Proposal summaries
B2395 - External validation of two studies on risk factors and prediction of childhood asthma - 26/02/2015
Background: We recently published two studies in which we developed a novel and robust tool for predicting asthma at school age in preschool children with wheeze or cough (REF1), and determined the association between breastfeeding and school-age lung function (REF2). The two studies made use of population-based cohorts from children of Leicestershire, United Kingdom.
Aim: We want to externally validate the findings of those two studies using the ALSPAC data set.
B2394 - Socioeconomic gradient of smoking comparing families where one or two parents smoke - 26/02/2015
We seek approval to repeat this analysis among the four English STELAR cohorts. Data requested are (at a given timepoint) socioeconomic status, number of smoking adults in the child's house, number of adults in the house (this addresses the issue of single parent families). In some of the cohorts, these outcomes may be available at more than one time point and this would allow us to see whether these observations are static or change over time.
B2393 - Using a genetic risk score for Coronary Artery Disease to investigate casusal influences on the metabolome - 19/02/2015
Multi-locus genetic risk profiles, or genetic risk scores (GRS) aggregate data from multiple SNPs to provide a robust genetic instrument for traits of interest. They are more powerful than single SNP GWAS scores as the use of multiple sites reduces the effects of pleitropy and minor allele frequencies. GRS have been developed for many conditions including CAD and obesity. They provide a useful genetic tool for probing the causal pathways of multifactorial diseases.
In this study we intend to use multiple GRSs developed from CARDioGRAMplusC4D SNPs as a genetic instrument of CAD to investigate associations between predictors of CAD and differences in metabolite profile in ALSPAC mothers and children. GRSs are the exposure variable in this case, and altered metabolite profile is the exposure. We will use a range of GRSs developed using varied SNP significance threshlds to demnstrate the robustness of GRSs a genetic instrument, while investigating the genetic influence on the metabolism at a pathway specific and global level.
Three GRSs for CAD will be produced based on highly strict, moderate, and lenient SNP significance thresholds using CARDioGRAMplusC4D data. A selection of the most significant SNPs will also be analysed seperately. The individual SNPs and strict GRS should reveal how specific SNPs or groups of SNPs influence isolated metabolic pathways related to CAD, while the more lenient GRSs demostrate the wider influence of genetic variants on global metabolism. These GRSs will be regressed against the top ten principle components of NMR metabolite data from mothers and children. Principle components that are significantly associated can then be deconstructed to reveal specific changes in metabolite levels. By using principle components instead of individual metabolite concentrations, the number of analyses is significantly reduced, and the components themselves may represent biologically meaningful metabolic pathways.
B2392 - Long-term outcomes of children with borderline personality disorder traits at 11-12 years - 19/02/2015
BACKGROUND: Recently there has been a growing body of research examining Borderline Personality Disorder in youth, i.e., childhood and adolescence (Hawes, 2014). Nevertheless, diagnosis in this age group remains controversial, partly due to concerns regarding the validity of the construct (Griffiths, 2011). Predictive validity reflects the degree to which BPD in youth is prognostic of future impairment, and is considered a crucial aspect of the validity of a construct (Van Os et al., 2009). While, a small body of literature has considered the stability of BPD symptoms over time, there are few studies that have examined the long-term clinical and psychosocial impacts of the disorder. The few studies that have reported negative outcomes in youth with BPD symptoms in community populations (e.g., Cohen et al., 2007; Winograd et al., 2008) utilised ad hoc, self-created assessments of BPD rather than established, validated tools. Furthermore, these studies did not consider the mechanistic pathways from early BPD symptoms to outcomes in late adolescence/early adulthood (e.g., do BPD symptoms increase risk of bullying exposure, subsequently heightening risk of depression symptoms?).
AIMS: To explore to what extent BPD symptoms at 11-12 years of age are predictive of future psychopathology and negative psychosocial outcomes, and to examine mechanisms via which increased risk manifests.
