Proposal summaries
B1549 - Association of maternal smoking and tooth eruption in ALSPAC - 11/04/2013
In a recent study we looked at the relationship between tooth eruption and adolescent anthropometric measures in ALSPAC. We found primary tooth eruption to be associated with height and weight at 17 years (unpublished Fatemifar et al. 2013). To gain a better understanding of factors effecting tooth development we believe that it is also important to understand exposures that may alter the timing of eruption and subsequently number of primary teeth at childhood. Smoking during pregnancy is known to reduce fetal development (1). We therefore hypothesise there will be relationship between maternal smoking during pregnancy and timing of tooth eruption.
Aims:
We aim to investigate the relationship between maternal smoking and primary tooth eruption. In doing so we need to take into account any confounders and mediators. We then aim to use a variant in a known nicotine receptor to conduct some instrumental variable analysis, in which we look at the relationship between maternal smoking and primary tooth eruption using the nicotine receptor variant as an instrument for maternal smoking.
Exposure variables:
Maternal Smoking
Paternal Smoking
Outcome variables:
Age at first tooth (15 months)
Number of teeth (15 months)
Confounding variables:
Birth weight
Maternal Education
Breast Feeding
Gestational Age
Maternal Age
Parity
1. Jaakkola,J.J.K. and Gissler,M. (2004) Maternal smoking in pregnancy, fetal development, and childhood asthma. American journal of public health, 94, 136-40.
B1548 - Identifying common genetic variants and putative genes associated with facial attractiveness - 11/04/2013
Facial attractiveness plays a crucial role in a variety of human interactions, including human mate choice. People prefer to date and marry facially attractive individuals. The preference for more attractive partners is warranted from an evolutionary perspective, given that facially attractive individuals have higher reproductive success than their less attractive counterparts and facial attractiveness is generally thought to indicate genetic quality in terms of disease resistance. People are also more likely to ascribe positive personality attributes to form same-sex appliances, employ and even vote for facially attractive individuals. Despite historical beliefs, facial attractiveness is not merely an arbitrary cultural convention. People from different cultures show strong agreement in what is considered facially attractive. Even young infants who have not been exposed to cultural norms, prefer to look at faces that adults describe as facially attractive. Previous studies have identified several facial cues (eg sexual dimorphism and symmetry) and hormones (eg testosterone and cortisol) that play a role in facial attractiveness. Yet despite the high estimated heritability of facial attractiveness, very few studeis have accessed the genetic variation underlying facial attractiveness. To our knowledge, only the human leukocyte antigen (HLA) genes have been investigated as candidate genes for facial attractiveness. Roberts et al found that HLA heterozygous men (ie men that have differenc copies of the HLA genes) were considered more attractive than HLA homozygous men (ie men that have similar copies of the HLA genes). Follow up studies have replicated this association in male, but not female subjects. Recent studies have shown that genome wide association (GWA) studies can successfully identify common genetic variants and genes which regulate quantitative heritable traits such as height and facial morphology. GWA studies therefore provide a more robust approach to identifying common genetic variants that are associated with facial attractiveness compared to candidate gene approaches that have been used for HLA).
