulties due to their ADHD symptoms whilst even in those with a diagnosis, the specific constellation of problem behaviours differs between individuals. This project aims to examine how differences in the symptom presentation and impairments in children are linked to other difficulties they have in childhood and as they grow into adulthood. It will also look at how genetic risks for ADHD and other disorders are related to these different presentations. This will be examined in both the general population (the ALSPAC cohort) and a clinical sample of children with ADHD, with additional replication in other international cohorts.

Impact of research: 
Increased understanding of the relationship between different presentations of ADHD behaviours and difficulties at both the disorder and subthreshold level. This can be informative for both our understanding of ADHD aetiologically and also for clinical understanding and planning for those with difficulties.
Date proposal received: 
Tuesday, 28 July, 2020
Date proposal approved: 
Tuesday, 28 July, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Genetic epidemiology

B3579 - Associations of COVID-19 Risk Perceptions with Mental Health Wellbeing and Risk Behaviours - 24/07/2020

B number: 
B3579
Principal applicant name: 
Maddy Dyer | School of Psychological Science, Tobacco and Alcohol Research Group, MRC IEU, University of Bristol
Co-applicants: 
Dr Hannah Sallis, Miss Jasmine Khouja, Dr Sarah Dryhurst, Dr Anna Blackwell, Professor Marcus Munafo
Title of project: 
Associations of COVID-19 Risk Perceptions with Mental Health, Wellbeing, and Risk Behaviours
Proposal summary: 

Risk perceptions are subjective judgements that people make about the characteristics and severity of a risk (Darker, 2013), and they can influence emotions and behaviours (Ferrer & Klein, 2015; Paek & Hove, 2017). Accuracy is critical; underestimating or overestimating the level of threat and danger can have negative consequences. For example, underestimation of risk in a pandemic can reduce adoption of protective and preventative health behaviours (Dryhurst et al., 2020; Khosravi, 2020; Leppin & Aro, 2009). While overestimation of risk can increase hoarding behaviour, potentially leading to shortages of medications and personal protective equipment (Abrams & Greenhawt, 2020). Overestimation of risk may also lead to reluctance to return to normal activities as national lockdowns ease.

As well as influencing behaviour, risk perceptions can negatively impact mental health and wellbeing. Among young adults in the Avon Longitudinal Study of Parents and Children (ALSPAC), wellbeing has reduced, and anxiety levels have almost doubled during the COVID-19 pandemic, compared to pre-pandemic levels (Kwong et al., 2020). This is an important public health issue, given that anxiety is associated with maladaptive coping strategies such as increased alcohol use (Dyer, Heron, Hickman, & Munafò, 2019). High risk perceptions may be one factor associated with this increase in anxiety and reduction in wellbeing. In this project, we will examine the bi-directional associations of COVID-19 risk perceptions with mental health, wellbeing, and risk behaviours, using genetic and self-report data. It is also important to examine the mental health and behavioural precursors of COVID-19 risk perceptions, given their influence on health behaviours.

Impact of research: 
It is important to identify modifiable predictors of poorer mental health and wellbeing, such as subjective risk perceptions, as this may inform intervention efforts. Keeping the risk of COVID-19 in perspective may help to prevent poorer mental health and wellbeing and subsequent harmful coping strategies. It is also important to identify predictors of COVID-19 risk perceptions, as this can affect health behaviours. This research may therefore have implications for public health education and risk communication.
Date proposal received: 
Thursday, 23 July, 2020
Date proposal approved: 
Friday, 24 July, 2020
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Statistical methods, Polygenic risk scores , Risk perception Mental health Wellbeing Risk behaviours (alcohol use, smoking/vaping) Epidemiology Genetic Epidemiology Psychology COVID-19

B3581 - Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Children - 24/07/2020

B number: 
B3581
Principal applicant name: 
Yee-Ming Chan | Boston Children’s Hospital; Harvard Medical School (USA)
Co-applicants: 
Dr. Joel N. Hirschhorn, Dr. Jia Zhu, Dr. Cecilia Lindgren, Prof. Debbie A. Lawlor, Dr. Abigail Fraser
Title of project: 
Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Children
Proposal summary: 

Polycystic ovarian syndrome (PCOS) is a major health concern that affects up to 10% of reproductive-aged women. This complex, heterogeneous condition is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction. Despite extensive physiologic and genetic studies, the treatment of PCOS remains limited by an incomplete understanding of the pathophysiology of the disorder. Identification of the genetic variants and pathways associated with PCOS susceptibility may provide insights into the pathogenesis of the condition and potential targeted treatments.