B2391 - Investigating putative risk factors for Alzheimers disease using Mendelian Randomization - 19/02/2015
The aim of this study to investigate the role of potential risk factors for Alzheimer's (AD) using Mendelian Randomization. Smoking, hypertension, increased body weight, dyslipidemia and type 2 diabetes have all been suggested as risk factors for AD but the results of epidemiological studies on them have been inconclusive.
In this project we are planning to use genetic variants that are robustly associated with the above exposures to test if they have a causal effect on AD through Mendelian randomization (MR). For blood pressure, BMI, lipids and type 2 diabetes the method of analysis will be a 2-sample MR in which the "reduced-form" estimate (the coefficient for the association between the IV and the outcome) and the "first-stage" estimate (the coefficient for the association between the IV and the exposure) are obtained from non-overlapping samples (Pierce and Burgess 2013). The instrumental variables for the MR analysis will consist of an allelic score calculated based on the results of independent genome-wide association studies of the above traits.
Polygenic risk scores will be calculated based on the results of published GWAS studies. These identified risk alleles will be used to calculate a polygenic score for each individual in an independent (target) sample (ALSPAC), corresponding to the mean number of score alleles (weighted by the logarithm of the odds ratio) across the set of SNPs, using PLINK. Standard linear regression models will be used to calculate coefficients for the association of the polygenic scores with the trait of interest in the ALSPAC target sample (first-stage coefficients). The reduced-form coefficients of the genetic variants/polygenic scores will be calculated in the International Genetics of Alzheimer's Project (IGAP) sample, which is independent of the target sample where the first-stage coefficients would be calculated. The IGAP sample is a collaboration of 4 groups in Europe and USA with approximately 60,000 individuals (either with AD or controls). Genetic data are available on all of them. We have obtained permission to perform this analysis in the IGAP sample.
B2390 - A study of origins correlates and determinants of locus of control - 12/02/2015
Locus of control (LOC) refers to the connections individuals perceive between their behavior and what happens to them. If they perceive such connections they are internally controlled; but if they see their outcomes as due to luck, fate or chance they are externally controlled. Even though researchers have found an internal LOC to be related positively to important aspects of human life including academic achievement, business success, physical and mental health and, in a United Nations study of 84 countries, to happiness, little is known about how internal and external LOC develop, their stability over time or whether they can be changed. Such information is important because over the past 30 years the average locus of control score for adults and children has become more external. We need to know why, and how to change that negative trend. The data to be used in this project include measures of LOC of parents during pregnancy and 16 years later, and of their children at ages 8 and 18 on over 12000 families. It is the only large study in the world that includes multiple assessments of LOC for children and their parents linked to relevant outcome measures. Statistical analyses will provide crucial information on how to foster internality and hence develop interventions.
B2389 - Coventry Reading Engagement Self-Belief and Teaching Project - 12/02/2015
The aims of this project are to examine the links between attitudes, self-belief and literacy behaviour and attainments. It is likely that these factors form a reciprocal relationship - i.e. success at reading means that a child believes that they can do well at reading, and they are therefore motivated to a) try harder when decoding unknown words and b) read for pleasure. In turn, both of these activities are likely to improve reading attainments. Previous studies have indicated a correlation between these areas but it is difficult to establish the cause of this correlation. Large-scale longitudinal work is required to assess whether these relationships exist and whether they vary with ability or age (for example, it could be that self-belief is more important for poor readers or in adolescence)
B2382 - Defining the mitochondrial DNA genetic bottleneck by studying the inheritance of low-level heteroplasmy between mothers and offspring - 12/02/2015
Our aim is to study low-level heteroplasmy in a large number of mother-child pairs using DNA samples already extracted for ALSPAC genotyping studies. We estimate that greater than 1000 pairs will be required to carry out a meaningful experiment, based on our pilot data from existing data sets. We will use ultra high depth next generation sequencing (IlluminaMiSeq) to carry out this experiment, allowing the detection of greater than 0.5% heteroplasmy from a standard genomic DNA sample. Statistical analysis will be carried out by Dr Ian Wilson at the Institute of Genetic Medicine. We will model the genetic bottleneck as done previously,7 and determine whether the background mtDNA sequence influences the rate of segregation of mtDNA heteroplasmy in healthy controls. We will then compare this to data acquired from humans transmitting pathogenic mtDNA mutations to determine whether they behave differently.8 This will advance our understanding of the underlying biology, and will be directly relevant to current work aimed at preventing the transmission of mtDNA mutations.