The primary aimof this study is to identify common genetic variants, and ultimately putative genes, that are associated with facial attractiveness using GWA methodologies. We specifically chose the ALSPAC dataset because it is, to our knowledge, the largest dataset with both facial images and GWA data. To accomplish this aim, 3D facial images obtained from the ALSPAC image set will be standardised for size and orientation. 30 (15 male) caucasian students from the United Kingdom (UK) will rate all the images for attractiveness on a seven point Likert scale over eight one-hour sessions (rate calculated from previous work). 30 raters are sufficient to produce an accurate measure of facial attractiveness. We request permission to have the images rated at the Perception Lab, University of St Andrew's (UK), because of the well-established image rating facilities, large participation pool and streamlined workflow; images are rated in the UK to reduce cross-cultural variation in attractiveness judgements. Attractiveness ratings will be averaged for each image. The ALSPAC team have cleaned and imputed a GWA study dataset consisting of 8365 individuals with genotype calls for ~2.5 million common variants spread across the genome. We will use this resource to conduct a 2 stage (discovery and replication) genome-wide association study. Initially the discovery phase will include analysing ~5000 individuals that have both genotypic data and facial images. Power analysis (PowerGwas/QT version 1.0) indicate a sample size of 5000 is adequate to provide 80% statistical power to detect single nucleotide polymorphisms (SNPs) that explain as little as 0.8% of the variance in facial attractiveness. The association between each of the ~2.5 million SNPs (exposure variables) and facial attractiveness (outcome variable) will be independently tested in the ALSPAC cohort using linear additive regression, while controlling for pubertal development. SNP associations that exceed the standard significance threshold for genome-wide significance (pless than 5 x 10-8), will be identified and replicated independently in additional cohorts, making up the second replication phase for the GWA study. To determine which genes (and pathways) are most likely associated with facial attractiveness we will conduct a range of post-hoc analyses including (a) assigning SNPs to genes, (b) epistasis modelling and (c) pathway analyses. Briefly, multiple genes are ascribed to each SNP and these genes are then prioritised using epistasis modelling and pathway analysis, allowing us to further identify which biological processes regulate facial attractiveness. In addition, we will calculate a more accurate heritability estimate of facial attractiveness; do a GCTA analysis to estimate the amount of phenotypic variance in attractiveness common SNPs explains; test the relationship between admixture and attractiveness; test the relationship between genome-wide heterozygosity and attractiveness using the ~2000 ALSPAC individuals who have whole genome sequencing data; and test the association between previously imputed classical HLA alleles and facial attractiveness separately for males and females. Based on previous work we predict that HLA alleles will be associated with male, but not female attractiveness. All GWA analyses will be conducted at the University of Bristol.
The second aimis to determine the association between health measures (exposure variables) and facial attractiveness (outcome variable). The health measures will be divided into prenatal risk factors (eg parental age, presence of gestational diabetes) and childhood health measures (eg body mass index, blood pressure and self-reported health). Facial attractiveness is generally assumed to serve as a 'health certificate', but studies testing this assumption mostly utilise a few self-reported health measures and small sample size (~N=40-200). The size and quality of the ALSPAC dataset, especially the wide range of physiological measurements, provides us with the ideal opportunity to test the association between health indices and facial attractiveness in male and female faces respectively. Based on previous research and work currently under review, we predict that facial attractiveness will be significantly associated with health measures, but more so for male than for female subjects.
The third aimis to determine whether SNPs associated with facial attractiveness are also associated with other traits proposed to indicate overall quality, specifically increased height, body mass index (BMI) within the health BMI range, increased sexual dimorphism (eg facial masculinity/femininity) and facial symmetry. To do so we will calculate morphometric or perceptual measures of sexual dimorphism and facial symmetry before testing the relationship between allelic scores of SNPs for facial attractiveness and these traits.
B1547 - DGKK variants and fetal growth - 11/04/2013
DGKK was the main gene found to be associated with hypospadias in a genome-wide association study (GWAS) (van der Zanden et al., 2011), which we replicated in a further study (Carmichael et al., 2013). Given that DGKK is expressed in the placenta (we know little else about it), and hypospadias is associated with fetal growth retardation (Carmichael et al., 2012), we hypothesized that DGKK variants would be associated with fetal growth. Preliminary data among 930 non-malformed, male, population-based controls that were part of our DGKK-hypospadias study suggest that DGKK variants are associated with increased risk of low birthweight (less than 2500 gm) among term infants (37 or more weeks gestation). However, the sample size was relatively limited (only 20 subjects were term and low birthweight). ALSPAC offers an excellent opportunity to examine this hypothesis in more depth and in a much larger sample (approximately 7,500 subjects).
Our hypothesis is that DGKK is associated with fetal growth. The aim of the proposed analysis is to examine the association of fetal growth with infant genetic variants (SNPs) in DGKK that were included in the Illumina 317 genotyping (GWAS) panel, which has been run on ALSPAC samples. Parameters reflecting fetal growth, as well exclusion criteria for genotyping data, will largely follow methods developed for use of ALSPAC data for the meta-analysis of GWAS data on fetal growth by Freathy et al. (2010). That is, we will examine the association of birthweight standardized to z scores adjusted for gestational age, as a continuous measure and as a dichotomy (ie, less than 10th percentile versus higher), and we will examine birth length, head circumference and ponderal index, all among singleton term infants. The Freathy et al. study did not examine growth among preterm infants, but we propose to also examine the association of the DGKK variants with preterm delivery and with birthweight adjusted for gestational age among infants born preterm. All analyses will be stratified by infant sex since DGKK is on the X chromosome. Potential covariates to consider inclue maternal age, parity, prepregnancy body mass index, smoking, and education (as a marker of socioeconomic status). We will restrict analyses to singletons.