We propose to study phenotypes in children that may be associated with PCOS, including obesity, dyslipidemia, and premature adrenarche. Premature adrenarche is a pediatric condition characterized by early production of adrenal androgens such as DHEAS and androstenedione and has been proposed to be a precursor to PCOS in girls. We will calculate a polygenic risk score for PCOS in prepubertal children and test for associations with premature adrenarche and associated cardiometabolic and hyperandrogenic outcomes and biochemical and anthropometric traits. In addition, we will examine these outcomes during the pre-pubertal period in girls who later develop a diagnosis of PCOS in adolescence and young adulthood.

The extension of PCOS genetics to prepubertal children provides the unique opportunity to 1) classify the PCOS pathways into ovarian-dependent factors and nonovarian-dependent factors and 2) characterize the pediatric phenotypes associated with PCOS genetic risk factors, and 3) understand the pre-pubertal manifestations of a future PCOS diagnosis. Overall, investigations in prepubertal children have the potential to provide valuable insights into the mechanisms of pathogenesis and targets for treatment for PCOS.

Impact of research: 
If associations between a polygenic risk score for PCOS and hyperandrogenic and cardiometabolic phenotypes in children are found, the findings would indicate that biological pathways independent of ovarian function contribute to the pathogenesis of PCOS. In contrast, if associations are not identified, it would suggest that ovarian function has a primary causative and/or an essential mediator role in the pathogenesis of PCOS, potentially limited to reproductive-age women. Broadly, this study and future studies will provide insight into the role that genetic risk factors for PCOS play in reproductive and cardiometabolic disease, and how these are shared or distinct between men and women. This study also has the potential to deepen our understanding of pediatric manifestations of genetic risk factors for PCOS, which may inform clinical care and counseling for children with premature adrenarche.
Date proposal received: 
Thursday, 23 July, 2020
Date proposal approved: 
Friday, 24 July, 2020
Keywords: 
Endocrinology, Diabetes, Fertility/infertility, Obesity, Computer simulations/modelling/algorithms, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Cardiovascular, Genetics, Sex differences

B3577 - Understanding the relationship between adverse childhood experiences and later mental health outcomes - 23/07/2020

B number: 
B3577
Principal applicant name: 
Becky Mars | University of Bristol (United Kingdom)
Co-applicants: 
Dr Laura Howe, Dr Abby Russell
Title of project: 
Understanding the relationship between adverse childhood experiences and later mental health outcomes
Proposal summary: 

Adverse childhood experiences (ACEs) such as abuse, bullying or family disruption are increasingly recognised as one of the most potent determinants of later mental health problems. Estimates suggest that mental health problems, including depression and self-harm are at least double among those who have been exposed to ACEs. Despite the recognised importance of ACEs to later mental health outcomes, relatively little is known about the characteristics of ACE’s that have the greatest impact. Firstly, many studies have relied on cumulative scores, whereby ACE’s are simply dichotomised and summed. This approach assumes that each ACE contributes equitably to the outcome of interest and that they operate via the same mechanisms. Other research has focused on the relationship between individual ACEs’ and mental health. Although such studies have provided useful insights, it is known that ACE’s often co-occur and most have failed to take account of this clustering. Person centred approaches such as Latent Class Analysis (LCA) could be used to identify variability in ACE profiles between individuals and investigate potential differential associations with mental health, demographic factors, and mechanisms. Secondly, little attention has been paid to the role of timing, chronicity, or recency of exposure in relation to mental health, and findings from existing studies have been inconclusive. Disentangling these effects is challenging as it may be that those who have been exposed earlier in childhood have also been exposed for longer. This PhD will address these limitations and generate valuable new insights into the relationship between ACEs and two mental health outcomes – depression and self-harm.

