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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B3659 - Effects of adolescent physical activity on physical and mental health in adulthood novel multivariate pattern analysis approach - 18/11/2020

B number: 
B3659
Principal applicant name: 
Ahmed Elhakeem | MRC IEU
Co-applicants: 
Dr Matteo Sattler
Title of project: 
Effects of adolescent physical activity on physical and mental health in adulthood: novel multivariate pattern analysis approach
Proposal summary: 

The benefits of physical activity (PA) for health are well established. However, limited evidence is available on the relative importance of specific intensities of PA as well as sedentary time for major health outcomes. In conventional analyses, accelerometer data are collapsed into only a few intensities (e.g. light, moderate-to-vigorous).This causes substantial loss of information and limits the detection of the relative importance of specific intensities. In this project we will use a novel multivariate pattern analysis approach to describe the entire PA intensity spectrum and examine the relative importance of different PA intensities on physical and mental health and mental wellbeing.

Impact of research: 
By using multivariate pattern analysis to study the the entire PA intensity spectrum and how this related to major health measures in adulthood, this study will advance our understanding how different intensities fo activity in adolescence relate to adult health.
Date proposal received: 
Friday, 13 November, 2020
Date proposal approved: 
Wednesday, 18 November, 2020
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Blood pressure, BMI, Bones (and joints), Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics, Metabolic - metabolism, Physical - activity, fitness, function, Statistical methods

B3652 - Genetics Adverse Childhood Experiences ACEs and Developmental and Behavioral Outcomes - 18/11/2020

B number: 
B3652
Principal applicant name: 
Hexuan Liu | University of Cincinnati (United States)
Co-applicants: 
Dr. J.C. Barnes, Dr. Joseph Nedelec, Breanna Clark
Title of project: 
Genetics, Adverse Childhood Experiences (ACEs), and Developmental and Behavioral Outcomes
Proposal summary: 

While previous research has consistently shown a relationship between adverse childhood experiences (ACEs) and developmental and behavioral outcomes later in life, understanding of mechanisms that explain the relationship is still insufficient. In particular, the role of genetics remains unknown. In this project, we propose to study how genetic factors and ACEs jointly and interactively affect individuals' developmental and behavioral outcomes, such as delinquent behavior and substance use. Specifically, we propose to examine whether and to what extent the influence of ACEs on the developmental and behavioral outcomes depends on children’s genetic susceptibility. Moreover, to what extent effects of parental genetic risk on child’s developmental and behavioral outcomes operate via ACEs.

Impact of research: 
The impact of this research will be three-folded. First, it improves our understanding of the role of genetics in research of ACEs on children’s developmental and behavioral outcomes. Second, it highlights the importance of childhood environment on children’s developmental trajectory. Finally, it provides insights to studies of intergenerational influences.
Date proposal received: 
Friday, 13 November, 2020
Date proposal approved: 
Wednesday, 18 November, 2020
Keywords: 
Social Science, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., GWAS, Childhood - childcare, childhood adversity, Development, Genomics, Genome wide association study, Offspring, Parenting

B3642 - Metabolic Health and Obesity-Relevant Diseases - 13/11/2020

B number: 
B3642
Principal applicant name: 
Marc J. Gunter | International Agency for Research on Cancer (IARC) (France)
Co-applicants: 
Dr Mary Playdon
Title of project: 
Metabolic Health and Obesity-Relevant Diseases
Proposal summary: 

Metabolic health is emerging as an important risk and prognostic factor for metabolic diseases, including cardiovascular disease (CVD), diabetes and cancer. (1-12) Metabolic health has been defined according to the presence or absence of a minimum number of cardiometabolic risk factors defined according to clinical cut-points (i.e. elevated waist circumference, triglycerides, blood pressure, and fasting glucose, low HDL-cholesterol, insulin resistance (HOMA-IR) and inflammatory biomarkers (hsCRP), or pharmacological treatment for these parameters). Obesity is associated with poor metabolic health, but metabolically unhealthy individuals may be at high risk of metabolic diseases, independent of BMI (metabolically unhealthy normal-weight phenotype, MUHNW) and obese individuals that are metabolically healthy may have similar disease risk to their lean counterparts (metabolically healthy obese phenotype, MHO). (1) Analysis of data from the US National Health and Nutrition Examination Survey showed that a substantial proportion of overweight or obese individuals are metabolically healthy and over 30% of normal weight individuals are cardiometabolically unhealthy. (13) The etiologies of the associations between these phenotypes and cardiometabolic disease risk are unclear. Recent studies have demonstrated the utility of using a metabolomics approach to explore the concepts of MUHNW and MHO in relation to cardiometabolic disease endpoints. For example, an 'obese metabolome' (metabolites related to insulin resistance, branched chain and aromatic amino acids, nucleotide metabolites, and several lipid classes) associated with a 2 to 5-fold increased risk of cardiovascular events, independent of BMI, in the TwinsUK cohort. (14) Matched for BMI, MUHNW individuals had higher visceral adiposity, higher blood pressure and were also more likely to become obese over time compared with their metabolically healthy lean counterparts. Such findings point towards the potential of metabolomics for disease risk stratification, where BMI alone can fail to identify a significant proportion of individuals that may be at risk for cardiometabolic disease. We propose to leverage the unique resources of COMETS to determine metabolites associated with metabolic health, how this profile associates with obesity-relevant diseases (i.e. obesity-related cancers and cardiovascular disease), and the extent to which metabolites mediate the association of body mass index with these outcomes.

