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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B3384 - Variants trait-causal via their effect on VDR binding - 13/10/2019

B number: 
B3384
Principal applicant name: 
Chris Ponting | MRC Institute of Genetics & Molecular Medicine (Midlothian)
Co-applicants: 
Dr. Neil Clark
Title of project: 
Variants trait-causal via their effect on VDR binding
Proposal summary: 

Genome-wide association studies (GWAS) do not pinpoint the disease-causal variant, and genomics experiments do not pinpoint which molecular events influence disease risk. What is needed are methods that combine GWAS and functional genomics to infer disease risk-altering causal variants. We aim to identify the variants that have a causal effect on trait via their effect on the binding of the Vitamin D Receptor (VDR). Two-sample Mendelian randomization is limited by unobserved pleiotropic effects of candidate variants which may explain trait effects independently of VDR binding. This project addresses this problem by adding the cis-acting DNA variants that explain Vitamin D (25OHD) Serum level in specific tissues to the model. This allows us to infer variants that are causal for physiological/disease trait variation via their effect on VDR binding.

Impact of research: 
Our research addresses a central problem in genetic epidemiology - the pleiotropic bias of the inferred causal effects. Separating the causal from the pleiotropic effects will allow us to identify variants that are causal via their effect on the binding of the Vitamin D Receptor. Identifying the causal effects at individual loci will reveal causal effects of Vitamin D that may be lost in studies examining the overall level of Vitamin D. Furthermore, our estimates of the size and direction of the causal effects may facilitate a translation into genotype and trait dependent therapeutic role for Vitamin D supplementation.
Date proposal received: 
Friday, 27 September, 2019
Date proposal approved: 
Friday, 27 September, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), This project is trait agnostic but aims to test any traits that overlap with UK-Biobank as we aim to compare the summarised results with the aim of replication of our analysis results., Computer simulations/modelling/algorithms, Statistical methods, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Mendelian randomisation

B3383 - Environment-wide association study for adiposity in ALSPAC - 27/09/2019

B number: 
B3383
Principal applicant name: 
Jie V Zhao | The University of Hong Kong (Hong Kong)
Co-applicants: 
Dr. C Mary Schooling, Prof. Debbie Lawlor, Dr. Ahmed Elhakeem
Title of project: 
Environment-wide association study for adiposity in ALSPAC
Proposal summary: 
Impact of research: 
The increased prevalence of obesity and related comorbidities is a major public health problem. Identifying the potential drivers of adiposity will be helpful for providing dietary recommendations, and identifying a healthy diet and lifestyle. Examining the underlying pathways will improve risk prediction for adiposity and chronic diseases, provide new insights into the prevention and treatment strategies, with direct relevance to clinical practice and population health.
Date proposal received: 
Thursday, 26 September, 2019
Date proposal approved: 
Thursday, 26 September, 2019
Keywords: 
Epidemiology, Obesity, Statistical methods, BMI, Nutrition - breast feeding, diet

B3382 - Eating disorders and anxiety Mapping developmental trajectories and their genetic underpinnings - 27/09/2019

B number: 
B3382
Principal applicant name: 
nadia micali | University of Geneva, Switzerland; UCL, UK
Co-applicants: 
Cynthia M Bulik, Zeynep Yilmaz, Dr, Katherine Schaumberg, Dr, Yufeng Liu
Title of project: 
Eating disorders and anxiety: Mapping developmental trajectories and their genetic underpinnings
Proposal summary: 

Eating disorders (ED) such as anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED) are debilitating and costly with few effective treatments. Comorbidity between ED and anxiety (ANX) and obsessive-compulsive disorder (OCD) is typical, with about two-thirds of individuals with ED also reporting lifetime ANX (including OCD). Comorbidity adversely impacts prognosis and time to recovery. Most ED and ANX phenotypes onset during adolescence, and evidence points to shared risk at the genetic level. ED and ANX phenotypes are moderately heritable. Genetic risk scores (GRS), which combine weighted risk from common variant single-nucleotide polymorphisms (SNPs) across the genome, are effective in defining psychiatric risk, although the focus has typically been on diagnoses. Integrating genetic risk information across multiple ED- and ANX- phenotypes could enhance predictive power of GRS while also specifying whether this genetic risk is best understood through a single factor vs. multiple factors. For instance, multiple metabolic, anthropometric, and psychiatric traits share genetic risk with AN. ANX also shows significant genetic overlap with psychiatric traits but less so with anthropometric and metabolic traits, suggesting shared risk between ED and ANX with psychiatric traits, but differential risk with metabolic and anthropometric traits. We will investigate this empirically using genomic structural equation modeling (GSEM) to identify genomic factors associated with ED and ANX phenotypes.
Additionally, we propose a fine-grained investigation of the association between ED and ANX by examining ED and ANX symptom trajectories across adolescence and into adulthood; to hone in on the biology that underlies ED and ANX change over time. At present, little is known about how ED and ANX symptoms affect each other across development, and how genetic risk influences their onset and course, though it is likely that genetic risk affects onset and course differently in adolescence vs. adulthood. Studying how ED and ANX are associated, both genetically and phenotypically, across development will advance early identification and targeted prevention and treatment of these conditions before threshold diagnoses crystallize.

