Proposal summaries
B208 - Regulation of fasting glucose and birthweight the impact of variation in the glucokinase gene - 01/01/1900
Variation in fasting glucose concentration (FPG) is important for human health. In the normal range FPG is associated with risk of type 2 diabetes and ischaemic heart disease independently of obesity. In pregnancy maternal FPG concentration is an important independent determinant of birth weight in non-diabetic mothers. There is evidence that the regulation of FPG has a strong genetic component.
The main regulator of FPG concentration is the enzyme glucokinase. Our preliminary data shows that common variants in the promoter region of the glucokinase gene are associated with FPG and fetal growth. The minor allele at GCK-30, present in 30% of the UK population raises FPG by0.06 mmol/l (0.04-0.11), p = 0.003; and, when present in the mother, birth weight by 64g (25-102), p = 0.001. We have next shown that variation, further upstream (rs3757840) of the gene, and with no obvious functional role, has a similar, but independent effect on FPG.
In this project we propose to test comprehensively the hypothesis that common genetic variation in GCK alters FPG and birth weight. We will use the latest approaches for capturing the important variation across a gene together with DNA resources from 28,799 mother-child pairs. This approach will establish, if our hypothesis is true, a definitive genetic component to the aetiology of normal variation in FPG and birth weight.
B693 - Confirmation of Genome-Wide association findings for obesity and obesity related traits - 01/01/1900
Recent advances in high-throughput genotyping technologies, coupled with the development of massive databases such as the International HapMap Project that catalogues millions of SNPs (single nucleotide polymorphisms), have set the stage for genome-wide association studies. Genome-wide association (GWA) studies are designed as two- or three phased studies. The first phase requires a dense set of hundreds of thousands of SNPs across the human genome, genotyped in a large sample of well-characterised individuals. The second and third phases aim to replicate and fine-map the most significant findings of the first phase in other large cohorts. Eventually, genome-wide association studies will identify new gene variants, previously unanticipated, that will contribute to a better understanding of the etiology of common disease and complex traits.
Our GWA study is designed for the identification of new, unanticipated gene variants that contribute to variation in obesity as well as BMI, and related traits, including age at menarche. This GWA study is undertaken as a collaboration between the MRC Epidemiology Unit and the WT Sanger Institute (Dr Ines Barroso) using a case-cohort design. The 1713 cases (defined as those with a BMI greater than 30kg/m2) and a random control cohort of 2200 individuals have been selected from the EPIC-Norfolk prospective cohort study, a population-based cohort of 25.663 men and women aged 40-79 years recruited in Norfolk, UK between 1993 and 1997. All 3913 individuals have been genotyped for two dense SNP-chips; i.e. the 500K GeneChip Mapping Sets of Affymetrix and the Sentrix HumanHap300 BeadChip of Illumina. We are currently analysing associations of this genome-wide data with obesity as a dichotomous outcome in the case-cohort study and with BMI, age at menarche and various metabolic variables as quantitative traits within the cohort study.
In order to increase the power to detect true positive signals Phase 1 will be expanded by performing a meta-analysis of two other cohorts with similar GWA phenotypic and data. We have recently established a long term collaboration with Vincent Mooser (GSK) and colleagues, who have performed a GWA study in the GSK-Lausanne cohort. The GSK-Lausanne population is comparable to the EPIC data as it is a cohort study of 6,205 Europid men and women from Lausanne, aged 35-75 years. This collaboration has a general aim to identify genes that contribute to various metabolic traits. The summary statistics from these GWA studies on these traits will be shared and meta-analysed at the MRC Epidemiology Unit.
Key to genomewide association studies is replication of the initial findings in more populations with similar characteristics. New genes identified by GWA will be taken forward for rapid confirmation studies in several large cohort studies. In addition to ALSPAC, these include a second equal sized case-cohort study within the EPIC cohort (n=3,900), the MRC-Ely study (n = 1,700), the MRC-Fenland study (currently n = 2,000), the Hertfordshire study (n = Outline 3,000), and the European Youth Heart study (n = 2,700).
B935 - Antioxidant gene modification of the effect of prenatal paracetamol on asthma - 01/01/1900
Having identified a possible interaction between a maternal Nrf2 SNP and prenatal paracetamol exposure on asthma risk, we would like to carry out further genotyping to confirm additional gene*paracetamol interactions.These include an additional Nrf2 SNP; GCL (relevant to glutathione synthesis); Melatonin receptor MTNR1b (melatonin is a powerful antioxidant linked to paracetamol toxicity); CYP2E1 (relevant to paracetamol toxicity).