Impact of research: 
We propose to leverage the unique resources of COMETS to determine metabolites associated with metabolic health, how this profile associates with obesity-relevant diseases (i.e. obesity-related cancers and cardiovascular disease), and the extent to which metabolites mediate the association of body mass index with these outcomes.
Date proposal received: 
Thursday, 5 November, 2020
Date proposal approved: 
Friday, 13 November, 2020
Keywords: 
Epidemiology, Diabetes, Obesity, Ageing, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., BMI, Metabolic - metabolism

B3653 - Birth mode impact on social behavior - 13/11/2020

B number: 
B3653
Principal applicant name: 
Will Kenkel | University of Delaware (USA)
Co-applicants: 
Title of project: 
Birth mode impact on social behavior
Proposal summary: 

This research will investigate whether birth mode shapes social behavior in childhood and adolescence. Cesarean delivery results in the newborn being exposed to lower levels of several important hormones than newborns delivered vaginally. These same hormones are known to shape social behavior throughout development, which leads us to hypothesize that birth is an important time for the developing brain. Disrupting hormonal signaling at birth via cesarean delivery is thus likely to impact the newborn's development.

Levels of each of the ‘birth signaling hormones’: oxytocin, arginine vasopressin, epinephrine, norepinephrine, and the glucocorticoids are lower following delivery by cesarean section compared to vaginal delivery, and there is substantial evidence for each of these hormones that manipulations in early life results in long-term neurodevelopmental consequences. This set of hormones has been extensively studied for their various roles in regulating social behavior in humans and non-human animals, often in a developmental context such as this, where manipulating their levels in early life alters social behavior throughout the rest of development. Furthermore, epidemiological associations have linked cesarean delivery with increased risk of autism spectrum disorder diagnosis and delayed social skills in early childhood. Finally, premature delivery is associated with markedly diminished rates of romantic attachment and sexual behavior. Thus, through multiple lines of evidence, we arrive at the central hypothesis: that birth mode can shape social behavior throughout the rest of life.

Impact of research: 
I hope that this work will yield a richer understanding of the neurodevelopmental consequences of birth mode. The next step for my research will be to experimentally explore these questions in a rodent model.
Date proposal received: 
Friday, 6 November, 2020
Date proposal approved: 
Friday, 13 November, 2020
Keywords: 
Endocrinology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Birth outcomes, Childhood - childcare, childhood adversity, Development, Equipment - MRI, Mothers - maternal age, menopause, obstetrics, Puberty

B3650 - LATERALCOG - Typical and atypical development of laterality - 09/11/2020

B number: 
B3650
Principal applicant name: 
SEGOND Hervé | Université de Strasbourg (FRANCE)
Co-applicants: 
HAMAOUI Jad
Title of project: 
LATERALCOG - Typical and atypical development of laterality
Proposal summary: 

The scientific literature provides several elements in favor of the existence of a link 1. between the fetal position at the end of gestation and the development of laterality, on the one hand; 2.between the type of fetal positioning (cephalic vs. breech) and developmental disorders of laterality and interhemispheric communications involved in cognitive functioning, on the other hand (cf. for review Güntürkün, & Ocklenburg, 2017 ). However, a lack of consensus remains today as to the nature of the relationship between the lateralization degree and cognitive development. Some theoretical positions consider that cognitive deficits are noted in individuals whose laterality is weakly established, in other words ambidextrous, while others consider ambilaterality as an advantage both in terms of language and visuospatial abilities (Boles & Barth , 2011; Chiarello, Welcome, Halderman, & Leonard, 2009; Johnston, Nicholls, Shah, & Shields, 2009). Innovatively, we suggest that this lack of consensus could be attributed to the existence of two distinct causes of ambidexterity with different developmental consequences.