Impact of research: 
important novel findings in risk for eating disorders
Date proposal received: 
Tuesday, 24 September, 2019
Date proposal approved: 
Wednesday, 25 September, 2019
Keywords: 
Epidemiology, Eating disorders - anorexia, bulimia, GWAS, Development

B3381 - Early Childhood Shyness Psychosocial Experiences and Trajectories of Cardiovascular Risk Factors across the Life-Course - 24/09/2019

B number: 
B3381
Principal applicant name: 
Alva Tang | University of Maryland (United States)
Co-applicants: 
Natalie Slopen
Title of project: 
Early Childhood Shyness, Psychosocial Experiences, and Trajectories of Cardiovascular Risk Factors across the Life-Course
Proposal summary: 

Shyness is a temperamental trait characterized by an anxious preoccupation with the self and heightened reactivity in social situations. This trait is moderately stable across the childhood to adulthood [1]. Shy children often express social withdrawal and internalizing problems (i.e., loneliness, anxiety and depressive symptoms), if they have experienced negative peer experiences, such as peer rejection and victimization [2-6]. In contrast, mutual and high-quality friendships [6, 7] as well as parenting styles characterized by high warmth and autonomy [4, 8-10] buffer against social withdrawal and internalizing problems among shy youth. While the link between shyness and later socioemotional problems is well-documented, little is known about physical health outcomes of shy children even though epidemiologic studies suggest that childhood social withdrawal/isolation, an outcome of childhood shyness, is an independent risk factor for increased cardiovascular disease (CVD) risk in adulthood [11-13]. Similarly, studies using animal models show that rodents and dogs with stable neophobic/inhibited traits have shorter lifespan, dampened immune response, and elevated glucocorticoid production [14-17]. Yet, no studies in humans have identified whether early temperamental shyness plays a role in increased CVD risk in adulthood and how temperamental shyness, peer and parental relationships shape the development of physiological systems linked to CVD risk across the lifespan to confer later health risks. This research proposal aims to address these knowledge gaps by considering a broad range of negative and positive peer-experiences in relation to CV risk factors measured from childhood to adulthood, and the potential role of child mental health within this relationship. Using the ASLPAC cohort, we will address the following questions:

References
1. Pérez-Edgar, K. and N.A. Fox, Temperament and anxiety disorders. Child and Adolescent Psychiatric Clinics, 2005. 14(4): p. 681-706.
2. Boivin, M., S. Hymel, and W.M. Bukowski, The roles of social withdrawal, peer rejection, and victimization by peers in predicting loneliness and depressed mood in childhood. Development and Psychopathology, 1995. 7(4): p. 765-785.
3. Gazelle, H. and G.W. Ladd, Anxious solitude and peer exclusion: A diathesis–stress model of internalizing trajectories in childhood. Child development, 2003. 74(1): p. 257-278.
4. Booth-LaForce, C. and M.L. Oxford, Trajectories of social withdrawal from grades 1 to 6: Prediction from early parenting, attachment, and temperament. Developmental psychology, 2008. 44(5): p. 1298.
5. Tang, A., et al., Shyness trajectories across the first four decades predict mental health outcomes. Journal of abnormal child psychology, 2017. 45(8): p. 1621-1633.
6. Oh, W., et al., Trajectories of social withdrawal from middle childhood to early adolescence. Journal of Abnormal Child Psychology, 2008. 36(4): p. 553-566.
7. Fordham, K. and J. Stevenson-Hinde, Shyness, friendship quality, and adjustment during middle childhood. The Journal of Child Psychology and Psychiatry and Allied Disciplines, 1999. 40(5): p. 757-768.
8. Booth-LaForce, C., et al., Parent and peer links to trajectories of anxious withdrawal from grades 5 to 8. Journal of Clinical Child & Adolescent Psychology, 2012. 41(2): p. 138-149.
9. Kiel, E.J. and K.A. Buss, Prospective relations among fearful temperament, protective parenting, and social withdrawal: The role of maternal accuracy in a moderated mediation framework. Journal of abnormal child psychology, 2011. 39(7): p. 953-966.
10. Lewis‐Morrarty, E., et al., Infant attachment security and early childhood behavioral inhibition interact to predict adolescent social anxiety symptoms. Child development, 2015. 86(2): p. 598-613.
11. Caspi, A., et al., Socially isolated children 20 years later: risk of cardiovascular disease. Archives of Pediatrics & Adolescent Medicine, 2006. 160(8): p. 805-811.
12. Danese, A., et al., Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. Archives of pediatrics & adolescent medicine, 2009. 163(12): p. 1135-1143.
13. Lacey, R.E., M. Kumari, and M. Bartley, Social isolation in childhood and adult inflammation: evidence from the National Child Development Study. Psychoneuroendocrinology, 2014. 50: p. 85-94.
14. Cavigelli, S.A., Behavioral Inhibition in Rodents: A Model to Study Causes and Health Consequences of Temperament, in Behavioral Inhibition. 2018, Springer. p. 35-58.
15. Cavigelli, S.A. and M. McClintock, Fear of novelty in infant rats predicts adult corticosterone dynamics and an early death. Proceedings of the National Academy of Sciences, 2003. 100(26): p. 16131-16136.
16. Corsetti, S., et al., Bold personality makes domestic dogs entering a shelter less vulnerable to diseases. PloS one, 2018. 13(3): p. e0193794.
17. Cavigelli, S.A., J.R. Yee, and M.K. McClintock, Infant temperament predicts life span in female rats that develop spontaneous tumors. Hormones and Behavior, 2006. 50(3): p. 454-462.