Impact of research: 
Improved understanding of the relationship between ACEs and mental health problems identification of mediators could inform potential targets for intervention identification of 'sensitive periods' of exposure could inform targeting of interventions
Date proposal received: 
Tuesday, 21 July, 2020
Date proposal approved: 
Thursday, 23 July, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Statistical methods

B3578 - Genetic and non-genetic influences on the development of psychiatric outcomes in children born with cleft lip and/or palate - 23/07/2020

B number: 
B3578
Principal applicant name: 
Evie Stergiakouli | MRC IEU, PHS
Co-applicants: 
Dr Sarah Lewis, Professor Marianne van den Bree, Prof Sir Michael Owen
Title of project: 
Genetic and non-genetic influences on the development of psychiatric outcomes in children born with cleft lip and/or palate.
Proposal summary: 

Cleft of the lip and/or palate is a common birth defect worldwide and occurs at a rate of one in 650 live births in the UK. Being born with cleft places a significant burden on children, their families and the health system as they require surgery (multiple times depending on cleft type), and other interventions to improve appearance, speech, hearing, dentition and other adverse outcomes. They are also at increased risk of psychological, psychiatric and cognitive problems [1]. There are several possible mechanisms underlying these associations that may be operating alone or together. First, they may reflect the psychological, developmental and social impacts of clefting and its treatment. Second, they may reflect genetic factors either as pleiotropic outcomes of genetic susceptibility to clefting or as independently inherited genetic risk.
The aetiology of both cleft and of psychiatric disorders is complex, with common risk alleles [3] [4] of individually small effects as well as rare genetic mutations of large effect and environmental factors playing roles. One group of rare mutations of large effect are Copy Number Variants (CNVs), referring to deletion or duplication of a part of the genome leading to differences between individuals in the number of copies of genes within the affected region. CNVs are known to increase risk of neurodevelopmental disorders (ND-CNVs), such as ADHD and autism, as well as mental health disorders but the presence and the impact of CNVs have not been studied in cleft [5].

The PhD project will provide the first detailed description of neurodevelopmental and mental health outcomes in children with cleft and examine the contributions of genetic and environmental factors. For this we will use two unique genetically informative clinical cohorts of children; the Bristol University Cleft Collective and the Cardiff University longitudinal ExperiencCes of people witH cOpy number variants (ECHO) study. Control samples will consist of the Avon Longitudinal Study of Parents and Children (ALPSAC) and the Millennium cohort which are deeply-phenotyped cohorts of typically developing children.

Impact of research: 
The PhD project will provide the first detailed description of neurodevelopmental and mental health outcomes in children with cleft and examine the contributions of genetic and environmental factors. Apart from high quality training to the student, this project has the potential of advancing our knowledge on the causes and outcomes of cleft in children.
Date proposal received: 
Wednesday, 22 July, 2020
Date proposal approved: 
Thursday, 23 July, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Developmental disorders - autism, Congenital abnormalities, Mental health, Cleft lip and/or palate, GWAS, Statistical methods, Development, Genetic epidemiology, Genetics, Genome wide association study

B3580 - Investigating the Activity of Transposon-Derived Regulatory Sequences in the Human Placenta - 04/08/2020

B number: 
B3580
Principal applicant name: 
Jennifer Frost | Queen Mary University of London (UK)
Co-applicants: 
Dr Miguel Branco
Title of project: 
Investigating the Activity of Transposon-Derived Regulatory Sequences in the Human Placenta
Proposal summary: 

The placenta is crucial for the initiation and maintenance of pregnancy. Common complications of human pregnancy, such as preeclampsia, often have unknown etiology but feature contributions from genetic and non-genetic causes. DNA exists in the cell bound by proteins and other molecules, forming a structure known as chromatin. The structural conformation of chromatin is just as important as the DNA code itself, since chromatin structure dictates which components of DNA are active, and therefore able to regulate the cell. Formalin-fixed placentas maintain the structural conformation of their chromatin, making them a uniquely valuable resource to identify the location and activity of regulatory DNA. My proposal seeks to investigate the causes of preeclampsia by comparing the chromatin structure in formalin-fixed placentas from control pregnancies and those complicated with preeclampsia. I will focus on regions of non-coding DNA that regulate gene activity, so-called gene promoters and enhancers, including a special subset of these regions known as transposons. Placental chromatin exhibits a unique structure compared to other tissues, featuring an open conformation around transposons, indicative of their activity in placenta. The activity of gene-regulatory DNA provides the basis of tissue and organ-specific developmental programs. As such, the development and function of the placenta is dictated by the activity of regulatory DNA, and structural variation at these regions can cause disease. I will test the hypothesis that chromatin structure variation of DNA regulatory sequences contributes to the causes of preeclampsia.