References
Carmichael SL, Mohammed N, Ma C, Iovannisci D, Choudhry S, Baskin LS, Witte JS, Shaw GM, Lammer EJ. Diacylglycerol kinase K variants impact hypospadias in a California study population. J Urol 2013;189:305-11.
Carmichael SL, Shaw GM, Lammer EJ. Environmental and genetic contributors to hypospadias: a review of the epidemiologic evidence. Birth Defects Res A Clin Mol Teratol 2012;94:499-510.
Freathy RM, Mook-Kanamori DO, Sovio U, Prokopenko I, Timpson NJ, et al. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 2010;42:430-5.
van der Zanden LF, van Rooij IA, Feitz WF, Knight J, Donders AR, et al. Common variants in DGKK are strongly associated with risk of hypospadias. Nat Genet. 2011;43:48-50.
B1546 - Social inequalities in allostatic load in childhood - 28/03/2013
Background:
Social inequalities in health, with people experiencing progressively worse health with increasing deprivation, are present throughout the world. Inequalities in health are not limited to mortality and life expectancy, with the incidence of physical and mental conditions being higher for individuals with lower socioeconomic position (SEP), including most cancers, heart disease, diabetes, depression and multimorbidity. However, the pathways, and particularly the underlying biological processes, linking poorer SEP and ill health are not well understood. Understanding the causal links between SEP and health are essential if inequalities are to be reduced in the UK and elsewhere.
Given the wide range of conditions that vary by SEP, it has been proposed that there are some common biological pathways in how SEP can 'get under the skin'. Through the exposure to environmental, psychosocial and behavioural factors that SEP results in, the body is put under demands that it can adapt to in the short-term (normal system regulation). However, if these exposures persist, dysregulation can occur. The 'wear and tear' on the body that will occur over long spells of such dysregulation is typically irreversible, eventually increasing the risks of poor health and functioning.
Cumulative physiological burden and dysregulation that occurs across multiple physiological systems throughout the lifecourse can be captured using the concept of allostatic load. The most widely used construct of allostatic load has been developed by Seeman and colleagues, where it is conceptualised using biomarker measures across an array of systems including the cardiovascular, metabolic and inflammatory systems. Allostatic load has been shown to predict the risk of major health outcomes including heart disease and all-cause mortality. Importantly, many of the individual components of allostatic load are not risk predictors for the same health outcomes associated with allostatic load. Assessing these biomarkers together as allostatic load helps us to understand the synergistic nature of the physiological burden on the body imposed by exposure to damaging environmental stressors. To date, there has been consistent (albeit small in number) evidence for lower SEP to be associated with higher allostatic load. Given the associations identified between SEP and allostatic load, and allostatic load and health, it is hypothesised that allostatic load is a mediator in the pathway between SEP and health. However, we are missing evidence for how SEP and allostatic load are associated throughout the lifecourse, how these associations can differ over time and place and if allostatic load is indeed a link between SEP and health. If allostatic load is a predictor of health, it would be expected that similar patterns of inequality would be seen in allostatic load as those seen with life expectancy and diseases like CHD. Greater knowledge on the relationship between SEP and allostatic load (and subsequent risk prediction of ill health) could be important for targeting interventions aimed at reducing inequalities in health that will have the broadest impact across the population. Understanding how the relationship between SEP and allostatic load differs according to factors such as age, gender and geographical location could be an important step in ensuring that these interventions are targeted correctly and efficiently.