Impact of research: 
Date proposal received: 
Monday, 23 September, 2019
Date proposal approved: 
Tuesday, 24 September, 2019
Keywords: 
Social Science, Diabetes, Hypertension, Obesity, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Cardiovascular, Development, Hormones - cortisol, IGF, thyroid, Immunity, Psychology - personality, Social science

B3380 - Dissect the interaction of age at first marriage and associated sociological traits with a genetic approach - 24/09/2019

B number: 
B3380
Principal applicant name: 
Qiongshi Lu | University of Wisconsin-Madison (United States)
Co-applicants: 
Tianchang Li, Jason Fletcher, PhD
Title of project: 
Dissect the interaction of age at first marriage and associated sociological traits with a genetic approach
Proposal summary: 

Marital behaviours are important human traits of great interest in sociology, psychology, and related fields. Sociological factors (e.g. educational attainment) have been demonstrated to strongly associate with AFM, especially for women. However, little is known about the genetic basis of marriage. Due to the growing interest in understanding the genetic basis of marriage and how it interacts with environmental factors, this proposed research will study the sociological factors associated with people’s age at first marriage (AFM) using a genetic approach. More specifically, this research aims to identify common genetic variants associated with AFM through a genome-wide association meta-analysis approach. In addition, we will quantify the genetic correlation between AFM and a variety of human traits such as personality and cognitive behaviour, assess the predictive accuracy of AFM using genetic information, and investigate how genetic and environmental factors interact to influence AFM. This research will potentially provide fundamental new insights into the genetic basis of marital behaviour in general and AFM in particular.

Impact of research: 
This research will provide fundamental new insights into the genetic basis of marital behaviour in general and AFM in particular. In addition, the proposed research will generate polygenic scores for AFM which allows us to dissect the interaction between genetic and life-course environmental factors underlying AFM.
Date proposal received: 
Monday, 23 September, 2019
Date proposal approved: 
Tuesday, 24 September, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Behaviour - e.g. antisocial behaviour, risk behaviour, etc., GWAS, Genome wide association study

B3377 - Is genetic predisposition to osteoarthritis associated with musculoskeletal pain in adolescents - 20/09/2019

B number: 
B3377
Principal applicant name: 
Aliya Sarmanova | MRC Integrative Epidemiology Unit, PHS/Musculoskeletal Research Unit Translational Health Sciences, Bristol University (United Kingdom)
Co-applicants: 
Professor Jonathan Tobias, Professor George Davey Smith, Professor Nicholas Timpson, Prof. Dr. Eleftheria Zeggini, Dr Monika Frysz, Miss April Hartley
Title of project: 
Is genetic predisposition to osteoarthritis associated with musculoskeletal pain in adolescents?
Proposal summary: 
Impact of research: 
Date proposal received: 
Wednesday, 18 September, 2019
Date proposal approved: 
Friday, 20 September, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Bone disorders - arthritis, osteoporosis, Statistical methods, Bones (and joints), Genetic epidemiology

B3378 - Lectin Histochemistry and Glycocalyx Measurement of the ALSPAC Placentas - A Feasibility Study - 04/10/2019

B number: 
B3378
Principal applicant name: 
Simon Satchell | University of Bristol
Co-applicants: 
Dr Colin Down, Dr Victora Bills, Dr Rebecca Foster
Title of project: 
Lectin Histochemistry and Glycocalyx Measurement of the ALSPAC Placentas - A Feasibility Study
Proposal summary: 

Pre-eclampsia is a common pregnancy complication and is one of the leading causes of death and injury to mothers and their babies worldwide. Pre-eclampsia occurs in the second half of pregnancy and is characterised by high blood pressure and protein in the urine. We do not fully understand why some women get this condition, but the function and leakiness of small blood vessels (capillaries) is important.

The glycocalyx, is a very thin gel-like layer which is found on the wall of all blood vessels. It seems to act as a barrier, controlling how much water remains inside the blood vessel. Researchers have recently started looking at the glycocalyx and have found in other conditions which cause leaky blood vessels (e.g. diabetes and kidney disease), the glycocalyx appears damaged.

Recently we have completed work to show that glycocalyx is not only present in blood vessels, but also the human placenta. We have done this by staining placenta with different proteins called lectins. These bind to the sugary glycocalyx, and when labelled with a fluorescent dye glow green under the microscope. We compare this green stain to a red membrane stain and can measure the depth of the glycocalyx.

We suspect that the glycocalyx is damaged in pre-eclampsia, like in other diseases.

ALSPAC offers an excellent resource of placental tissue, however, many of these specimens have been stored for a number of years and we know the glycocalyx can be a fragile structure. We propose a feasibility experiment, whereby the research team could look a small selection of ALSPAC placentas to examine if the glycocalyx has been preserved and can still be measured.