Impact of research: 
This research will provide proof-of-principal that archived placental samples can provide information on the gene regulatory status of the genome of the sample. Further, there will be a direct impact of the data provided from the samples in this study, in the identification of non-coding regulatory regions that are potentially involved in preeclampsia. This would lead to future expansion of the study into related pregnancy complications such as fetal growth restriction, pre-term birth, and recurrent miscarriage. This study will provide candidate genomic sequences for future research, as well as genetic screening and therapy in two ways: Most disease associated sequence variation is found in non-coding regions, and our data will be an important resource, revealing non-coding candidate regulatory regions impacted by epigenetic variation, which indicates that their genetic variation may also be disease-causing. In the future it will be key to investigate the presence of SNPs in candidate regulatory regions that we identify, which may alter transcription factor binding sites, for example, affecting gene expression. Secondly, the proposal investigates epigenetic variation between preeclampsia and controls, variation that is potentially impacted by environmental conditions and uniquely amenable to therapeutic intervention. Finally, by focusing our analysis on transposons, which are highly repetitive regions and poorly understood, this project will elucidate novel candidate genes and regulatory pathways that may contribute to the pathogenesis of preeclampsia.
Date proposal received: 
Thursday, 23 July, 2020
Date proposal approved: 
Thursday, 23 July, 2020
Keywords: 
Developmental biology, Fertility/infertility, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., DNA sequencing, Chromatin immunoprecipitation, Biological samples -e.g. blood, cell lines, saliva, etc., Birth outcomes, Development, Epigenetics, Expression, Genetic epidemiology, Genomics, Growth, Mothers - maternal age, menopause, obstetrics

B3576 - Religious belief and reaction to Corvid-19 pandemic - 21/07/2020

B number: 
B3576
Principal applicant name: 
Jean Golding | UoB (GB)
Co-applicants: 
Dr Kate Northstone
Title of project: 
Religious belief and reaction to Corvid-19 pandemic
Proposal summary: 

To provide exemplar analyses for inclusion in a grant application

Impact of research: 
The grant will be funded
Date proposal received: 
Monday, 20 July, 2020
Date proposal approved: 
Tuesday, 21 July, 2020
Keywords: 
Epidemiology

B3572 - Does attachment style in childhood predict mental health difficulties in early adulthood - 20/07/2020

B number: 
B3572
Principal applicant name: 
Philippa Clery | University of Bristol (UK)
Co-applicants: 
Dr Liam Mahedy, Dr Angela Rowe
Title of project: 
Does attachment style in childhood predict mental health difficulties in early adulthood?
Proposal summary: 

Attachment theory explains social, relationship and personality development across the lifespan (Bowlby 1969) and has been shown to provide a psychological framework for understanding mental ill health (Mikulincer & Shaver, 2007). The basic postulation is that very early childhood social interactions with primary caregivers are internalised to create and maintain conscious and unconscious mental representations of the self and others. These form the basis of ‘attachment styles’, which have an impact on close relationships and ability to regulate emotions. There is extensive evidence that attachment style is a predictor of coping strategies, adjustment in response to stressors and therefore a vulnerability to mental health problems (see Mikulincer & Shaver 2012 for a review). Research has widely demonstrated an association between secure attachment style and well-being and positive mental health, whilst both insecure attachment styles (anxious and avoidant) have been associated with poor relationship quality, psychological vulnerability and maladjustment, and mental health difficulties (e.g. Sroufe et al., 1999; Hankin et al., 2005; Mikulincer & Shaver 2007; Groh 2016; Spruit 2019). However, the direction of causality is less well established as most studies rely on cross-sectional design and measure attachment style as a discrete variable at a single point in adulthood.

