Proposal summaries
B3118 - Genome-wide association study of anxiety and depression - 24/05/2018
Genome-wide association studies (GWAS) have been instrumental in highlighting associations between genetic variants and 1000s of traits. A recent GWAS of major depressive disorder (MDD) by the psychiatric genetics consortium (PGC) has recently identified 44 genetic variants associated with the disorder (Wray et al., 2018). We plan to include ALSPAC data from the mothers and the children in the next round of analysis for both forthcoming MDD and anxiety PGC GWAS. We will prepare summary statistics from the GWAS to be shared with the PGC and perform subsequent in cohort analysis. This will be a big step towards incorporating ALSPAC data into psychiatric genetics. The summary statistics will contain no identifiable information.
B3133 - Exploring the longitudinal effect of early maturation on physical and mental wellbeing - 14/06/2018
Research suggests that children who reach puberty early are at risk of poorer health and wellbeing. Such âearly maturingâ children also tend to take part in riskier health behaviours, such as smoking, drinking alcohol and risky sexual activity. However, most studies look at these links at a single point in time, which limits how confident we can be that early maturing causes poorer wellbeing. Few studies have looked at what factors may increase or decrease some of these risks. Our study aims to use the ALSPAC data explore three questions relating to the longer-term health risks of adolescents who mature early. The first builds on work we have done with parents, showing many believe we should judge whether or not a child is overweight differently if they are an early maturer, to avoid labeling them as overweight when they are not. This is a particularly important time to consider how we respond to children's weights, as it is the point at which over 95% of children in England are weighed and measured as part of the National Child Measurement Programme. Some parents have been strong critics of this process, so public health teams and parents alike are interested in exploring how we could interpret and use this information better. To explore whether it is appropriate to use the same means of classifying early and on-time maturers as overweight, we will apply an adjustment for maturity to our calculations of weight status for children at age 11, and explore whether this is a better way of predicting which children will have higher/lower future health risks at age 17 (including obesity, blood pressure and other risk factors). Second, we will compare which factor at at age 10/11 is the stronger predictor of wellbeing in later adolescence; being overweight, or maturing early. Finally, to explore what factors might help children to avoid some of the potential consequences of maturing early, we will look at whether childrenâs views of the strength and importance of their relationships with parents and peers influence the effect of being an early maturer on their wellbeing by the age of 17 (including depression, positive wellbeing, and risk behaviours such as smoking and drinking).
B3067 - DNA methylation and brain structure - 01/03/2018
Studies highlighted the role of genetic variation in brain anatomy (Hibar et al., 2015), but environmental factors might also be involved. The aim of the current study is to investigate to what degree epigenetic variation (DNA methylation) at birth is associated with brain structure across different ages. Secondary analyses aim to follow-up on promising methylation markers at later time points.
This project is part of a collaborative effort within the PACE consortium.
B3561 - Exploring how much complex trait variation is captured by DNA methylation in epigenome-wide association studies - 23/06/2020
There are small chemicals that can be added to or removed from genes. These chemical changes may be related to changes in various human traits. For example smoking may cause a decrease in the number of these chemicals present at one or many genes. Currently it is not fully understood how these chemical changes are related to changes in human traits and this project aims to assess how chemical changes across many genes may relate to changes in human traits.
B604 - The association of birth weight with physical and cognitive development of schoolchildren population based birth weight standards versus customised birth weight standards
Fetal growth is an important indicator of fetal well-being. The timely detection of pathologically impaired fetal growth is a prerequisite for the quality of antenal care, because of its apparent links to perinatal morbidity and mortality1, as well as adverse effects in childhood and later life2.
The prevalence of impaired fetal growth depends on the definition used. Population-based birth weight standards define 'small for gestational age' as the lowest tenth or fifth percentile, or as two standard deviations below the main birth weight for gestational age. This definition, however, includes 'natural' smallness. Therefore, it is essential to adjust for this normal variation in order to identify those infants who are pathologically small. Maternal weight, height, ethnic origin, parity and the infant's gender have all been found to be significantly associated with physiological variation in birth weight3. Professor J Gardosi developed the so-called customised growth charts, which are based on a new definition of fetal growth, thereby focussing on fetal growth potential, which takes in account the aforementioned variables (www.gestation.net).
Customised birth weight percentiles allow distinction between small, healthy newborns and those who are pathologically small3. Individually adjusted birth weight percentiles are more clearly associated with Apgar scores, perinatal outcome and neonatal morphometry indices than the unadjusted birth weight percentiles4. In this context, however, the association with long-term morbidity, such as cognitive and physical development, has never been examined.
ALSPAC is a longitudinal population-based cohort study, which includes all variables needed to analyse the long-term effects of intrauterine growth restriction on physical and cognitive health of schoolchildren.