Impact of research: 
If it can be confirmed that glycocalyx has been preserved in the ALSPAC placentae, this would provide excellent provisional data for a grant application for further work with the ALSPAC placentas. A larger study could investigate differences in the placental glycocalyx in health and disease and help further elucidate the pathophysiology of pre-eclampsia. The translational potential is exciting and could include glycocalyx as a biomarker, diagnostic tool or even a therapeutic target in pre-eclampsia.
Date proposal received: 
Thursday, 19 September, 2019
Date proposal approved: 
Friday, 20 September, 2019
Keywords: 
Biochemistry/structural biology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Medical imaging, Biological samples -e.g. blood, cell lines, saliva, etc., Blood pressure

B3376 - Evaluating diet at age 30 ALSPAC-G1 - 19/09/2019

B number: 
B3376
Principal applicant name: 
Eleanor Winpenny | MRC Epidemiology Unit, University of Cambridge
Co-applicants: 
Dr Esther van Sluijs, Polly Page
Title of project: 
Evaluating diet at age 30 (ALSPAC-G1)
Proposal summary: 

Poor quality diet is associated with increased risk of heart disease, stroke, type 2 diabetes, many forms of cancer and mental illness. Poor quality diet is the top contributor to mortality globally, and is estimated to cost the NHS £6billion per year.
The period of adolescence to early adulthood is the time when prevalence of overweight and obesity develops most rapidly, making this an important time to understand the contribution of diet to these developing risk factors. Adolescence and early adulthood is a time of rapid personal development and changing lifestyles. It also is the time when adult behaviours, including adult dietary patterns, are developed and established. Understanding the factors that influence development of adult diet is an important first step in developing strategies to change behaviour.
However, there has been little assessment of diet in young adults. Online tools (INTAKE24) are now available that make reporting on nutritional intake easier, allowing online completion of recalls of daily intake, and automated data processing. These validated tools make the collection of diet data in large samples more feasible, and are now being implemented in large-scale dietary surveys across many countries by researchers at the MRC Epidemiology Unit.
This application focusses on assessing the diet of young adults (age 28-30) in the ALSPAC cohort. This data will then be used together with other data collected within ALSPAC, or from linked datasets, to understand (1) the changes in environment and lifestyle which help to explain why individuals have adopted their current diets, and (2) the relationships between diet and measures of heart and blood health. The data will also be available for further research studying associations between diet at age 30 years and longer term measures of health and disease.

Impact of research: 
There is limited robust data available on dietary intake during early adulthood, both globally and in the UK. Collection of this data will allow research which helps us to understand the role of diet within pathways which lead from socioeconomic determinants to cardiovascular and metabolic disease. In particular this research will provide information on the populations at risk for development of poor diet during early adulthood, and suggest opportunities for public health intervention. For example research based on this data could identify particular population groups or particular early adulthood life transitions that increase risk of a poor quality diet, suggesting a particular target for intervention. In the future this data will allow for further research addressing associations between diet in early adulthood and later health and disease, for example to understand whether diet in early adulthood plays an independent role in future disease risk.
Date proposal received: 
Tuesday, 17 September, 2019
Date proposal approved: 
Tuesday, 17 September, 2019
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Cancer, Diabetes, Hypertension, Obesity, Nutrition - breast feeding, diet

B3372 - Changes in metabolomic measures attributable to body composition during puberty and young adulthood - 16/09/2019

B number: 
B3372
Principal applicant name: 
Inge Verkouter | Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands (Netherlands)
Co-applicants: 
Dr Joshua Bell, Prof Nicholas Timpson, Dr Linda O'Keeffe, Dr Raymond Noordam, Dr Renée de Mutsert, Dr Dennis Mook-Kanamori, Prof Frits R Rosendaal
Title of project: 
Changes in metabolomic measures attributable to body composition during puberty and young adulthood
Proposal summary: 

Body weight gain during adulthood is known to be associated with a higher risk of cardiometabolic diseases, such as type 2 diabetes and cardiovascular diseases. In addition, body weight gain contributes to higher (mostly abdominal) body fat later in life, as compared with body weight maintenance. Body fat that is stored in the abdomen (android body fat) is strongly associated with the risk of cardiometabolic disease, whereas peripheral body fat (gynoid body fat) is believed to be less detrimental for cardiometabolic health. Cardiometabolic disease is accompanied by changes in the blood metabolic profile, such as changes in cholesterol, fatty acids, amino acids and factors related to inflammatory processes. It is not known whether body fat measures, such as total body fat, trunk fat, leg fat and arm fat, measured during childhood and adolescence are associated with changes in the metabolite profile at young adulthood. Additionally, it is not known whether or how the metabolite profile changes following the onset of puberty, and whether these changes can be attributed to prior changes in body composition.
Therefore, we will examine the change in the metabolite profile following the onset of puberty, and we will examine the relation between fat indices at different stages of development (e.g. before and after puberty) and changes in the metabolite profile. In addition, it is known that men and women have a different body fat distribution, with men having more trunk fat, and women having more leg fat. We will examine whether the regional fat indices in men and women differentially associate with changes in the metabolic profile during childhood and adolescence.

Impact of research: 
Metabolites are important intermediates of phenotypes and disease, and therefore contribute to research on the underlying mechanisms of disease. However, there is lack of longitudinal studies in metabolomics, therefore little is known about changes in metabolite profiles. This research will contribute to unravelling the metabolic changes before, during and after puberty, and whether these metabolic changes are attributable to changes in body composition with use of repeated measures of metabolites in ALSPAC. Thereby, this research will contribute to elucidating the critical periods when the first indications of cardiometabolic disease later in life (as changes in metabolite levels) will develop.
Date proposal received: 
Thursday, 12 September, 2019
Date proposal approved: 
Monday, 16 September, 2019
Keywords: 
Epidemiology, Obesity, Metabolomics, Metabolic - metabolism

B3373 - Prenatal Hg exposure and DNA methylation consortium analysis - 16/09/2019

B number: 
B3373
Principal applicant name: 
Paul Yousefi | MRC Integrative Epidemiology Unit, University of Bristol (United Kingdom)
Co-applicants: 
Gemma Sharp, Caroline Relton
Title of project: 
Prenatal Hg exposure and DNA methylation consortium analysis
Proposal summary: 