Impact of research: 
The development of knowledge in this field constitutes a major societal issue, given the evocation in the scientific literature of the frequent belonging of "laterality disorders" to the clinical picture of many developmental and learning disorders in children (Kershner, 2019; Penolazzi, Spironelli, Vio & Angrilli, 2006; Xu, 2014), disorders that are most often diagnosed too late, during the first school learning, without allowing us to have a precise perception of the nature of these laterality disorders. This issue is all the more important given that these laterality disorders affect a large part of the population in vulnerable situations, since they are not only associated with disturbances in oral and written language (including developmental dyslexia, to which we are concerned, which concerns 6 to 15% of school-age children, dysgraphia, dysorthography, dysphasia and language delay), but also intellectual deficit, psychoses (e.g. schizophrenia), neuro-developmental disorders such as autism (affecting 1 in 150 people in France, according to the High Autority of Health, 2017), epilepsy, as well as deviant behavior. These laterality disorders could even appear as an interesting way of research in the determination of the etiological factors of the Coordination Acquisition Disorders (CAD) or Developmental Coordination Disorders (DCD), also called developmental dyspraxia (Gérard and al., 2005), resulting in early impairment of postural control (static and dynamic balance disorders), coordination and motor learning (lack of tonic regulation, slowness, imprecision, difficulties in relation with novelty, writing impairment), whose co-occurrence with specific language and reading disorders is noted in ± 60% of DCD cases (Vaivre-Douret et al., 2011). The investigation of the links between laterality in development and dyslexia is also part of the incentives of the various calls for scientific projects aimed at understanding the mechanisms at play in the late expression of lasting disorders (such as dyslexia constellation). In addition, the developmental consequences of breech birth would provide a very important source of information for our partners in obstetric hospital services, with a view to guide the evolution of childbirth practices (births by caesarean section vs. routes natural).
Date proposal received: 
Thursday, 5 November, 2020
Date proposal approved: 
Monday, 9 November, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, - Developmental disorders - autism - Cognitive impairment - Learning difficulty e.g. dyslexia - Pregnancy - e.g. postnatal depression, birth outcomes... - Speech/language problem - Coordination Development Disorder , - Qualitative study -Statistical methods, - Birth outcomes - e.g. state of the neonate, presentation during pregnancy, presentation at onset of labor and at delivery - Method of delivery - Cognition - cognitive function - Development - Handedness - Intelligence - memory - Mothers - maternal age, obstetrics - Siblings - Speech and language - Balance - Laterality

B3651 - Microbiome transfer and intergenerational transmission of mental health - 09/11/2020

B number: 
B3651
Principal applicant name: 
Sam Cartwright-Hatton | university of sussex (United Kingdom)
Co-applicants: 
Abigail Thomson, Dr Kathryn Lester
Title of project: 
Microbiome transfer and intergenerational transmission of mental health
Proposal summary: 

Mental health problems run in families. This arises from a range of genetic and environmental factors.

Recently, we have seen the impact that the human microbiome has on physical health (e.g inflammatory bowel disease, asthma, obesity) and mental health (depression, anxiety, autism).

Like mental health, the microbiome also runs in families, likely because of environmental transfer of microbiota between family members and, in particular, the seeding of the neonatal microbiome during the birth process. We wondered whether the sharing of microbiomes within families may partially explain familial similarities in mental health.

It is not possible to conduct an experiment, interrupting the transfer of microbiota from mother to child, to see if this had an impact on transfer of intergenerational risk for mental health problems. However, nature (helped along by NHS maternity services) provides us with a natural experiment: Approximately 20-25% of births are via caesarean section, and there is mounting evidence that this results in substantially lower mother-child microbiome transfer than vaginal birth. This microbiome transfer process can be further interrupted by other factors, including prenatal/perinatal antibiotic use and breastfeeding practices.

This study will explore the impact of early-life microbiome transfer on the intergenerational transmission of mental health problems.

Impact of research: 
To our knowledge, this research will be the first to offer an insight into the mental health impacts of disrupted microbiome colonisation at birth. More particularly, it will allow us to explore the role of the intergenerational transmission of microbiome on the intergenerational transmission of mental health - a potential new mechanism through which risk factors for child mental health are forged.
Date proposal received: 
Friday, 6 November, 2020
Date proposal approved: 
Monday, 9 November, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Microbiome

B3646 - Computational approaches to modelling parent -infant behavioural data - 11/11/2020

B number: 
B3646
Principal applicant name: 
Rebecca Pearson | Bristol Medical School
Co-applicants: 
Romana Burgess, Professor Ian Nabney, Ilaria Costantini, Dr Iryna Culpin
Title of project: 
Computational approaches to modelling parent -infant behavioural data
Proposal summary: 

This PhD project will use data modelling techniques to explore the behavioural transmission of mental health conditions from mother to infant. This will involve an extensive analysis of coded video data of mother-infant interactions captured using wearable headcams in CoCo90s and comparing to other data in partner cohorts. Initial data analysis will involve computing the frequencies, durations, and rates per minute of behaviours for each subject. Following this, statistically significant inferences between modes will be extracted using graphical modelling, Bayesian inference and pattern recognition methodologies. Additionally, behavioural comparisons will be drawn between mothers with and without mental health conditions. It is hoped that findings from this research will be used to inform interventions to improve mental health outcomes for mother and infant.

Impact of research: 
Methodological innovation and clinical insights
Date proposal received: 
Thursday, 29 October, 2020
Date proposal approved: 
Monday, 2 November, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Computer simulations/modelling/algorithms

B3647 - Air pollution exposure and childhood obesity - 02/11/2020

B number: 
B3647
Principal applicant name: 
Serena Fossati | ISGLOBAL (Spain)
Co-applicants: 
Martine Vrijheid
Title of project: 
Air pollution exposure and childhood obesity
Proposal summary: 

Prenatal exposure to air pollution is robustly associated with fetal growth
restriction and low birth weight, a risk factor for altered cardio-metabolic diseases
later in life. Air pollution has also been associated with obesity and
cardiometabolic disease in adulthood. However, little is known on the association
between air pollution and obesity in infancy and childhood