B2386 - The development of an integrated OMICS signature that links in utero air pollution to growth and cardiovascular health - 05/02/2015
Hypotheses:
In utero particulate matter exposure has been linked to adverse pregnancy outcomes such as low birth weight and intrauterine growth retardation, which in turn have been linked to adult cardiovascular disease and metabolic abnormalities such as obesity, hypertension, insulin resistance and glucose intolerance. These findings suggest that adverse intrauterine conditions that promote reduced birthweight, such as air pollution exposure, may also promote lifelong susceptibility to cardiovascular diseases. Although it is becoming clear that in utero exposure to environmental stressors plays a role in fetal metabolic programming, the mechanisms are still unclear. The investigation of OMICS measurements at different molecular levels provides an insight into the biological pathways involved in the process linking in utero air pollution exposure to early life growth and cardiovascular development.
Aims:
The objective of this project is to derive a molecular pathway linking in utero air pollution exposure to fetal and childhood growth and to study potential consequences on the development of the cardiovascular system. I address four main objectives:
1) The investigation of prenatal and postnatal growth in association with in utero air pollution exposure.
2) The derivation of biomarkers (within in each OMICS level) linking prenatal air pollution exposure to growth trajectories in the first years of life.
3) The identification of common patterns across different OMICS levels (cross-omic analyses) in order to get an insight into the biological pathways involved in the association between in utero air pollution exposure and growth.
4) The investigation of the role of early life growth and the derived OMICS signature in the association between prenatal air pollution exposure and cardiovascular endpoints in childhood and early adulthood.
B2385 - Genome wide association study for physical activity and sedentary behaviour - 05/02/2015
This analysis will form part of an expanded meta-analysis for self-reported moderate and vigorous leisure time activity and sedentary behaviour. Our first goal is to capture a dichotomous trait corresponding to moderate and vigorous leisure activity. Such activity would not include occupation-related activity (i.e. shoveling, heavy-lifting) and/or light leisure activity (i.e. walking, gardening). The second goal is to capture all aspects of sedentary behaviour for which we defined four traits; three dichotomous traits, reflecting sedentary behaviour at work, home and during commuting, and one continuous trait: TV viewing.Separate GWAS analyses will be run for male and female offspring and the mothers. Covariates included in the models are age and body mass index.
B2384 - Novel Epidemiological Methods to Infer Causal Effects of Risk Factors on Neuropsychiatric Cardiovascular Disorder - 29/01/2015
BACKGROUND
This project focuses on developing methodological applications for analysing "omics" data resources (genome-wide genotypes, metabolomics, the epigenome), an area that has exciting prospects for observational epidemiology (Brion et al., Curr Epidem Rep 2014). We have previously published work indicating that genome-wide allelic scores can be used to data-mine large numbers of associations between biological intermediates and disease-related outcomes and screen for potentially causal relationships (Evans, Brion et al., PLoS Genetics 2013). We would like to build on this work and investigate the use of similar allelic scores in studies based on metabolomic and epigenetic measures. In addition, we would like to develop and implement novel applications of Mendelian Randomization to these genome-wide genotype, epigenetic and metabolomic measures, such as by implementing bidirectional MR (Welsh et al., J Clin Endocrin Metab, 2010) and MR for mediation (Relton & Davey Smith, IJE 2012). We would then implement these methods to test causal relationships involving blood methylation (epigenetic) markers and metabolomic measures.
AIMS
1.To develop and test novel epidemiological approaches, such as Mendelian Randomization and data-mining approaches, that exploit the availability of high throughput biological data (genome-wide single nucleotide polymorphism (SNP) data, epigenetic, metabolomic).