Mercury (Hg) is an environmental pollutant that can persist and bio-accumulates as methylmercury (MeHg) through the food chain. Foetuses are especially vulnerable to prenatal exposure since mercury can cross the placental barrier and the blood brain barrier is not fully developed until several months after birth. Prenatal exposure to Hg has been associated with impaired foetus development, such as reduced placental functioning and foetal growth. Prenatal exposure to Hg has also been associated with effects on child neuropsychological development. The specific mechanisms of toxicity related to these associations remain unclear, although some research has suggested that dramatic DNA methylation changes and epigenetic remodelling during early embryogenesis could be involved. Thus, cells and tissues acquire new methylation patterns that may persist in foetal development and childhood. To date, only three studies have been conducted relating Hg and epigenome-wide DNA methylation in cord blood with sample sizes between 138 and 321. These studies have identified altered expression in unique genomic regions as well as methylation changes in specific CpG sites. This study proposes to to investigate the association between prenatal Hg exposure and epigenome-wide methylation.

Impact of research: 
The primary academic beneficiaries of this project will be environmental and biological scientists who will gain insight into the role of the epigenome and environmental Hg exposures. Researchers in the field of life course epidemiology will benefit from a clearer understanding of the role of epigenetic mechanisms in the programming of later health and behaviors. Academics at all career stages, from PhD students to senior academics will have the opportunity to engage with and benefit from the research proposed.
Date proposal received: 
Thursday, 12 September, 2019
Date proposal approved: 
Monday, 16 September, 2019
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Microarrays, Environment - enviromental exposure, pollution

B3374 - Is the polygenic risk score for Alzheimers disease and cognitive function manifest in childhood/adolescent brain structures - 16/09/2019

B number: 
B3374
Principal applicant name: 
Neil Davies | Integrative Epidemiology Unit (United Kingdom)
Co-applicants: 
Roxanna Korologou-Linden, Emma Anderson, Yoav Ben-Shlomo, Laura Howe
Title of project: 
Is the polygenic risk score for Alzheimer’s disease and cognitive function manifest in childhood/adolescent brain structures?
Proposal summary: 

This project will try to understand how early Alzheimer's disease is manifest through the use of genetic risk scores. Genetic risk scores (irrespective of whether an individual has Alzheimer's disease) are useful in examining prodromal phenotypes. We aim to investigate whether Alzheimer's disease is manifest in childhood and adolescence through the use of brain MRI data in ALSPAC.

Impact of research: 
To understand how early Alzheimer's disease in manifest.
Date proposal received: 
Friday, 13 September, 2019
Date proposal approved: 
Monday, 16 September, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Mental health, Statistical methods, Mendelian randomisation

B3375 - Understanding the causal pathways between childhood maltreatment and cardiovascular disease - 16/09/2019

B number: 
B3375
Principal applicant name: 
Ana Luiza G Soares | University of Bristol (UK)
Co-applicants: 
Abigail Fraser
Title of project: 
Understanding the causal pathways between childhood maltreatment and cardiovascular disease
Proposal summary: 

Maltreatment (physical, sexual and emotional abuse and neglect) in childhood is common and has both immediate and long-lasting negative effects. People who suffer maltreatment have a higher risk of many health conditions, including obesity, heart attack and stroke. However, it is not well understood why this is the case and at what age ill health starts to manifest. Unhealthy eating, smoking, physical inactivity and inadequate sleep may play a role in this relationship, but mental health issues, such as anxiety and depression, inflammation and other biological factors can also be involved. These factors might have separate effects but also act together, and these mechanisms might differ between men and women. This research aims to understand when the cardiovascular consequences of maltreatment appear, the pathways that link childhood maltreatment to heart disease in later life and whether these mechanisms differ by sex. This will help to identify potential targets for interventions to prevent heart disease in those who suffered maltreatment. We will use data from several British studies (ALSPAC, UK Biobank, the 1958 British Birth Cohort, Millennium Cohort and Growing up in Scotland), that have assessed maltreatment in early life and have measures of cardiovascular health indicators at different ages to understand when, why and how people who suffered maltreatment in childhood have a higher risk of heart disease in later life.

Impact of research: 
Childhood maltreatment is common, and there is a robust association between maltreatment and several adverse health outcomes, including cardiovascular disease (CVD). Understanding when this association emerges and the mechanisms that link childhood maltreatment to cardiometabolic outcomes will improve our understanding of the aetiology of CVD, and will inform prevention efforts, thus reducing the burden of CVD in some of the most vulnerable people in society. By identifying and quantifying the contribution of multiple mediating factors, such as diet, physical activity, sleep, mental health and inflammation, to the association between childhood maltreatment and CVD, we will identify potential targets for interventions aimed at secondary prevention of CVD in maltreated individuals. If these mechanisms differ by sex, interventions might need to be tailored differently for maltreated men and women. Therefore, the results of the proposed research will be value to patients, clinicians and policy makers.
Date proposal received: 
Friday, 13 September, 2019
Date proposal approved: 
Monday, 16 September, 2019
Keywords: 
Epidemiology, Obesity, Statistical methods, Childhood - childcare, childhood adversity

B3370 - ALSPAC families - 20/09/2019

B number: 
B3370
Principal applicant name: 
Neil Davies | MRC IEU (UK)
Co-applicants: 
Prof George Davey Smith, Dr Tim Morris
Title of project: 
ALSPAC families
Proposal summary: 

This proposal will look to obtain DNA samples from ALSPAC participant (G1) family members, including fathers and siblings.