Preliminary work:
I have recently led on a study paper looking at the relationship between SEP over the lifecourse and allostatic load (to be submitted April 2013). This study used a structured modelling approach comparing various theoretical models of the influence of SEP on health across the lifecourse that encompass the accumulation of risk, critical/sensitive periods and social mobility models. We found that the accumulation model of lifecourse SEP had the best model fit for the association with allostatic load in men and women aged approximately 35, 55 and 75 from the West of Scotland Twenty-07 Study (although the results were less convincing at older ages). However, the results also indicated that childhood was a particularly important time-point for the link between SEP and allostatic load. Since March 2013 I have also been leading on a study investigating some of the potential mediators (behavioural, psychosocial and material factors) between SEP and allostatic load using the Twenty-07 Study. This work has been funded by a six-month MRC Centenary Award.
Aims:
The overall aim of the fellowship is to examine if allostatic load, as a measure of cumulative physiological burden, is a mediator in the association between lower SEP and poorer health outcomes, including physical and mental health and mortality. The specific aim of the project using ALSPAC data is to examine allostatic load inequalities by SEP in children. Very little evidence exists in the development of allostatic load in childhood and its association with SEP, although there is good evidence for social patterning in adolescence. In addition, our preliminary work above has indicated the importance of childhood as a possible critical period in the development of adult allostatic load. Other data on childhood circumstances will also help answer if any patterning is driven by factors such as disease in infancy.
Hypotheses:
Lower SEP (based on a latent parental SEP construct) will be associated with higher allostatic load scores in children aged 9 from the ALSPAC study. This association will be partly mediated by disease in infancy and poorer conditions at birth (e.g. low birth weight, small for gestational age).
Exposure variables:
Parental SEP (education, income, social class, housing tenure, financial difficulties and area deprivation)
Outcome variables:
Allostatic load - a score produced from several bookmarkers (blood pressure, pulse rate, cholesterol, glycated haemoglobin (diabetes marker), waist-hip ratio, C - reactive protein (inflammation marker) and IL-6 (inflammation marker))
Confounding variables:
Sex, disease, birth weight, gestational age, ethnicity
Please note, any data provided will be stored on secure drive spaces at SPHSU, which only I have access to.
B1545 - The Changing Nature of Lone Parenthood and its consequences - 28/03/2013
Research Aims
The study will focus on four inter-related research questions.
1. Who becomes a lone-parent and what are the consequences?
How does lone-parenthood today differ from the past when it was relatively rare? Are lone-parents an increasingly (or decreasingly) "selected" group of the population? How might we expect lone-parents families to fare (in terms of employment, income and poverty) had they not become lone-parents?
2. How long does lone-parenthood last and what is the nature of parents' relationships before and after periods of lone-parenthood?
Most mothers who become lone-parents at the time of their child's birth will have partnered by the time their child is five years old, whilst many married / cohabiting relationships will founder resulting in lone-parenthood for older children. How have these patterns evolved? Do they offer important information for the variation in children's experiences?
3. Are lone-parents becoming more heterogeneous?
Is lone-parenthood becoming increasingly polarized, as has been found in US, with some mothers managing to maintain their incomes through work and maintenance while others fare poorly? Or is lone-parenthood a dominant characteristic leading to poor outcomes for parents and children regardless of background? What are the longer term consequences of lone-parenthood for mothers - does it leave a long term scar even after re-partnering or children leaving home?
4. How does lone-parenthood influence children's outcomes and has this changed over time?
How does family structure, including lone-parenthood and re-partnering (step-parenthood), influence children's outcomes? How does this map onto the patterns in the variation in lone-parenthood described in the preceding questions? To what extent does the background of lone-parents (e.g. age, education) matter in determining children's outcomes? And how does lone-parenthood affect children's social mobility?
Estimation Techniques (Exposure and Outcome Variables)
The analysis will use simple descriptive statistics and panel data techniques to address the research questions set out above. Our first step will be to examine lone-parent status across all data sets. Family status will be defined at the child's birth, at early school age (around age 6), end of primary school (age 11) and end of compulsory schooling (age 16). Re-partnering will be treated as a separate status to intact partnerships from birth. Much of our analysis will focus on lone mothers, who constitute over 90 percent of the lone parent population, although we will also examine lone fathers as a single distinct category where sample sizes allow.