B3069 - Early-onset depression characterising development and identifying risks - 06/03/2018
Major depressive disorder (MDD) is the most common mental illness and is the single leading cause of years lived with disability. Depression that begins early (by the early 20s) predicts particularly poor mental health and social outcomes and a chronic and relapsing course of symptoms over time. The strongest and most common risk factor for early-onset MDD is depression in a parent â this risk is likely to involve both environmental and inherited components.
In this project, we will characterise the trajectory of depressive symptomatology over adolescence and early adult life. We will test whether antecedent risk and protective factors identified in previous work influence the trajectory of symptoms over time. We will develop an algorithm to quantify individual risk for early-onset depression.
B603 - The effect of common disease associated genetic variants on transcriptomic and early life phenotypes
ALSPAC has pre-existing data on transcriptomic and phenotype variables related to disease. This is necessary in order to assess the effect of known disease causing variants in early life phenotypes.
B2561 - IgG antibody analysis in ALSPAC participants
B3070 - Hypothesis driven analysis of Avon Longitudinal Study early adversity and epigenetic modulation impacting on addiction - 06/03/2018
Why do people who experience early adversity have a higher chance of developing addiction? Do these experiences leave a biological scar? To answer these questions, we will use information from a group of babies, tracked since birth and who are now in their twenties. We will use new statistical methods and information on their early life, DNA and use of alcohol and tobacco as young adults, to identify which specific experiences change their biology and are linked to development of addiction.
B3005 - Hypertensive disorders of pregnancy and mental and behavioural disorders in offspring - 22/03/2018
There has been increasing research attention to the impact of in utero exposures to specific perinatal risk factors and their potential impact on diseases later in life. One of these is hypertensive disorders of pregnancy (HDP), a perinatal condition which affects up to 10% of pregnancies globally. Current evidence shows that HDP are associated with an increased risk of offspring cardiovascular, immune, metabolic disorders in later life. HDP are also responsible for various adverse perinatal outcomes such as preterm birth, low birth weight and intrauterine growth restriction, which are known risk factors for numerous mental health morbidities. In addition, HDP may also affect brain development via utero-placental vascular insufficiency and fetal malnutrition and lead to subsequent neurobehavioral difficulties. A lot of research has been conducted on the associations between HDP and cognitive functioning in offspring, however, evidence on the effect of intrauterine exposure to HDP on offspring mental and behavioural disorders is not well-established.
Two systematic reviews conducted by this team, one currently under review and the other one accepted by the British Journal of Psychiatry have shown that HDP had a negative impact for a range mental or behavioural disorders. Our finding showed that preeclampsia was associated with increased risk of offspring schizophrenia. The risk of Autism spectrum disorder was also 32% higher in offspring who had intrauterine exposure to preeclampsia as compared to those non-exposed. However, we found inconclusive finding on the effect of HDP and other mental and behavioural disorders, suggesting the need of further studies to progress this area of research. Following on from these findings, this PhD project aims to add to the existing evidence in a meaningful way by conducting a high quality, large sample, birth cohort study.
B3095 - Genome-wide association analysis of voting behaviour for Mendelian randomization - 11/04/2018
Genome-wide association studies (GWAS) have been critical in identifying thousands of genetic variants associated with complex traits and diseases. For certain complex traits however, it may be the case that there is difficulty in phenotypic measurement and this can lead to issues of statistical power. This is particularly problematic for behavioural phenotypes that may be predominantly determined by the environment, as is the case for educational attainment and well-being (Okbay et al., 2016; Okbay et al., 2016; Rietveld et al., 2013). Genetic analyses of such phenotypes can be hindered by the fact that individual SNPs have limited explanatory power and any associations found may not be causal or may be mediated by many other intermediate phenotypes (Krapohl et al., 2014). However, such studies have enabled the description of common genetic contributions to complex behaviours. Taken together, these GWAS results form a pool of genetic variants which may then be used in Mendelian randomization (MR) analyses; both looking at the effect of these features on outcomes but also the effect of outcomes on them.
This project will use newly collected data in the Avon Longitudinal Study of Parents and Children cohort to analyse voting behaviour. Firstly, we aim to conduct a GWAS on voting behaviour to discover any genetic variants associated with this complex trait. Additionally, we plan on considering the potential of using MR analysis to look at this behavioural phenotype. Specifically, we aim look at the effect of well instrumented risk factors on voting behaviour itself, i.e. âbackwards MRâ.
References
Krapohl, E. et al. The high heritability of educational achievement reflects many genetically influenced traits, not just intelligence. Proc. Natl Acad. Sci. USA 111, 15273â15278 (2014).
Okbay, A. et al. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses (vol 48, pg 624, 2016). Nature Genetics 48, 1591-1591 (2016).