2.To apply these novel methods to infer the causality between risk factors, such as environmental exposures and biomarkers, with cardiovascular and psychological outcomes, through potentially mediating epigenomic and metabolomic pathways.
B2383 - MR of blood pressure and NMR metabolites - 29/01/2015
Higher blood pressure is associated with increased cardiovascular and renal disease and premature mortality. Although some of the biological pathways and disease endpoints linked to blood pressure changes are well understood, a large number of them remain unexplained. Higher blood pressure is associated with other risk factors for cardiovascular and renal disease, including dyslipideamia, hyperglycaemia and insulin resistance (referred to collectively as metabolites) and higher levels of inflammatory markers, which might mediate any causal effect of higher blood pressure on later disease. But associations with these other risk factors and their joint role in causing later disease could reflect several different alternatives:
1.Blood pressure causes variation in these other risk factors and via these effects causes later CVD and other diseases.
2.These other risk factors cause variation in blood pressure and the primary causal agents are the metabolites/inflammatory markers with blood pressure being more downstream and proximal to disease endpoints.
3.There is a bidirectional causal relationship between BP and metabolites/inflammatory markers
4.There is no causal relationship between blood pressure and metabolites/inflammatory markers, but rather the association is confounded, for example by socioeconomic position, lifestyle characteristics and obesity. .
In preliminary analyses, we have already identified a number of metabolites from the NMR platform that are strongly correlated with BP. We want to extend this work by using Mendelian randomization (MR) to determine whether the relationships are causal and if so which direction they are in (i.e. to distinguish which of the 3 alternatives listed above is most likely).
With UCLEB we can increase the number of available individuals to more than 30 000, all with blood pressure measurements, GWAS or other array genotyping, and NMR metabolites and inflammatory markers.
We will use the known BP genetic instruments to assess whether BP is causally related to the metabolites and inflammatory markers (alternative 1 or 3 above vs 4) and metabolite instruments from recent GWAS to test whether metabolites are causally related to BP (alternative 2 or 3 vs 4).
B2381 - Trajectories of Brain Injury in the ALSPAC cohort - 22/01/2015
Aims:
The aim of the study is to investigate the trajectories of traumatic brain injury (TBI) from childhood into adolescence using the ALSPAC cohort. In particular the study will explore the impact that a single TBI event and recurrent TBI events will have on aspects of social cognition, risk behaviour engagement and general cognition. The control groups will include participants who have had a broken bone/fracture and also participants who have never had an injury. There will be exploratory analyses conducted to see whether the detrimental effects of recurrent TBI events are greater than for a single TBI event.
Social cognition can be broadly conceived as the ability to understand other people through emotion perception and empathy and also by inferring the beliefs, intentions and feelings of others 1 Following a TBI event, many facets of social cognition have been shown to be impaired, such as the recognition of facial emotional expressions 1-4; however, current evidence is hampered by small, heterogeneous sample sizes 1.
Engagement in risky behaviour such as substance use has been implicated as an outcome of TBI 5-8. One large cohort study demonstrated that a TBI injury requiring hospitalisation between the ages of 0-5 years old increases the risk for adolescent substance use 5; while findings from another birth cohort indicate that drinking to intoxication is more common among 14 year olds who have experienced a TBI compared to those who have not 6. Ilie and colleagues 7 found that high school students who had experienced a TBI had higher odds of using illicit substances, were twice as likely to consume hazardous amounts of alcohol and were at greater risk for cannabis dependence. Likewise, in a group of incarcerated youths, those with a TBI history were found to be more likely to engage in risky alcohol and cannabis use as well as weekly use of another illicit drug prior to incarceration; this was also the case for participants reporting multiple TBI events9. In comparison to a single TBI event, individuals who have experience two or more TBI events have reported more frequent alcohol, tobacco and illicit drug use 8.
The sequelae of TBI is characterised by cognitive problems 10. Corrigan and colleagues 11 compared different characteristic profiles of TBI histories in persons with substance use disorders and found that a TBI event occurring between the ages of 6-10 may lead to slower processing speed and a greater number of cognitive complaints, while working memory was more impaired in those with a severe adult TBI, mild adolescent injury or multiple mild injuries. Elsewhere, processing speed has been found to be more impaired in participants with more than one TBI resulting in loss of consciousness than in participants who have had just one TBI 8.