B415 - BLANK - 01/01/1900
Genetics, Speech and Language
B2438 - Metabalomic profile of alcohol consumption in adolescents - 01/01/1900
Aims:
1) To assess the how alcohol consumption affects metabalomic profile
2) To identify a genetic instrument for metabolites that are associated with alcohol consumption
B929 - Bladder Control in Bilateral Cerebral Palsy a Population-based Study - 01/01/1900
With regards to children with cerebral palsy, very little information about attainment of urinary continence is available. The long-term physical, psychosocial and financial burden of incontinence in the cerebral palsy patient is considerable and in order for the paediatrician to begin addressing these important issues further information regarding the normal attainment of bladder control in children with cerebral palsy has to be established. This is the aim of this study.
METHODS
The original study:
The data in this study originate from a previously published population based study (Scrutton and Baird 1997) which established a cohort of children with bilateral cerebral palsy born from 1989 to 1992 (inclusive) to mothers resident at the time of birth within the geographically defined area of the South East Thames Regional Health Authority (SETRHA) in south east England in order to monitor the children's hip development up to the age of 5 years using serial hip X-rays. It is for this reason that children with hemiplegic cerebral palsy are not included. The South East Thames Health Region at the time had a population of 3.65 million with 205 958 live births during the study period. A comparison of epidemiological data between SETRHA and England and Wales showed similarities between the two. For original methods of recruitment, details of ethical permission and consent, and diagnosis of cerebral palsy the reader is referred to the original paper (Scrutton and Baird 1997).
Present study:
For the purposes of this study, a questionnaire containing details of the child's attainment of bowel and bladder control by day and night, as well as parental concerns or presence of abnormal bladder and bowel symptoms, was used. This questionnaire was administered by physiotherapists to the parents of the children sometime after their third birthdays together with other information required for the original study at that time. The parents/carers were asked to post the questionnaire back to the investigators in a self-addressed envelope. Almost all were returned between the third and fourth birthdays, although one was returned at 5 years. After 5 years of age, a visit was carried out by the original authors, mostly in the child's home together with the parents. A number of parameters were obtained during this visit including confirmation of the diagnosis of cerebral palsy, the nature of the motor disorder including distribution (quadriplegia, diplegia, double hemiplegia and paraplegia) and type (hypertonia, ataxia, involuntary movements, hypotonia and ataxic diplegia after Hagberg 1985), learning level (as ascertained from other medical or educational sources), severity of disability and the age of attainment of bladder and bowel control by day and night. For funding and practical reasons these visits were carried out between 7 to 9 years of age. A closing visit questionnaire, including further continence data was completed some time after the age of 14 years (up to age 19 years) in this cohort, in a similar manner to the above. Whilst the stated aim of this study is to establish the age of attainment of bladder control in subjects with cerebral palsy, data on bowel control have been analysed simultaneously for two reasons: availability and therefore ease of analysis together with bladder data, and the fact that bowel and bladder control are physiologically and developmentally linked, and have been shown by previous authors to follow each other sequentially (Stein and Susser 1967, Largo and Stutzle 1977, Crawford 1989).
Definitions:
Cerebral palsy has been taken to mean all non-progressive disorders of movement and posture caused by a defect or lesion in the brain by 15 months chronological age, and not part of another syndrome which has a motor component. Those with syndromes including a high risk of skeletal or joint anomalies and children whose disorder had no clinical trunk or lower-limb involvement were also excluded. Each child's paediatrician provided written confirmation of the diagnosis at 5 years of age.
Bladder and bowel control was defined as being reliably continent with socially acceptable toileting even if help was required.
Definitions of learning level, severity of disability and type (Hagberg 1989)/distribution of motor disorder are defined and classified according to the Gross Motor Function Classification System (GMFCS).
RESULTS
The results of bladder and bowel continence attainment will be presented in a longitudinal manner together with details of any abnormal patterns which will be discussed. The data collected at three years and eight years of age have already been analysed and analysis of the data available at 16-19 years of age is currently awaited. The only available control comparison group is a series of international studies which are for the large part retrospective, cross-sectional and not population based and neither are they collected from a British population with a similar birth date.
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.
B600 - Investigation of the role of bone size relative to body size in the pathogenesis of fractures in childhood
Aims
(i) Whether changes in bone size relative to body size contribute to the increased risk of fracture during puberty will be established, by examining the relationship between longitudinal changes in these parameters across puberty.
(ii) Whether the higher risk of fracture in pubertal boys compared to girls is related to gender differences in bone size relative to body size will be determined.
(iii) Whether small bone size relative to body size represents a stable trait that once established in childhood persists following puberty will be investigated.
B2714 - Latent disease risk for coronary artery disease sample based recall by genotype for detailed metabolomic screening - 03/05/2017
This project looks to understand how genetic predisposition to coronary heart disease is manifest in early life. The idea here is that although young people have not yet presented with adult/mature disease, there may be metabolic signatures of later life disease risk which differ by genetic factors and are which mark carriers of these genotypes as different. Importantly, showing differences in metabolic profile at earlier ages may lead to the ability to target and modify these factors to aid later life disease risk.