By using a large prospective birth cohort, we will be able to (a) investigate the prospective relationship and (b) use latent variable modelling of repeated measures of attachment to create a more robust and detailed measure of attachment style. This will aid more nuanced explanations of how and when insecure attachment style may lead to mental ill health, such that the association can be interrogated to identify possible intervention targets.

This proposal has implications for healthcare provision and public health policies around childhood and parental interventions to support research to address the growing number of mental health difficulties in later adolescence.

Impact of research: 
This research will be able to determine whether there is a prospective relationship between attachment style in childhood and mental health outcomes of depression and self-harm at 18 years of age, helping identify if this is a causal link or what the key confounders are in this relationship. This has significant implications for nature and timing of interventions to target attachment styles or other factors, to inform an effective public health response, including parenting programmes, psychological intervention, or school and social environments.
Date proposal received: 
Friday, 17 July, 2020
Date proposal approved: 
Monday, 20 July, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Attachment style, Statistical methods, Childhood - childcare, childhood adversity, Parenting, Psychology - personality

B3573 - The impact of loneliness in your adults - 20/07/2020

B number: 
B3573
Principal applicant name: 
Antonieta Medina-Lara | University of Exeter (United Kingdom)
Co-applicants: 
Professor Anne E Spencer
Title of project: 
The impact of loneliness in your adults
Proposal summary: 

Recent data show young adults (age 16-30) experiencing extreme loneliness. Loneliness has a detrimental impact on health and wellbeing, however existing studies largely focus on older adults, meaning the full impact in young adults is unclear. Of particular concern is the likely adoption of negative health behaviours (including addictions), the harmful overuse or underuse of NHS services, and potential for self-harm or suicide in young adults experiencing loneliness. Also, of concern is the negative impact on milestones such as finishing school, further education and getting a first job, which contribute to household wealth and wellbeing. This research aims at using the ALSPAC data to assess the impact and cost of young adult loneliness in the UK with respect to health status, over or under use of health care resources, education attainment and unemployment. Regression analysis will identify correlations between variables, while causal relationships will be investigated through instrumental variable analysis and propensity score matching. Results will be used to update existing costs estimates that have focused only on older adults. Analysis will be conducted on data before, during and after COVID-19 to consider the prevalence and impact of young adult loneliness through COVID-19, given the likely exacerbation of loneliness in the context of social distancing. This research will develop understanding and inspire greater consideration of loneliness in young adults promoting cross-sector involvement and improved support.

Impact of research: 
This research aims at understanding the impact and cost of young adult loneliness on public health, NHS resources and the wider economy. Given current rates of loneliness in this group of the population and the fact that previous literature has focused mainly exclusively in older population this piece of research will complement what we know about loneliness and fill the gap in the literature. We also hope that the results of this research will help improve our understanding of loneliness in young adults and have the evidence to help building a case for greater awareness of loneliness and for encouraging future research in this age group. It will also promote the need for cross-sector action where effects are observed in health, education and wider economic sectors. In turn this will promote happier and healthier young adults where the negative consequences of loneliness are reduced as a result of greater understanding and attention from policymakers and more targeted support.
Date proposal received: 
Friday, 17 July, 2020
Date proposal approved: 
Monday, 20 July, 2020
Keywords: 
Health Economics, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3570 - Role of inflammation and psychosocial variables in the associations between prenatal maternal stress and offspring mental health - 14/07/2020

B number: 
B3570
Principal applicant name: 
Ian Colman | University of Ottawa (Canada)
Co-applicants: 
Zahra Clayborne
Title of project: 
Role of inflammation and psychosocial variables in the associations between prenatal maternal stress and offspring mental health
Proposal summary: 

Risk towards poor mental health is impacted by a number of biological, psychological, and social factors that work together throughout the lifespan and across generations. A large body of research supports the influence of the prenatal environment on children’s developmental and mental health outcomes. For example, prenatal depression has been linked to later risk of depression in children, and prenatal depression, prenatal anxiety, and stressful life events during pregnancy have all been associated with risk of anxiety disorders in children. There is also growing interest in understanding the potential biological causes that may drive these relationships. In particular, inflammation has been suggested as a potential factor that may influence these associations, due to its role in the onset of depression and other mental and physical health disorders. However, few studies to date have examined the role of inflammation in relationships between prenatal maternal stress and child and adolescent mental health outcomes, calling for continued research in this area.