Predictors of TBI from birth cohort studies include male gender 6,12, parental alcohol misuse 6, a punitive parenting style and the number of adverse life events experienced by the family 12. These will be controlled for in the proposed study.
B2380 - Metabolic effects of statin therapy longitudinal and genetic evidence - 22/01/2015
Aims: Statins are first-line therapy for cardiovascular prevention, yet the effects of statins on lipoprotein subclasses and circulating fatty acids remain unclear. Statin usage may further influence other pathways beyond lipid lowering. We aim to assess the detailed metabolic effects of starting statin therapy by quantitative NMR metabolomics profiling in 4 longitudinal cohort studies with 2 20 years of follow-up (including ALSPAC mothers).
Hypotheses: Starting statin usage is associated of all LDL lipids to a similar extend, but deviating patterns may be observed for detailed VLDL subclasses and their cholesterol and triglyceride levels. We hypothesize that statin lower all fatty acid concentrations, but more so for omega-6 fatty acids than for omega-3 and mono-unsaturated fatty acids. Finally, we will assess the effects of statins on numerous small molecules (including amino acids, glycolysis precursors and ketone bodies) to examine potential non-lipid effects of statins. Longitudinal analyses will be corroborated by genetic analysis, using established genetic instruments to proxy the effect of the statin target: HMGCoA reductase inhibition. Analyses: Associations with starting statin usage with NMR-based metabolite data will be meta-analysed in 4 cohorts including ALSPAC mothers. Genetic associations of 2 SNPs in HMGCR will be tested in 9 population-based cohorts including ALSPAC children & mothers.
Confounding variables: Longitudinal analyses will be adjusted for age and sex. Genetic analyses will be adjusted for age, gender, and population structure if available.
B2379 - Using parents experiences to investigatehow to prevent high risk primary school children developing antisocial and criminal behaviour - 22/01/2015
Aims:
The study aims to investigate what interventions, services or policies could help prevent primary-school
children with conduct problems, living in high risk families, from developing antisocial and criminal
behaviour as they grow older. The study aims to take a broad view as to what could help and has therefore
been designed in two phases. Phase One is a qualitative longitudinal interview study with ten families to
build hypotheses about what might help. I would like to use ALSPAC data in Phase Two of the study. In
Phase Two the aim is to access longitudinal data on larger samples of similarly high need families that
include a child with behaviour problems to explore issues arising from the qualitative interviews. I aim to
explore possible modifiers (referred to as 'modifying factors') of the association between risk factors and
outcomes (antisocial and criminal behaviour in later adolescence). The aim is not to identify pre-existing
protective factors but to look at changes occurring between beginning primary school and adolescence
which appear to indicate a move onto a more positive trajectory. Outcomes will be compared for matched
groups of children who have or have not experienced the modifying factor/exposure. The matching will
be based on risk factors for the ultimate outcomes of interest, i.e.antisocial and criminal behaviour at ages
16+, and it is proposed that propensity score matching be used. This matching will make use of existing
knowledge about factors associated with resilience in an effort to control for these and isolate the impact
of later occurrences (e.g. Bowen, Heron, Steer, & El Comy, 2008). The method is imperfect for looking
at effectiveness of intervention but provides one route to addressing the possibly serious consequences of
prioritising easy-to-research interventions.
B2378 - Do social cognitive deficits at an early age predict substance abuse problems at later ages - 22/01/2015
Aims
The aim of this project is to explore whether early deficits in social cognition are associated with later substance abuse problems. Previous studies have shown that impairments of social cognition are common amongst individuals who abuse substances. For example, alcohol (1), opiate (2), and tobacco (3) use have all been associated with impaired recognition of facial emotional expression. Additionally, these impairments persist when smokers become abstinent (4) and when alcoholics are detoxified (5), suggesting addicted individuals' may rely upon substances to aid their social cognitive abilities. Furthermore, these deficits are sustained up to ~2 months into sobriety (6). This raises the question of whether it is substance abuse itself that cause these deficits, or whether these deficits lead to substance use (for example, to enhance certain aspects of social cognition).
