Proposal summaries
B3384 - Variants trait-causal via their effect on VDR binding - 13/10/2019
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.
B3383 - Environment-wide association study for adiposity in ALSPAC - 27/09/2019
B3382 - Eating disorders and anxiety Mapping developmental trajectories and their genetic underpinnings - 27/09/2019
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.
B3381 - Early Childhood Shyness Psychosocial Experiences and Trajectories of Cardiovascular Risk Factors across the Life-Course - 24/09/2019
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 diathesisâstress 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. LewisâMorrarty, 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.
B3380 - Dissect the interaction of age at first marriage and associated sociological traits with a genetic approach - 24/09/2019
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 peopleâs 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.
B3378 - Lectin Histochemistry and Glycocalyx Measurement of the ALSPAC Placentas - A Feasibility Study - 04/10/2019
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.
B3377 - Is genetic predisposition to osteoarthritis associated with musculoskeletal pain in adolescents - 20/09/2019
B3376 - Evaluating diet at age 30 ALSPAC-G1 - 19/09/2019
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.
B3372 - Changes in metabolomic measures attributable to body composition during puberty and young adulthood - 16/09/2019
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.
B3373 - Prenatal Hg exposure and DNA methylation consortium analysis - 16/09/2019
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.
B3374 - Is the polygenic risk score for Alzheimers disease and cognitive function manifest in childhood/adolescent brain structures - 16/09/2019
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.
B3375 - Understanding the causal pathways between childhood maltreatment and cardiovascular disease - 16/09/2019
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.
B3371 - Nutritional biomarker in adolescence and adulthood and associations with socioeconomic trajectories and cardiometabolic outcomes - 10/06/2020
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 (age 13 to 30) 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, changing lifestyles, and is the time when adult behaviours, including adult dietary patterns, are developed and established. Understanding the factors that influence development of diet is an important first step in developing strategies to change behaviour.
There is limited data available on changes in diet through adolescence and early adulthood in the UK. Self-reported diet data is notoriously biased, however recent advances in biomarker research have established several biomarkers that are reliable indicators of consumption of specific foods and food groups. In this project we will analyse blood samples from the ALSPAC cohort, taken at age 13, 15, 17, 24 and 30, to derive measures of intake of fruit and vegetable, dairy and fish intake.
We will use these measures of diet to assess (1) changes in diet across adolescence and early adulthood, (2) associations between socioeconomic changes in adolescence and early adulthood and changes in diet, (3) the role of changes in diet in pathways linking socioeconomic determinants and risk factors for cardiovascular disease.
B3370 - ALSPAC families - 20/09/2019
This proposal will look to obtain DNA samples from ALSPAC participant (G1) family members, including fathers and siblings.
B3369 - Social causes and consequences of depressive symptom and high BMI comorbidity - 21/09/2019
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.
B3368 - Maternal postnatal stress and pathways to childhood growth - 09/09/2019
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 childâs infancy and toddlerhood is related to the childâs 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.
B3367 - Maternal nutritional status in pregnancy and offspring Autism Spectrum Disorder a social perspective - 21/09/2019
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 childâs 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 childâs risk of developing autism. The project will apply âcausal methodsâ which are statistical methods which better estimate causal relationships from observation data when compared to conventional methods with measure âassociationâ. 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.
B3366 - Non-alcoholic fatty liver disease and cardiac function in young adults - 06/09/2019
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.
B3365 - Specifying Risk for Driven Exercise in Eating Disorders - 02/09/2019
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.
B3363 - Large-Scale Evaluation of the Effect of Rare Genetic Variants on Psychiatric Symptoms and Cognitive Ability - 02/09/2019
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 âhitâ of the CNV. However, our understanding of the impact of CNVs on psychiatric symptomatology, RDoC domains and neurocognitive ability (termed âdimensional neuropsychiatric phenotypesâ) 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.