In addition, although the relationships between prenatal stress and child and adolescent mental health outcomes are well-established, children continue to be exposed to a number of influences, both positive and negative, after birth. For example, research suggests that the relationships between prenatal stress and child outcomes may differ depending on how mothers are able to cope with the stress they experience, including their degree of partner and social support, and availability of psychological resources including higher self-esteem and self-efficacy. Furthermore, a growing number of studies suggest that parenting behaviours may play an important role in these associations. For example, children exposed to parental warmth and positive relationships with their mothers and fathers may be buffered to the impacts of early adversity; conversely, children exposed to maltreatment or harsh parenting may exhibit increased vulnerability. Considering how both maternal coping resources and parenting further increase or reduce the risk towards chronic inflammation and later mental health outcomes in children exposed to prenatal stress, however, is an area that requires further investigation. In addition, the influence of many coping resources and parenting behaviours on later inflammation is an understudied area.

Impact of research: 
We anticipate the publication of 3 papers in peer-reviewed journals as a result of this project – results will also form part of a doctoral thesis. Additional dissemination strategies will involve presentation of findings at national and international conferences, and communication of findings through social and news media. The proposed research will have potential implications for both practice and policy. Understanding the role of parenting and maternal coping resources in relationships between prenatal maternal stress and offspring immune and mental health outcomes can inform and promote interventions that may lessen the burden of poor mental and physical health in children.
Date proposal received: 
Monday, 13 July, 2020
Date proposal approved: 
Tuesday, 14 July, 2020
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Childhood - childcare, childhood adversity, Development, Immunity, Offspring, Parenting

B3568 - The genetics of speech sound disorder - 13/07/2020

B number: 
B3568
Principal applicant name: 
Yvonne E Wren | University of Bristol (UK)
Co-applicants: 
Professor Angela Morgan, Dr Dianne Newbury
Title of project: 
The genetics of speech sound disorder
Proposal summary: 

There is variation in when and how children develop speech in early childhood. Some children experience difficulties in the process but many of these have speech which is well developed by the time they start school. Some children have persistent problems which continue into early childhood. These problems can be associated with problems with educational attainment in older childhood as well as having difficulties in making themselves understood. Some of these children will have problems with their speech as a result of subtle problems with the coordination of the movements required for speech while others will have difficulties associated with the cognitive skills involved in developing speech. Some will have problems with both.
Genes have been identified which are associated with some types of speech and language difficulties but it is not yet clear what part genes may play in persistent speech sound disorder. The analysis outlined in this proposal will enable us to determine to what extent children's problems with speech after they have started school may be associated with genetic factors rather than environmental factors. This information will help us identify how best to help children who present with these difficulties to speech and language therapists and in school.

Impact of research: 
An understanding of the genetic basis for persistent speech sound disorder
Date proposal received: 
Thursday, 9 July, 2020
Date proposal approved: 
Monday, 13 July, 2020
Keywords: 
Genetics, Speech/language problem, Gene mapping, Speech and language

B3569 - Do asthma and ADHD have shared developmental origins - 13/07/2020

B number: 
B3569
Principal applicant name: 
Seif Shaheen | Institute of Population Health Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (UK)
Co-applicants: 
Dr Raquel Granell, Dr Evie Stergiakouli, Prof Anita Thapar
Title of project: 
Do asthma and ADHD have shared developmental origins?
Proposal summary: 

Children with asthma are more likely to suffer from attention deficit hyperactivity disorder (ADHD), but we do not understand why; it may be because the two conditions are influenced by similar risk factors early in life or by similar genes which affect lung and brain development. We will investigate this in ALSPAC. Gaining a better understanding of the causes of these common childhood conditions could ultimately lead to ways to prevent them.

Impact of research: 
We will shed new light on why asthma and ADHD are associated in children.
Date proposal received: 
Sunday, 12 July, 2020
Date proposal approved: 
Monday, 13 July, 2020
Keywords: 
Epidemiology, Respiratory - asthma, Genetic epidemiology

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