Impact of research: 
Date proposal received: 
Friday, 30 October, 2020
Date proposal approved: 
Monday, 2 November, 2020
Keywords: 
Epidemiology, Obesity, Statistical methods, Environment - enviromental exposure, pollution

B3625 - Green Spaces and Multiple Child Health Outcomes - 02/11/2020

B number: 
B3625
Principal applicant name: 
Amanda Fernandes | ISGLOBAL (Spain)
Co-applicants: 
Serena Fossati, Mark Nieuwenhuijsen, Martine Vrijheid
Title of project: 
Green Spaces and Multiple Child Health Outcomes
Proposal summary: 

Early-life urban stressors have been identified as a risk to the onset of non-communicable diseases. An accumulating body of evidence is suggestive for health-promoting effects of exposure to green spaces. However, the association between green spaces and harmful or beneficial effects on children health is still poor for most outcomes, and the underlying mechanisms remain unclear. Outcome wide analysis have recently been proposed as a way to evaluate the effects of exposures over numerous important outcomes. Indeed, some exposures may be harmful for some outcomes and beneficial for others, including green spaces exposures. This approach also has the advantage to better control for confounding for the effects of the exposure on all outcomes simultaneously. It is different from the traditional one-outcome approach and more similar to GWAS (genome wide associations) or EWAS (epigenome wide associations) or ExWAS (exposome wide associations). For outcome-wide approaches, larger datasets are needed so LifeCycle is a good opportunity to apply this novel method. The idea is to add as many outcomes as possible, this is the great interest of the outcome wide approach.

Impact of research: 
Date proposal received: 
Friday, 30 October, 2020
Date proposal approved: 
Monday, 2 November, 2020
Keywords: 
Epidemiology, Allergy, Cognitive impairment, Obesity, Statistical methods, Childhood - childcare, childhood adversity

B3648 - Exposure to urban natural environments and birth outcomes - 02/11/2020

B number: 
B3648
Principal applicant name: 
Maria Torres | ISGLOBAL (Spain)
Co-applicants: 
Martine Vrijheid
Title of project: 
Exposure to urban natural environments and birth outcomes
Proposal summary: 

Previous studies have associated exposure to urban natural environments during
pregnancy with improved birth outcomes. But there are still some gaps in the
knowledge:
(1) The results showed different patterns in different settings maybe because of
their differences in climate, vegetation type, culture, etc. There is a need to
evaluate this association in a larger sample size with standardized methodology
from several cohorts
(2) The majority of previous studies are focused on birth weight. But the available
evidence on the association between natural environments and other birth
outcomes is still scarce or null
(3) The vast majority of previous studies are focused on green spaces and the
availability of studies focused on the association between blue spaces and birth
outcomes is very scarce

Impact of research: 
Date proposal received: 
Friday, 30 October, 2020
Date proposal approved: 
Monday, 2 November, 2020
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Birth outcomes

B3644 - Infection during childhood and cognitive function - 09/11/2020

B number: 
B3644
Principal applicant name: 
Emma Anderson | University of Bristol
Co-applicants: 
Dr Evie Stergiakouli , Rebecca Scanlan
Title of project: 
Infection during childhood and cognitive function
Proposal summary: 
Impact of research: 
Improve scientific understanding of the impact of childhood infections on cognitive capability of children, and thus improving our understanding of whether infection in childhood could go on to affect risk of Alzheimer's disease by lowering cognitive function. May help inform public health prevention strategies for dementia
Date proposal received: 
Wednesday, 28 October, 2020
Date proposal approved: 
Monday, 2 November, 2020
Keywords: 
Epidemiology, Cognitive impairment, Infection, Statistical methods, Cognition - cognitive function

B3645 - Is there a causal association between insulin signalling and myopia pathogenesis - 11/11/2020

B number: 
B3645
Principal applicant name: 
Denize Atan | University of Bristol
Co-applicants: 
Mr Max Gillies
Title of project: 
Is there a causal association between insulin signalling and myopia pathogenesis?
Proposal summary: 

Myopia, or short-sightedness, is one of the most common causes of sight impairment worldwide. By 2050, five billion people- half the world’s population- will be short-sighted, compared to ~1.4 billion people today.
People with myopia have relatively long eyes, so that light is focused in front of the retina instead of directly onto it. Since the eye continues to grow throughout childhood, someone who develops myopia as a child will continue to get worse as they grow older, with greater risk of sight-threatening complications.
Previously, we showed that for each additional year we spend in education, the more myopic we become, on average, as a population. Evidence from other studies suggests that this may be because we spend less time outside, reducing our exposure to natural daylight. Other risk factors for myopia include the time we spend on near work, urbanization, socioeconomic position, diet, pregnancy-related factors and genetics. Children with myopia tend to engage in less physical activity, but physical activity alone is not protective against myopia.
Myopia is more prevalent in countries adopting a Western diet and lifestyle, and many of the genes that increase the risk of myopia are involved in insulin/glucose signalling and obesity/fat metabolism. Insulin signalling also appears to influence the normal growth of the eye. As the Western diet is linked to greater intake of food with higher energy loads, one hypothesis is that compensatory increases in blood glucose and insulin levels send increased growth signals to the eyes.
This project aims to determine how genetic and environmental factors interact with insulin signalling to affect myopia. Changes in insulin signalling happen naturally in children around puberty, and so we would like to use information in the Avon Longitudinal Study of Parents and Children on eye growth, glasses prescriptions, blood levels of glucose and insulin before, during and after puberty on thousands of children followed prospectively from birth, to find out how they interact to affect eye growth. Additionally, there are normal variants in our genes that influence fasting levels of insulin and glucose and we will find out how these genetic variants are linked to myopia. These analyses should provide novel insights into the relationship between insulin signalling and myopia, and have the potential to identify novel targets for treatment.