Impact of research: 
Date proposal received: 
Tuesday, 10 September, 2019
Date proposal approved: 
Tuesday, 10 September, 2019
Keywords: 
Epidemiology

B3369 - Social causes and consequences of depressive symptom and high BMI comorbidity - 21/09/2019

B number: 
B3369
Principal applicant name: 
Fanny Kilpi | University of Bristol, MRC IEU
Co-applicants: 
Dr Laura Howe
Title of project: 
Social causes and consequences of depressive symptom and high BMI comorbidity
Proposal summary: 

Adolescence is a key life course stage during which influences from the family of origin can influence later socioeconomic attainment and health and may be a particularly vulnerable time for the interaction between mental and physical health and social disadvantage. This project examines how circumstances from early-life such as family socioeconomic position and adverse childhood experiences shape the co-occurrence and co-development of depressive symptoms and overweight in adolescence and the socioeconomic consequences the comorbidity may have.

Impact of research: 
The objective of this research project is to enhance our understanding of the social risks associated with the comorbidity of depressive symptoms and overweight in adolescence. The project is particularly timely and important due to the evidence of increasing overweight and depression rates in adolescents. A major goal of the research will be on generating awareness and a stronger evidence base of the early-life determinants of mental and physical health comorbidity, as well on the need to intervene early to reduce the long-term consequences of adolescent health problems. The findings can thus help to inform policies to help intervene early in the accumulation of social disadvantage and ill health, which has the potential of substantially improving population health.
Date proposal received: 
Monday, 9 September, 2019
Date proposal approved: 
Monday, 9 September, 2019
Keywords: 
Social Science, Mental health, Obesity, Longitudinal data analysis, BMI

B3368 - Maternal postnatal stress and pathways to childhood growth - 09/09/2019

B number: 
B3368
Principal applicant name: 
Lawrence Schell | University at Albany, State University of New York (USA)
Co-applicants: 
Elizabeth Holdsworth, Allison Appleton, DrPH
Title of project: 
Maternal postnatal stress and pathways to childhood growth
Proposal summary: 

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

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

Impact of research: 
This research will significantly advance knowledge of how stress can be transmitted transgenerationally in ways that may influence health and physiology throughout life. It will also significantly advance knowledge of the mechanisms by which psychosocial stress can influence childhood growth. This work will be published in peer-reviewed journals in public health and anthropology, and will contribute to the dissertation project of a PhD Candidate.
Date proposal received: 
Friday, 6 September, 2019
Date proposal approved: 
Monday, 9 September, 2019
Keywords: 
Anthropology, Mental health, Obesity, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Physical growth and development, Statistical methods, BMI, Bones (and joints), Childhood - childcare, childhood adversity, Development, Epigenetics, Hormones - cortisol, IGF, thyroid

B3367 - Maternal nutritional status in pregnancy and offspring Autism Spectrum Disorder a social perspective - 21/09/2019

B number: 
B3367
Principal applicant name: 
Alastair Leyland | University of Glasgow (UK)
Co-applicants: 
Ms Catherine Friel
Title of project: 
Maternal nutritional status in pregnancy and offspring Autism Spectrum Disorder: a social perspective
Proposal summary: 

What a mother eats during pregnancy has previously been established to programme their infants health in later live, even tracking through to adulthood. However, despite compelling evidence to support foetal programming of physical health, neurodevelopment has remained understudied. Recently, autism has gained increased attention within this field of research. Although largely caused by genetic factors, it is now estimated that approximately 20% of the risk of developing autism relates to environmental factors, of which nutrition is a main focus. Preliminary evidence indicates that the risk of developing autism may be reduced through consumption of a nutritionally adequate diet or nutritional supplements. Furthermore, the presence of social patterning is unknown. Health inequities are observed in numerous health outcomes as low socioeconomic position groups experience more adversity including poorer diet quality. Thus, it is possible that, where an association existed between maternal diet and their child’s risk of autism, it may also be socially patterned.

Two datasets will be compared for this project, ALSPAC and a second dataset called the Norwegian Mother and Child Cohort Study. The data from each cohort will be analysed in the same way.
This project will apply statistical methods that estimate if there is an association between maternal nutritional intake during pregnancy and the child’s risk of developing autism. The project will apply ‘causal methods’ which are statistical methods which better estimate causal relationships from observation data when compared to conventional methods with measure ‘association’. A key way in which this occurs is through adjusting for confounders which vary over time, such as early infant nutrition. Both pregnancy and early infant nutrition such as breastfeeding, complementary feeding and nutrition in the early years have been associated with neurodevelopment and so the effects measured in pregnancy may be further altered by nutrition consumed in childhood. Lastly, results will be stratified by socioeconomic position to more clearly assess the presence and the degree of social patterning in this relationship.