The data will allow us to provide a description of the growth of lone-parenthood over time and across the cohorts. It will also allow us to measure duration of lone-parenthood for children at various ages in the birth cohorts. To do this we will add information of the duration of the relationship prior to the birth to form a typology of lone-parenthood by age of child, duration of lone-parenthood and stability of surrounding relationships. This typology will then be mapped across the cohorts and changes over time will be compared as well as onto child outcomes at ages 6, 11 and 16 to gauge the size of educational deficits at each age for children in or have moved through lone-parent families into re-partnered families. This can also be extended to adult economic and social outcomes, including marriage, fertility and lone-parenthood. So we will assess patterns on social mobility for children growing up in lone-parent families for the early cohorts.
As we are particularly interested in the diversity of experience of lone-parenthood an important question is whether lone-parenthood is more damaging to women's economic position depending on their route into lone-parenthood. We will investigate the influence of education and labour market experience on outcomes for lone-parents; routes into lone-parenthood (including past relationship histories, age of children on becoming a one parent and labour market attachment) and the duration of lone-parenthood. In addition, as paid work has increasingly become the "social norm" for women, has a greater divide developed between lone-parents with strong labour market attachment and earnings and will examine how lone-motherhood has changed in response to increased female labour market opportunities. We will use regression based approaches to condition on observable differences prior to lone-parenthood but it is difficult to also predict what the effects of extremely unhappy relationships would have had if families remained intact. So a number of approaches can be undertaken, each with strengths and weaknesses so as to give as robust a picture as possible. As the data are longitudinal this will allow the use of "fixed effects" estimators, or their equivalents in forms other than linear regression, to further condition out unobservable characteristics of parents and children. Propensity score matching can be used to remove observable differences in socio-economic origins between lone-parent and couple families (including step-parent families), and also to match families by duration of relationships.
The data on children will provide insights into the relationship between the components of our typology and the test scores, so that we can identify which elements of the lone-parent typology appear to lower test scores. We will use regression based approaches to condition on observable differences. In particular we would envisage using propensity score matching to remove observable differences in socio-economic origins between lone-parent and couple families. For those children where lone-parenthood occurs after age 6 or so, and so a pre-lone-parenthood observation of test scores is available a value added model structure will be employed.
B1544 - Evaluation of a child-parent screening approach to identify people with famillal hypercholesterolaemia in ALSPAC - 28/03/2013
AIMS
Familial hypercholesterolaemia (FH) is one of the commonest inherited disorders affecting about 1 in every 500 people in theUK. The condition causes an increase in the "bad" form of blood cholesterol (LDL-cholesterol) which places affected people at much higher risk of suffering heart attacks or angina, or requiring by-pass operations. About 1 in 2 men with FH suffer a heart problem by age 50, and 1 in 3 women suffer a heart problem by age 60. Some sufferers are recognised as having the condition either because they have evidence of fat deposits in the skin or eyes, suffer a heart attack at a very young age, come from a high-risk family, or are found to have an extremely high level of blood cholesterol when they have a blood test (often for an unrelated reason). However, of the 110,000 sufferers thought to exist in theUK, only about 15% are aware that they have the condition.
Statin drugs reduce the blood level of LDL-cholesterol and the risk of heart disease and are a safe and effective preventative intervention in people with FH. There is therefore interest in developing a national screening strategy to detect people with FH early in order that they can receive statins in order to reduce death and disability from heart disease in this group.
B1543 - Prevalence and co-morbidities of specific language impairment SLI in middle childhood - 28/03/2013
Aims
(1) To determine the prevalence and detection of specific language impairment (SLI) in middle childhood.
(2) To identify the most common comorbid deficits associated with SLI in the educational, social, emotional and behavioural domains.
(3) To examine the association between key factors (e.g., language abilities, gender) and educational, social, emotional and behavioural outcomes in typical (non-SLI) children and children with SLI.
(4) To raise awareness of SLI in middle childhood and develop knowledge and understanding of SLI as children approach the primary-secondary school transfer.
Hypotheses
(1) SLI is a developmental condition and is subject to changes over time. We hypothesise that the prevalence of SLI amongst children in middle childhood in the ALSPAC sample would be beween 5 and 10%, with boys showing a higher prevalence than girls.
(2)SLI is associated with a range of comorbidities: deficit in pragmatic language skills, difficulties in literacy, numeracy and science learning, and a higher prevalence of emotional, behavioual and peer problems compared with their typically developing (TD) peers.