Impact of research: 
The above analyses will help us determine whether genetic and environmental changes in insulin/IGF1 signalling are major determinants of axial growth in children and myopia pathogenesis. If so, they would explain how myopia is linked to increasing urbanisation, diet, BMI, height and PHV during puberty, and why GWAS and studies of animal models of myopia implicate insulin/IGF pathways. They might also point the way to novel therapies for myopia that target downstream effector molecules in the insulin/IGF1 signalling pathway, e.g. PI3K/AKT. The efficacy of topical atropine eye drops for myopia suggests that local or topical delivery routes could be an option
Date proposal received: 
Wednesday, 28 October, 2020
Date proposal approved: 
Friday, 30 October, 2020
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Diabetes, GWAS, Statistical methods, Ageing, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Nutrition - breast feeding, diet, Puberty, Statistical methods, Vision, BMI, Childhood - childcare, childhood adversity, Epigenetics, Genetic epidemiology, Genetics, Genome wide association study, Hormones - cortisol, IGF, thyroid, Mendelian randomisation

B3639 - Cell type-specific DNA methylation meta-analysis for ADHD symptoms - 27/10/2020

B number: 
B3639
Principal applicant name: 
Dr Doretta Caramaschi | MRC IEU
Co-applicants: 
Mandy Meijer, MSc, Dr Marieke Klein, PhD
Title of project: 
Cell type-specific DNA methylation meta-analysis for ADHD symptoms
Proposal summary: 

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, characterized by symptoms of inattention and/or hyperactivity and impulsivity. Not only people with ADHD experience these symptoms, but also people without ADHD can show these symptoms. The development of ADHD (symptoms) is partially genetic, and can also be influenced by factors in someone’s surrounding, for example prenatal nicotine exposure. Genetics and surrounding factors can interplay and this can be reflected in DNA methylation. Knowing which DNA methylation patterns are associated with ADHD symptoms, can teach us more about the molecular mechanisms underlying ADHD (symptoms). These DNA methylation profiles are cell type-specific. Up to now, most methylome-wide association studies have been performed in whole blood, in which multiple blood cells are present. Because the different blood cells have distinct DNA methylation profiles, it is possible that meaningful signal is cancelled out in whole blood measures. Therefore, we think there might be valuable signal in cell type-specific DNA methylation, done by a statistical method called epigenomic deconvolution. This could give us more insight in the molecular mechanisms of ADHD symptoms.

Impact of research: 
We hope to find robust and specific DNA methylation associations to ADHD symptoms, in the different domains in a cell type-specific manner. This information could lead to the identification of new biomarkers and potential new biological pathways to better understand ADHD-related behaviour.
Date proposal received: 
Tuesday, 20 October, 2020
Date proposal approved: 
Tuesday, 27 October, 2020
Keywords: 
Epidemiology

B3640 - Investigating genetic influences on ASD autistic traits and trajectories of autistic traits - 27/10/2020

B number: 
B3640
Principal applicant name: 
Zoe Reed | University of Bristol (UK)
Co-applicants: 
Professor Marcus Munafò, Professor Geoge Davey Smith
Title of project: 
Investigating genetic influences on ASD, autistic traits and trajectories of autistic traits
Proposal summary: 

Previous research has shown that autism spectrum disorder is caused by a combination of both genetic and environmental factors. Although studies have identified genes that associated with having ASD, the specific pathways involved in the development and progression of ASD is not well understood. In addition, less is known about the genetic contributions to autistic traits in the more general population and also on the progression of these autistic traits. In this project we would like to address this important gap in our knowledge by investigating these genetic contributions in more detail and by attempting to identify the specific biological pathways that lead to the development of ASD, autistic traits and the progression of these traits over time. To do this we will use data from several cohorts, including Children of the Nineties. The results from this study may inform population health and may help develop more targeted interventions for individuals with ASD symptoms.