Impact of research: 
This project will inform prevention strategies by addressing three main research gaps; estimating causality, identifying critical periods and exploring health inequalities. Firstly, this research will estimate the causal association between nutritional status in pregnancy and the risk of autism in offspring. In doing so, it will address the lack of evidence supporting a healthy diet in pregnancy. Furthermore, it is well recognised that misinformation in pregnancy is common and that dietary information may be more affected than information regarding general health. Yet at present, there is limited evidence on the impact of obesity, weight gain and diet in pregnancy on outcomes in offspring. Secondly, by identifying critical periods we can target prevention strategies more effectively. This project measures the impact of nutritional status in pregnancy, breast or formula feeding and infant dietary intake. All of which may have independent or accumulative effects on autism. Through contributing to the evidence base on a healthy diet in pregnancy this project will feed into a larger pool of evidence that informs national guidelines such as NICE: Maternal and Child Nutrition (PH11). Thirdly, exploring health inequalities may also help to target prevention strategies to those most in need. The UK Government stipulated that proportional universalism should be incorporated into prevention strategies however, few studies measure health inequalities. By evidencing health inequalities this project may indicate where to target resources and it may promote confidence in dietitians to open-up discussion on health inequalities. Through contributing to the evidence base on a healthy diet in pregnancy this project will feed into a larger pool of evidence that informs national guidelines such as NICE: Maternal and Child Nutrition (PH11).
Date proposal received: 
Friday, 6 September, 2019
Date proposal approved: 
Friday, 6 September, 2019
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Cognitive impairment, Speech/language problem, Statistical methods, Birth outcomes, BMI, Nutrition - breast feeding, diet, Offspring, Speech and language, Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Cognition - cognitive function, Communication (including non-verbal), Development, Epigenetics, Genetic epidemiology, Mothers - maternal age, menopause, obstetrics

B3366 - Non-alcoholic fatty liver disease and cardiac function in young adults - 06/09/2019

B number: 
B3366
Principal applicant name: 
Rosalind Tang | Bristol Medical School, University of Bristol
Co-applicants: 
Dr Abigail Fraser
Title of project: 
Non-alcoholic fatty liver disease and cardiac function in young adults
Proposal summary: 

Although there are many common risk factors between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease, e.g. obesity, NAFLD may be associated with cardiovascular disease, independently from other established cardiovascular risk factors.

Impact of research: 
This analysis will contribute to clarifying whether NAFLD is implicated as a causal risk factor in the aetiology of cardiovascular disease or whether it is simply the hepatic manifestation of metabolic syndrome.
Date proposal received: 
Tuesday, 3 September, 2019
Date proposal approved: 
Friday, 6 September, 2019
Keywords: 
Epidemiology, Hypertension, Obesity, Non-alcoholic fatty liver disease, cardiovascular disease, cerebrovascular disease, Medical imaging, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Blood pressure, BMI, Cardiovascular, Liver function, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Statistical methods, Ultrasonography

B3365 - Specifying Risk for Driven Exercise in Eating Disorders - 02/09/2019

B number: 
B3365
Principal applicant name: 
Katherine Schaumberg | University of Wisconsin - Madison (USA)
Co-applicants: 
Dr. Nadia Micali, Dr. Cynthia Bulik
Title of project: 
Specifying Risk for Driven Exercise in Eating Disorders
Proposal summary: 

Physical activity can be rewarding and lead to anxiety reduction, and physical activity levels in the general population are heritable, suggesting individual differences in the degree to which physical activity is reinforcing via biobehavioral pathways. Increases in physical activity are often associated with positive mental health outcomes, though more is not always better. For example, up to 40% of individuals with bulimia nervosa and up to 60% of those with anorexia nervosa present with driven exercise (exercising in a driven manner to control weight and shape). Driven exercise is a serious, concerning, and understudied eating disorder symptom. Existing research points towards compulsivity and general propensity to exercise as potential risk factors for driven exercise. At present, our understanding of the developmental etiology of driven exercise is poor, and the extent to which this symptom relates to patterns of PA during development is unknown.
We will examine risk for driven exercise in the ALSPAC cohort by identifying trajectories of physical activity during development and identifying whether these trajectories associate with driven exercise and eating disorder diagnoses in adolescence and emerging adulthood. We will then investigate the developmental timing and predictive strength of driven exercise in relation to eating disorder onset and maintenance. Finally, we will evaluate the degree to which genetic risk profiles inform risk for driven exercise.

Impact of research: 
At present, we know relatively little about the etiology of driven exercise, its relationship to premorbid activity levels, or how to manage this symptom in the context of ED treatment and recovery. In addition, we do not understand factors that contribute to the substantial variability in physical activity among those with EDs, and why only a portion of individuals present with the symptom of driven exercise. Given the critical need to improve early identification of and treatment for individuals with eating disorders, and even more-so for those who engage in driven exercise, enhancing our understanding of the risk for and development of driven exercise is paramount. Identifying associations between driven exercise, physical activity patterns, eating disorder onset, and the genetic architecture of driven exercise could point towards relevant biological mechanism(s), aid in early identification of at-risk youths, and ultimately inform therapeutic activity recommendations during eating disorder recovery. Further, this research will offer a blueprint for studying other presentations of physical activity dysregulation present in developmental psychopathology (e.g. hyperactivity, restlessness), and clarifying the degree to which various activity symptoms arise from shared versus unique risk.
Date proposal received: 
Sunday, 1 September, 2019
Date proposal approved: 
Monday, 2 September, 2019
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Eating disorders - anorexia, bulimia, Mental health, Statistical methods, BMI, Genetic epidemiology, Psychology - personality, Physical - activity, fitness, function

B3363 - Large-Scale Evaluation of the Effect of Rare Genetic Variants on Psychiatric Symptoms and Cognitive Ability - 02/09/2019