(3) Children with SLI, however, are just as likely as their TD peers to display prosocial behaviour.
Exposure variables
- Expressive language skills
- Receptive language skills
- Performance and verbal IQ
- Speech problem and speech therapy attendance
- Education provision and special education needs (SEN)
- Milestones in understandng and talking; speech and language development
- Gender
Outcome variables
- Conduct problems
- Hyperactivity
- Emotional symptoms
- Peer relations
- Prosocial behaviour
- General behaviour or personality problems
- Pragmatic language skills
- Reading skills
- Educational attainment in English, maths and science
Confounding variables
- Family history of speech and language problems
- Medical problems (epiliepsy)
- Developmental milestones and difficulties, eg fine and gross motor skills, social development, developmental delay, diagnosis of autism/ASD.
- Hearing impairment
- Number of other children in family
- Number of people living in the household
- First language
- Maternal education
- Parental employment
- Family income
- Age
- Ethnicity
B1542 - Associations between changes in DNA methylation and changes in adioposity - 28/03/2013
The role of epigenetic modifications in obesity is poorly understood. Some associations between DNA methylation in cord blood and BMI in later childhood have been demonstrated, but the causality of these associations requires further investigation. Any causal relationships between epigenetic modifications and obesity could operate in either direction - DNA methylation may alter transcriptional regulation and hence affect obesity, or alternatively obesity may lead to changes in DNA methylation. We propose to study this by examining the associations between changes in DNA methylation and changes in adiposity in the Avon Longitudinal Study of Parents and Children (ALSPAC).
The associations between changes in adiposity and changes in epigenetic modifications will be assessed using measurements of adiposity and DNA methylation at birth and ages 7 and 15/17 years. Adiposity will be assessed by weight and height at all ages, and by DXA-assessed fat mass at 7 and 15/17 years. The associations will be investigated in multiple ways in order to compare methodological approaches to investigating changes in methylation. We will:
1. Identify the 100 methylation sites that change the most between each pair of sequential time points, and assess whether change in methylation at these sites is associated with change in adiposity
2. Perform principal components analysis (PCA) of changes in all 450k methylation sites to identify patterns of change in methylation, and relate the scores from these principal components to changes in adiposity
3. Perform partial least squares (PLS) analyses - a method that has similarities to PCA. PCA identifies combinations of variables that explain the greatest proportion of variance in those variables. In contrast, PLS identifies combinations of variables which explain the greatest proportion of variance in an outcome (in this case change in adiposity)
4. Perform latent class analysis of changes in methylation and relate these to change in adiposity
If any associations between changes in DNA methylation and changes in adiposity are identified, we will use a genetic risk score for obesity as an instrument for obesity changes, and perform a Mendelian Randomisation analysis to assess the direction of causality.
B1541 - Childhood body size and growth and later risk of haemorrhagic stroke - 28/03/2013
AIM
The aim of this Ph.D.-study is to investigate associations between birth weight, childhood body mass index (BMI), height and growth in weight and height, respectively, and the risk of hemorrhagic stroke later in life. Moreover the question of which biological parameters that underlie the observations made when examining the associations between these particular anthropometric parameters and later risk of hemorrhagic stroke, will also be investigated. As associations between the mentioned anthropometric parameters in childhood and cardiovascular disease (CVD) have been found, and as CVD shares many risk factors with hemorrhagic stroke, it is plausible that associations exist here as well. Thus, low birth weight, high and/or low BMI, height and accelerated gain in weight and/or in height are possible risk factors for hemorrhagic stroke.
BACKGROUND AND SIGNIFICANCE
Stroke causes 9% of all deaths around the world and is the second most common cause of death after ischemic heart disease. Stroke is also a major cause of disability worldwide and consumes about 2-4% of total health-care costs, and in industrialised countries it accounts for more than 4% of direct health-care costs. Approximately 10-15% of all strokes are caused by intracerebral hemorrhage.
Well-established risk factors for hemorrhagic stroke are arterial hypertension, anticoagulant usage, cerebral aneurysms, age, family history of strokes and excessive alcohol intake. Smoking, diabetes, high cholesterol, obesity, and a sedentary lifestyle are risk factors for all types of strokes. The identified risk factors for stroke only explain about 60% of the attributable risk, whereas more than 90% of ischemic heart disease is explained by identifiable risk factors.