Impact of research: 
This research will lead to a better understanding of the genetic influences on autistic trait trajectories which will be useful to compare to those for ASD and autistic traits. Results from our analyses may inform future population health policies and interventions targeted at those with symptoms of ASD.
Date proposal received: 
Friday, 23 October, 2020
Date proposal approved: 
Tuesday, 27 October, 2020
Keywords: 
Epidemiology, Developmental disorders - autism, GWAS, Statistical methods, Genetic epidemiology, Genetics, Genome wide association study, Mendelian randomisation, Statistical methods

B3635 - Prescriptive drug use during pregnancy a pharmacoepidemiological study of the risks and benefits to mothers and offspring - 27/10/2020

B number: 
B3635
Principal applicant name: 
Neil Davies | MRC IEU (Avon)
Co-applicants: 
Ciarrah-Jane Barry, George Davey Smith, Venexia Walker
Title of project: 
Prescriptive drug use during pregnancy: a pharmacoepidemiological study of the risks and benefits to mothers and offspring
Proposal summary: 

Pregnant women are heavily underrepresented in clinical trials as it would be unethical to conduct a human trial in which the potential outcome is a birth defect in the offspring. Between 2000-2010, over 97% of clinically approved drugs in the US had an undetermined teratogenic risk (the risk of foetal abnormality from exposure to a drug) or adverse developmental effect in human pregnancy . This presents a significant problem as there are a range of chronic conditions that require ongoing treatment, such as epilepsy, hypertension, auto-immune disorders or psychiatric disorders that may precede or develop during the pregnancy. This can mean women are deprived of medication due to clinical reservations or are prescribed medications that cause potential harm to the offspring. Given the inability to perform RCTs, the harmonisation of pharmacoepidemiological and genetic data is an alternative way to evaluate the potential risks currently associated with continuing medications to provide reliable information for clinicians and patients. The main objective of this PhD is to establish reliable evidence for the intrauterine exposure of prescription drugs on the mother and offspring by triangulating evidence from the Clinical Practice Research Datalink (CPRD), The Norwegian Mother, Father and Child Cohort Study (MoBa) and ALSPAC.

Impact of research: 
Further data on the effect of prescription drugs in utero.
Date proposal received: 
Wednesday, 21 October, 2020
Date proposal approved: 
Tuesday, 27 October, 2020
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Birth outcomes, Cognition - cognitive function, Genetic epidemiology, Genetics, Mendelian randomisation, Offspring

B3641 - Adolescent insufficient sleep epigenetic changes and the risk of developing AUD and neuropsychiatric comorbidities - 27/10/2020

B number: 
B3641
Principal applicant name: 
Luisa de Vivo | Physiology, Pharmacology and Neuroscience, University of Bristol (United Kingdom)
Co-applicants: 
Doretta Caramaschi, PhD, Daniela Franchini, PhD, Michele Bellesi, MD, PhD, Rebecca Richmond, Daniele Marcotulli
Title of project: 
Adolescent insufficient sleep: epigenetic changes and the risk of developing AUD and neuropsychiatric comorbidities
Proposal summary: 

Epidemiological research has shown that adolescents worldwide are chronically sleep deprived due to increased use of technology at night, consumption of caffeinated beverages, as well as more academic and social demands (1-3). Sleep fragmentation and sleep loss have been associated with emotional dysregulation (4), increased psychosis (5), and higher risk-taking behaviours, including substance abuse (6). Adolescents are particularly exposed to the risk of developing substance use disorders (SUDs) and related psychiatric comorbidities (7,8), hence it is particularly important to measure to what extent and how adolescent chronic sleep restriction contributes to the development of such mental disorders. So far, longitudinal analysis using ALSPAC data have found that less total sleep time at age 15 years predicts symptoms and diagnosis of anxiety and depression later in life (9). However, the prospective association between adolescent sleep and development of SUDs has not been explored.
One of the mechanisms through which sleep loss can affect brain function is by inducing epigenetic changes, dynamic modifications that can powerfully regulate gene expression, without changing the heritable genetic sequences. Epigenetic changes in the form of DNA methylation have been associated with both altered sleeping patterns (10,11) and SUDs in adults (12-15). Our goal is to determine whether adolescent sleep patterns predict the risk of developing SUDs later in life and to what extent epigenetic changes are associated with both adolescent chronic sleep restriction and drug consumption. Since, despite recent declines, alcohol remains the substance most widely used by today’s teenagers, this research proposal will focus on alcohol drinking and alcohol use disorders. The results of this analysis will guide future causal experiments to identify the biological mechanisms mediating the consequences of sleep loss and to develop new strategies to reduce alcohol abuse and improve mental health.