B3073 - Development of Caetanos discontinuity endogeneity test and application to the effect of vegetarianism on health - 06/03/2018
Observing that an exposure (e.g. higher meat intake) is associated with an outcome (e.g. higher BMI) does not necessarily mean that the exposure caused the outcome. Other factors may "confound" the association by causing both the exposure and the outcome. Such confounding can be difficult to detect if the factors responsible have not been measured. A recent study proposed a method to detect confounding by unmeasured variables if they cause discontinuous variation in the exposure. We intend to develop this method further and apply it to the question of whether eating meat affects a person's BMI. The method should tell us whether simple observation of people's meat intake and BMI reveals the causal effect or is confounded.
B3109 - Predictive genomic classifiers for the risk assessment of common learning disabilities in children - 29/05/2018
Learning disabilities are common disorders characterized by unexpected difficulty with a specific mode of learning in the context of adequate intelligence and academic opportunity. The high prevalence of these disorders in the general population represents a costly burden to the educational system and affected individual are often at risk for long-term adverse psychological and socioeconomic outcomes. Intervention programs work, but are more effective when tailored to individuals and administered earlier in life. The pre-symptomatic detection of individual who are at risk of developing learning disabilities, and who are more likely to benefit from early intervention, is therefore an important diagnostic opportunity with major economic and societal implications. The objective of this project is to evaluate the diagnostic performance and predictive value of genetic variants associated with learning disabilities in the ALSPAC cohort.
B3091 - Solids and formula feeding as risk factors for morbidity in infancy - 29/03/2018
A recent large scale evidence review has demonstrated the importance of exclusive breastfeeding to 6 months with partial breastfeeding continued though the first year of life, but few studies have considered whether starting solids earlier than 5-6 months, but with continued breastfeeding, increases the risk to health or causes earlier cessation of breastfeeding.
The review also found new evidence from the developing world that giving extra iron in children who are not short of iron may cause increased infections and slower growth. Formula milks which have higher iron content than either breast milk or doorstep milk are currently recommended from 6 months to 12 months where an infant is not breastfeeding to prevent iron deficiency anaemia and iron fortified follow on formulas are widely advertised. However the potential risks of iron supplemented formula milks have never been examined.
B3099 - Lung function growth and residential greenness in the ALSPAC cohort - 19/04/2018
There is increasing evidence that residential greenspaces (proximity to and amount of green spaces and vegetation around a person's home) may be associated with various health outcomes, including increased physical activity levels and respiratory health outcomes, such as asthma. As lung function is associated with both physical activity and asthma, it could thus also be associated with greenspaces. However, to date, no study has examined whether an association between residential greenspaces and lung function exists in children, and what potential pathways may be playing an important role. Using the ALSPAC data, this study aims to fill this research gap.
B3110 - Computational Models for the Prediction and Prevention of Child Traumatic Stress - 29/05/2018
More than 20% of children will experience a traumatic event before they are 16 years old. Of those who experienced a trauma, a sizable minority will develop Posttraumatic Stress Disorder (PTSD), and other deleterious developmental, health, and psychiatric consequences (herein called Child Traumatic Stress). To diminish the considerable burden of traumatic stress on children and their families, the capacity to predict a childâs risk and to intervene to diminish this risk is extremely important. The literature on prediction of child traumatic stress from risk factors has yielded only modest results and - of those risk factors found to be predictive â it is difficult to determine which represent processes would lead to a diminution of risk, if effective intervention were applied. Almost certainly, traumatic stress results from a complex set of interacting bio-behavioral and social environmental processes, unfolding in specific ways over the course of development, and related to specific aspects of the traumatic exposure. Our project aims to apply state-of-the-art Machine Learning predictive modeling methods with a wide array of risk variables from the ALSPAC data set to generate reliable and accurate predictive models of PTSD and other child traumatic stress outcomes. We also aim to apply advanced non-experimental causal discovery algorithms to discover potentially remediable processes leading to traumatic stress outcomes that may reveal new opportunities for preventative intervention.
B3075 - Genetic vulnerability to schizophrenia and major depressive disorder and the risk of childhood adversities - 08/03/2018
Since the recent publication of large genetic studies to identify genetic risk factors for debilitating psychiatric disorders such as schizophrenia and depression, it has been possible to use this genetic information to study to what extent genetic risk to, for example, schizophrenia or depression predict risk for psychiatric problems prior to the development of clinical disorders. Particularly interesting is to investigate how a child's genetics make him or her more vulnerable to the exposure of stressful life events. Moreover, it is still unclear to what extent this relationship mediates the association between genetic risk and childhood psychiatric problems.