B2377 - Clarifying the SES-Health Gradient The Case for an Epigenetic Mechanism - 15/01/2015
Socioeconomic status (SES), an individual's position in society, is defined by a number of interrelated individual, structural, and environmental factors (e.g., income, education, neighborhood). We have known for some time that an SES-health gradient exists (i.e., low SES associated with poor health, high SES associated with good health) but exactly what it is about SES that gets into the body to shape health is still unclear. Yet, understanding these biological mechanisms will be critical for minimizing the costs of low SES for health as well as maximizing the benefits of high SES for health. This lack of clarity may reflect variations in the measurement of SES, a lack of recognition of factors that influence for whom the SES-health gradient will hold and, until recently, limited availability of epigenetic data. We contend that in order to clarify how SES might get into the body to influence health we should first, determine which indictor(s) of SES, and in which combinations, might work to influence biological mechanisms and second, we should consider whether there might be specific factors that influence for whom SES might get into the body to influence mental and physical health. We believe that psychological well-being is an excellent candidate. The key biological mechanism that we will focus on in these relationships is DNA methylation.
B2376 - Child PTSD and longitudinal adverse outcomes - 15/01/2015
The aim of the proposed study is to provide information regarding potential adverse outcomes associated with trauma exposure and posttraumatic stress symptoms (PTSS). Existing data suggest that youth trauma exposure and/or PTSS are associated with adverse outcomes in several domains including: substantially increased odds of objective physical disease states (Seng et al, 2004); poorer educational attainment (Hurt et al, 2000); engagement in substance use and other risky behaviours (Begle et al, 2011); and increased likelihood of antisocial behaviours/involvement in the youth juvenile justice system (Ford et al, 2010; Abram et al, 2004). However, existing studies are predominantly cross-sectional raising issues of cause versus consequence; or they have focused on specific populations or types of trauma, limiting the generalisability of the findings. The longitudinal data afforded by the ALSPAC cohort would allow for an analysis of whether youth trauma and PTSS contribute to later adverse outcomes, even once concurrent problem levels are taken account of.
B2375 - Genetic and environmental risk factors for the development and maintenance of PTSD with the ALSPAC cohort - 15/01/2015
B2364 - Genetics and genomics of polycystic ovary syndrome and related sub-phenotypes - 08/01/2015
Polycystic ovary syndrome (PCOS) is a complex disorder causing metabolic disturbances and reduced fertility in women of reproductive age, the definition of which is an on-going debate among researchers in the field. PCOS is characterized by hyperandrogenism, chronic anovulation and glucose homeostasis. It is one of the most common endocrinopathies affecting 5-15% of women of reproductive age worldwide and causes more than 75% of cases of anovulatory infertility. The etiology of PCOS is largely unknown though contains a clear genetic component. However, to date, the only available PCOS genome-wide association data have reported 11 significant loci and come from a study of Han Chinese individuals. We, in the PCOS consortia, that consists of 15+ research teams, are gearing up to perform their first and second waves of genome-wide and also exome-wide association meta-analyses in up to 15,000 cases and 80,000 controls of European decent, as well as extensive pathway analysis and genomic follow-up. The overall aim is to identify genetic variation, transcripts and pathways that are associated with PCOS susceptibility (and related subphenotypes). We will perform case:control analysis for PCOS itself and for some of the related subphenotypes which present as dichotomous outcomes. We will in parallel perform quantitative analysis for subphenotypes that are quantitative traits. We will adjust for standard confounders like age and also investigate what effect related phenotypes like BMI have on the PCOS results by performing both adjusted and unadjusted analysis. The genetic and genomic discovery paired with biologic follow-up, holds the promise of bridging and linking knowledge from the metabolic and gynecologic disease fields and yield clinically useful information.