1. Crowley SJ, Wolfson AR, Tarokh L, Carskadon MA. An update on adolescent sleep: New evidence informing the perfect storm model. J Adolesc. 2018;67:55-65. doi:10.1016/j.adolescence.2018.06.001
2. Short MA, Weber N, Reynolds C, Coussens S, Carskadon MA. Estimating adolescent sleep need using dose-response modeling. Sleep. 2018;41(4). doi:10.1093/sleep/zsy011
3. Owens J, Adolescent Sleep Working Group, Committee on Adolescence. Insufficient sleep in adolescents and young adults: an update on causes and consequences. Pediatrics. 2014;134(3):e921-932. doi:10.1542/peds.2014-1696
4. Ben Simon E, Vallat R, Barnes CM, Walker MP. Sleep Loss and the Socio-Emotional Brain. Trends Cogn Sci. 2020;24(6):435-450. doi:10.1016/j.tics.2020.02.003
5. Ritter PS, Höfler M, Wittchen H-U, et al. Disturbed sleep as risk factor for the subsequent onset of bipolar disorder--Data from a 10-year prospective-longitudinal study among adolescents and young adults. J Psychiatr Res. 2015;68:76-82. doi:10.1016/j.jpsychires.2015.06.005
6. Short MA, Weber N. Sleep duration and risk-taking in adolescents: A systematic review and meta-analysis. Sleep Med Rev. Published online March 27, 2018. doi:10.1016/j.smrv.2018.03.006
7. Spear LP. Alcohol Consumption in Adolescence: a Translational Perspective. Curr Addict Rep. 2016;3(1):50-61. doi:10.1007/s40429-016-0088-9
8. Saalfield J, Spear L. The ontogeny of ethanol aversion. Physiol Behav. 2016;156:164-170. doi:10.1016/j.physbeh.2016.01.011
9. Orchard F, Gregory AM, Gradisar M, Reynolds S. Self-reported sleep patterns and quality amongst adolescents: cross-sectional and prospective associations with anxiety and depression. J Child Psychol Psychiatry. Published online June 17, 2020. doi:10.1111/jcpp.13288
10. Massart R, Freyburger M, Suderman M, et al. The genome-wide landscape of DNA methylation and hydroxymethylation in response to sleep deprivation impacts on synaptic plasticity genes. Transl Psychiatry. 2014;4(1):e347-e347. doi:10.1038/tp.2013.120
11. Lahtinen A, Puttonen S, Vanttola P, et al. A distinctive DNA methylation pattern in insufficient sleep. Sci Rep. 2019;9(1):1193. doi:10.1038/s41598-018-38009-0
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13. Lohoff FW, Roy A, Jung J, et al. Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation. Mol Psychiatry. Published online May 12, 2020. doi:10.1038/s41380-020-0734-4
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15. Camilo C, Maschietto M, Vieira HC, et al. Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents. Rev Bras Psiquiatr Sao Paulo Braz 1999. 2019;41(6):485-493. doi:10.1590/1516-4446-2018-0092

Impact of research: 
The results of this analysis will help us determine the role of adolescent sleep patterns in contributing to the development of substance use disorders and related psychiatric comorbidities, informing the public and policy makers on the importance of promoting a correct sleep hygiene to reduce future health problems. The EWAS in adolescents with altered sleep patterns will help identifying possible biomarkers for chronic sleep restrictions and point us towards some of the biological processes mediating the negative effects of poor sleep. These processes will be further investigated in the future by designing causal experiments in animal models that will allow to target separate molecular components and identify their contribution to the development of substance use disorders. Our final goal is to find novel therapeutic strategies to counteract the negative consequences of adolescent sleep impairment, reduce alcohol abuse and improve mental health.
Date proposal received: 
Friday, 23 October, 2020
Date proposal approved: 
Tuesday, 27 October, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Mental health, Statistical methods, Epigenetics

B3643 - National Core Studies Longitudinal Health and Wealth Research Capability - 30/10/2020

B number: 
B3643
Principal applicant name: 
Nic Timpson | University of Bristol
Co-applicants: 
Lynn Molloy
Title of project: 
National Core Studies: Longitudinal Health and Wealth (Research Capability)
Proposal summary: 

National Core Studies Longitudinal Health and Wealth (LHW NCS) is funding researchers from different UK universities (Bristol, UCL, LSHTM, Oxford, Edinburgh) to analyse data collected from LPS and linked data to answer key research questions on COVID-19.

Impact of research: 
Research will help to answer questions posed by government on COVID-19.
Date proposal received: 
Monday, 26 October, 2020
Date proposal approved: 
Tuesday, 27 October, 2020
Keywords: 
COVID-19, Infection, Statistical methods

B3603 - Harnessing genetics to understand the role of DNA methylation in healthy aging - 30/10/2020

B number: 
B3603
Principal applicant name: 
Josine Min | MRC IEU, University of Bristol
Co-applicants: 
Jonathan Mill , Professor Caroline Relton, Dr. Jordana Bell, Professor Imre Berger, Dr. Gibran Hemani, Professor Tom Gaunt, Dr. Eilis Hannon
Title of project: 
Harnessing genetics to understand the role of DNA methylation in healthy aging
Proposal summary: 

DNA methylation (DNAm) plays a central role in gene regulation. It helps to define how cells respond to environmental signals and, ultimately, contributes to health or susceptibility to disease. However, the amount and the effects of differences in DNAm from one person to another is poorly understood. Understanding DNAm variability is a complex area of research as DNAm varies from one type of cell to another and can change over time. In addition, DNAm is influenced by genetic, molecular and environmental and other factors. So far, most epidemiological studies of DNAm have been performed in blood comprising diverse cell types. Furthermore, it is unknown whether DNAm changes lead to other molecular changes (for example gene expression) or whether the reverse is true, with molecular changes leading to changes in DNAm. Together, this makes the interpretation of DNAm variability difficult.

A powerful avenue into researching the functional consequences of changes in DNAm levels is to correlate DNA sequence variants such as single nucleotide polymorphism (SNPs) to DNAm levels to find both local and distal (for example on other chromosomes) effects. Having completed the largest genetic study of DNAm worldwide to date (through the Genetics of DNA Methylation Consortium) by scanning 10 million SNPs genomewide, we have identified 270k SNP-DNAm associations. This was achieved by analysing about 400,000 DNAm sites in blood, which is only 2% of 28 million DNAm sites across the genome. There is a huge potential for improved understanding of DNAm variation between individuals and its influence on health and disease by studying other regulatory regions of the genome, disease-relevant cell type or context and by developing novel epidemiological approaches where effects of multiple cell types and regulatory features are combined in a population-based setting.