B number: 
B3363
Principal applicant name: 
David Glahn | Boston Children's Hospital
Co-applicants: 
Dr. Sebastien Jacquemont, Dr. Laura Almasy, Dr. Josephine Mollon, Dr. Emma Knowles, Dr. Sam Mathias, Dr. Amanda Rodrigue, Dr. Catherine Brownstein, Dr. Richard Smith, Dr. Guillaume Huguet, Dr. Laura Schultz​
Title of project: 
Large-Scale Evaluation of the Effect of Rare Genetic Variants on Psychiatric Symptoms and Cognitive Ability
Proposal summary: 

Rare copy number variants (CNVs) are strongly associated with neuropsychiatric disorders, suggesting that they might serve as a magnifying glass to study general mechanisms of psychopathology as otherwise subtle perturbations to neuropsychiatric functions may be more clearly discerned through the major ‘hit’ of the CNV. However, our understanding of the impact of CNVs on psychiatric symptomatology, RDoC domains and neurocognitive ability (termed ‘dimensional neuropsychiatric phenotypes’) is limited in at least three ways. First, the effects sizes of the vast majority of CNVs on neuropsychiatric phenotypes remain poorly understood and their rarity will likely to prevent individual association studies. Prior studies concentrated on the most recurrent CNVs, leaving more than 90% of these variants undocumented. Second, for CNVs frequent enough to be studied individually, the full spectrum of phenotypic variation is unknown because ascertainment has been performed through neurodevelopmental and specialty clinics, which presumably represent the severe end of the phenotypic spectrum. Only a few studies have been conducted in unselected populations. Finally, many CNVs seem to impact the same neuropsychiatric domains, suggesting a poly/omnigenic model for psychiatric symptomatology, RDoC domains and neurocognitive ability. Based on this hypothesis, our previous work has shown that genetic scores and functional annotations can accurately predict the effect of any CNV on IQ but these approaches have not yet been extended beyond IQ to other dimensional neuropsychiatric phenotypes. We will fill these knowledge gaps with a novel, multidisciplinary, collaborative project that leverages existing archival data (n=255,303) to estimate and predict the effect sizes of CNVs (duplications and deletions) on dimensional neuropsychiatric phenotypes. Our aims include 1) phenotypic harmonization; 2) characterizing previously identified risk CNVs for mental illness in a large in general population cohorts and in samples ascertained for mental illnesses; 3) examine the contribution of common variants to variable expressivity of rare CNVs via polygenic risk scores (PRS) in the domains of mood, psychosis, developmental disability, and general cognitive ability; and 4) develop novel models to explain the effect size of any rare CNVs on dimensional neuropsychiatric phenotypes. Finally, we will develop tools for data sharing.

Impact of research: 
The scientific premise of our application is that rare CNVs, which are strongly associated with neuropsychiatric disorders, provide a unique window into the genetic architecture of mental disorders that can be exploited to better understand idiopathic neuropsychiatric disorders. There are currently several knowledge gaps that limit the insights that CNVs provide for understanding the pathobiology of mental illness. Our application is designed to address three of these gaps. As we are using only existing data and previously collected DNA samples, there are no direct therapeutic benefits for subjects in this study. However, increased knowledge about genetic architecture of mental illness provides significant potential benefits to society in general, and to patients with mental illnesses and their families in particular. Since the risks of participating in this study only minimally exceed those of routine clinical review, we believe the potential benefits, though primarily indirect, exceed the minimal risks. Characterizing the effect of rare CNVs on a host of neuropsychiatric phenotypes should provide invaluable clues to the elusive pathophysiology of mental illnesses, which are common, debilitating, and costly diseases. Furthermore, if we detect the means to identify individuals with genotypes that predispose to such disorders, either with genetic signatures or with neurocognitive measures, this information could be used for a primary prevention strategy and possibly suggesting new approaches to treatment. Any novel insights into biological mechanisms that predispose individuals to mental illnesses could contribute to the development of novel diagnostic and therapeutic strategies.
Date proposal received: 
Thursday, 29 August, 2019
Date proposal approved: 
Monday, 2 September, 2019
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Developmental disorders - autism, Cognitive impairment, Mental health, Obesity, Computer simulations/modelling/algorithms, Cohort studies - attrition, bias, participant engagement, ethics

B3364 - Do womens expectations impact their birth experience and health outcomes - 03/09/2019

B number: 
B3364
Principal applicant name: 
Abi Merriel | PHS
Co-applicants: 
Abigail Fraser, Rebecca Pearson
Title of project: 
Do women’s expectations impact their birth experience and health outcomes?
Proposal summary: 

Expectations of birth are thought to have important effects on a woman’s experience of birth, and her satisfaction with her care. For her to have a positive experience, her priority expectations need to be met. If there is a gap between her expectations and the reality of her birth, it may impact on her psychological and physical wellbeing postnatally. This gap has been documented widely in the published literature when speaking to women and staff. However, there has been little opportunity to quantify this gap, or the impact it has.

This study provides a unique opportunity to quantify and explore the expectation-reality gap, by using data collected over two decades. The Avon Longitudinal Survey of Parents and Children has been following women who had children in the South West of England in 1991/2, it has now started to follow their daughters having their babies. This means that inter-generational trends can be explored.
This work will allow us to define the expectation-reality gap and explore what causes it, its effects and suggest ways for reducing it in the future.

Impact of research: 
It will enable us to quantify the gap, see if it has changed over time (between g1 and g2) and this understanding, along with understanding people's prior experience and other factors may allow us to establish possible determinants of the gap.
Date proposal received: 
Sunday, 1 September, 2019
Date proposal approved: 
Monday, 2 September, 2019
Keywords: 
Social Science, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Birth outcomes

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