Okbay, A. et al. Genome-wide association study identifies 74 loci associated with educational attainment. Nature 533, 539-+ (2016).
Rietveld, C.A. et al. GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment. Science 340, 1467-1471 (2013).
B3114 - Tracking Sleep Phenotypes 2 15-05-2018 - 234902 - 26/05/2018
Sleep matters to those who care for young children. The duration and timing of sleep can have a profound effect on a young childâs everyday behaviour, learning and health and also has a significant impact on the routines and wellbeing of the adults who provide his or her care. Yet there is surprisingly little evidence regarding the developmental function of early sleep patterns. Current understanding of the processes underpinning normative transition in sleep patterns, the prevalence of specific sleep phenotypes and persistence in sleep patterns across time is limited. This study will utilise genetic and environmental data, alongside longitudinal sleep data to examine the prevalence, persistence and developmental significance of childhood sleep phenotypes.
This knowledge will inform clinical, public health and educational policy and practice where management of sleep is an issue of controversy and also inform parenting practice where early child sleep behaviours can have a major impact on family functioning, parent well-being and child development.
B602 - EU Call - ENRIECO
We are writing to all the birth cohorts in Europethat we know have an interest in environment and health to ask them to participate in this coordinating action (list attached). We have already contacted quite a number of them and leaders in various projects such as GA2LEN, ESCAPE, HIWATE and they have agreed to participate. We would like you to read the text below and let us know if you are interested in taking part in this proposal. We need an answer very soon since the deadline for submission is 25 February. Besides extracting currently available information, we also hope to generate new information (but are limited to what can be done within a coordinating action and available funding) and we have proposed a number of ideas, but other ideas are welcome. Please indicate if you are interested in any asap (and correct any incorrect information), and whether you are willing to take the lead of any of the ideas/WPs.
B3071 - Parental alcohol use and offspring mental health - 06/03/2018
Previous research has shown detrimental offspring outcomes for children prenatally exposed to alcohol. However, uncertainty remains as to whether these negative offspring outcomes are due to the intrauterine environment, or environmental influences after birth, for example parental lifetime drinking. Further investigation is required to assess the impact of parental alcohol use on offspring outcomes. The research that has been previously conducted in this area has focused on academic outcomes, with less focus on the influence maternal and partner drinking may have on offspring mental health.
In addition, valid reports of alcohol use may be affected by under-reporting. Using parental methylation markers that are predictive of alcohol use, could be a more biologically valid method for assessing alcohol consumption. These methylation-based biomarkers were developed by Liu et al (2018) and are currently being validated by co-applicants (LZ) in ALSPAC. The proposed study will use such biomarkers to assess if this produces a stronger signal, in comparison to self-reported alcohol use.
B3096 - Does cognitive vulnerability modify the association between stressful life events and future depression - 11/04/2018
Several studies have found that the experience of stressful life events (ranging from more severe events, such as divorce or bereavement, to daily hassles, such as family-related obligations) can lead to symptoms of depression. However, the impact of these events varies, and not everyone who experiences a stressful event goes on to experience depression. Weâre interested in studying whether cognitive vulnerability, the tendency to make negative causal inferences about an event, can explain this difference (i.e., is an effect modifier). That is, the interpretation of the event, rather than exposure to the event alone, may be particularly important for predicting future depression. This study aims to investigate how the impact of stressful events varies between people, and why certain people go on to experience depression while others do not. These findings could inform potential targets for interventions which intend to prevent depressive symptoms.
B601 - Maternal reproductive history and the outcome of labour
B3072 - BIOMAP - Genome-Environment Interactions in Inflammatory Skin Disease - 06/03/2018
Atopic dermatitis (AD) and psoriasis affect a substantial percentage of the population. The mechanisms of disease, endotypes, co-morbidities of these diseases remain poorly understood. There is need to define the heterogeneous and homogeneous aspects of AD and psoriasis and identify the impact of environmental factors, genetic factors and molecular pathways. This will give rise to more precise targeted treatments. The BIOMAP project will bring together existing resources from European cohorts and industry to meet this challenge. ALSPAC, with it's rich longitudinal phenotyping and molecular data is well suited to contribute to this project.
B3097 - A meta-analysis of maternal smoking GFI1-CpGs and cardio-metabolic phenotypes in adults - 17/04/2018
Individuals exposed prenatally to cigarette smoke tend to have lower birthweight and have higher risks for a variety of detrimental health outcomes later in life. Cigarette smoke exposure is also associated with DNA methylation changes at gene GFI1, and recent evidence suggests that these changes may play a role in the lower birthweight of exposed infants. We would like to determine if there is evidence that these DNA methylation changes may also play a role in risk factors for other health outcomes of prenatal cigarette smoke exposure. We would specifically like to investigate factors related to cardiovascular and metabolic health.