We propose to integrate a suite of state-of-the-art technologies to characterise the functional role of DNAm. We will use novel sequencing technologies based on long reads with the ability to measure all 28 million sites and to determine both the DNAm level and the genotype at single molecule level. We will exploit these properties to provide insights on highly complex genomic regions, differential DNAm between alleles and detection of different modifications. We will systematically map genetic influences on DNAm across a wide range of tissues, cell types and ancestries. We will use this resource to understand the regulatory role of non-coding variants associated with disease traits by studying shared genetic variation and by using genotype as a causal anchor. We will further develop epidemiological approaches to explore the functional role of DNAm variation between individuals in large population-based epidemiology studies. We will validate causal relationships between DNAm sites and traits with epigenetic editing experiments where we manipulate DNAm sites to study the effects of gene regulation to disease. We will establish an openly accessible data resource that will enhance our understanding of environmental and genetic influences on genome function in humans.

Impact of research: 
The epigenome may harbor useful information about life-time exposures and disease risk factors. Large mQTL resources will be of use to the scientific community to elucidate mechanisms of genome regulation, to control for genetic confounding in EWAS, to identify causal pathways between molecular factors and disease risk and to elucidate functional effects of GWAS variants.
Date proposal received: 
Monday, 19 October, 2020
Date proposal approved: 
Thursday, 22 October, 2020
Keywords: 
Epigenomics, Healthy aging, Long read methylome sequencing, Epigenetics

B3585 - Qualitative review of ALSPAC recruitment and virtual visits by QuinteT Qualitative Research Integrated within Trials - 19/10/2020

B number: 
B3585
Principal applicant name: 
Marcus Jepson | University of Bristol
Co-applicants: 
Title of project: 
Qualitative review of ALSPAC recruitment and virtual visits by QuinteT (Qualitative Research Integrated within Trials)
Proposal summary: 

ALSPAC has received funding to complete a data collection sweep for original ALSPAC participants that was due to commence in September 2020 and to continue data collection with the ALSPAC-G2 (children of the children cohort). The original objective of bringing QuinteT into ALSPAC was to learn from their trials activity and to deploy techniques for engagement, measurement, update/change of approach to improve study performance. ALSPAC also aims to improve recruitment in key groups; Males, low SES, disengaged and ethnic minorities. A proposal was funded by the CRN for QuinteT to review ALSPAC engagement activities with a subset of male participants involved in the FIT substudy.
Due to the Covid-19 pandemic, ALSPAC has had to cease all face to face data collection activities. ALSPAC is now looking to develop a “virtual visit” and would like to use the CRN funding for QuinteT evaluate the effectiveness of our messaging around these virtual visits and to help evaluate the success of these visits from the participant perspective.

Impact of research: 
Improve documentation to participants, which we hope will improve the participant experience
Date proposal received: 
Friday, 16 October, 2020
Date proposal approved: 
Monday, 19 October, 2020
Keywords: 
Epidemiology, Cohort studies - attrition, bias, participant engagement, ethics

B3638 - Pathways to eating disorders and self-harm the role of memory and self-esteem - 19/10/2020

B number: 
B3638
Principal applicant name: 
Naomi Warne | University of Bristol (United Kingdom)
Co-applicants: 
Dr Helen Bould, Dr Jon Heron, Professor Paul Moran
Title of project: 
Pathways to eating disorders and self-harm: the role of memory and self-esteem
Proposal summary: 

Eating disorders and self-harm are serious health problems in young people, and are associated with poor outcomes. Rates of self-harm and eating disorders increased over adolescence and young adulthood. Further research on mechanisms occurring early in life that underlie the development of both self-harm and eating disorders in adolescence are required to inform potential preventative measures and treatment interventions.
Adverse Childhood Experiences (ACEs) are robustly associated with both eating disorders and self-harm and may act as a common risk factor for both. However, not everyone who has a stressful experience in childhood goes on to develop psychopathology, and it is unclear what factors may predispose an individual to develop self-harm or eating disorders following an ACE.

Subjective experience has been shown to be more important than objective reports in predicting psychopathology following ACEs. Therefore, two candidate mechanisms via which ACEs may lead to eating disorders and self-harm are 1) how individuals remember events in their past, their autobiographical memory, and 2) how people perceive themselves and their self-worth, their sense of self and self-esteem.

This project will investigate whether different features of autobiographical memory, as well as self-esteem, are on the pathway from ACEs to self-harm and eating disorders.

Impact of research: 
This project will lead to a greater understanding of the processes involved in the development of self-harm and disordered eating in adolescents and young adults. This analysis represents one research strand of three where we hope to identify whether memory and self-esteem could be novel intervention targets for individuals with self-harm and eating disorders.
Date proposal received: 
Monday, 19 October, 2020
Date proposal approved: 
Monday, 19 October, 2020
Keywords: 
Epidemiology, Eating disorders - anorexia, bulimia, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function

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