The most important of the risk factors for hemorrhagic stroke is arterial hypertension, as it induces degenerative vascular changes that can result in ruptured vessels or micro-aneurysms leading to intracerebral hemorrhage. Excessive use of alcohol is thought to increase the risk of intracerebral hemorrhage by impairing coagulation and directly affecting the integrity of cerebral vessels. High cholesterol levels are known to cause atherosclerosis and thus increase the risk of thrombo-embolic (ischemic) stroke. The vascular degeneration caused by atherosclerosis is, however, likely to increase the risk of rupture and thereby the risk of hemorrhagic stroke. In contrast, some Asian studies have found that low cholesterol levels are associated with the risk of hemorrhagic stroke, suggesting that it causes the arterial wall to weaken and small intra-parenchymal cerebral arteries to subsequently rupture.
Furthermore, it has been found that greater BMI or relative weight in adulthood is strongly associated with the risk of total and ischemic stroke. A J-shaped association between adult BMI and hemorrhagic stroke has been found, thus low and high BMI values increase the risk. Other studies have examined different measures of body size: e.g. adult waist-to-hip ratio and found associations with both ischemic and hemorrhagic stroke. Height is thought to be a surrogate marker of early life and childhood conditions. In studies that have investigated the association between adult height and risk of hemorrhagic stroke an inverse relationship has been found.
Although risk factors for hemorrhagic stroke have been found in adulthood, would it not be better if they could be detected already in childhood? There is evidence that at least a part of the risk may originate in utero as studies consistently find that low birth weight is associated with an increased risk of hemorrhagic stroke. Studies investigating if there are risk factors in childhood, however, are lacking. Childhood BMI, childhood height and growth in height are associated with risk of coronary heart disease (CHD) in adults, and it is therefore likely that these factors also are associated with the risk of hemorrhagic stroke. Despite the plausibility of the associations, few studies have investigated how childhood body size is associated with hemorrhagic stroke. Results from the studies that have are inconsistent, and this is likely due to the low numbers of cases included (less than 100 per study). Therefore, the proposed research will address a gap in the knowledge of childhood body size and growth and its later health consequences.
PROJECT DESCRIPTION
This Ph.D project will be based on data from two epidemiological cohorts. The large Copenhagen School Health Records Register (CSHRR) will serve to investigate the birth weight and childhood anthropometry in relation to risk of hemorrhagic stroke. By using the very detailed data from the smaller Avon Longitudinal Study of Parents and Children (ALSPAC) it will be possible to investigate what biological associations that underlie such particular feature of birth-weight childhood-anthropometry association with later stroke risk. The studies are described in below.
THE CSHRR STUDIES
The CSHRR is an electronic database of information from health examinations on 372.636 schoolchildren who attended school in the capital city of Denmark from 1936 to 2005. The CSHRR contains virtually every school child that attended school in Copenhagen. The children were given full health examinations annually. Essential personal information and dates along with birth weight and height and weight measurements have been computerized.
The CSHRR contains a unique personal identification number, assigned by the Danish Civil Registration System (CRS), for 329,968 (88.5%) of the children. Via the CRS number, the cohort has been linked to the National Cause of Death Register (NCDR) and the National Hospital Discharge Register (NHDR). The size and the prospective and serial measurements of body size along with the age structure of the cohort, where many members have reached middle age, make the CSHRR well suited for studying diseases that occur later in life, such as hemorrhagic stroke.
Therefore, using the CSHRR, the following hypotheses will be investigated:
* Low birth weight increases the risk of hemorrhagic stroke
* High and/or low BMI in childhood increases the risk of hemorrhagic stroke
* Accelerated weight gain increases the risk of hemorrhagic stroke
* Short height in childhood increases the risk of hemorrhagic stroke
* Accelerated growth in height increases the risk of hemorrhagic stroke
Childhood will be defined as 7 to 13 years of age as these are the ages of children in the CSHRR. There are 3.458 cases of hemorrhagic stroke among the cohort members, however these numbers will increase as this is from an older linkage to the NCDR and the NHDR. Furthermore, a sub-set of the CSHRR will be augmented by the use of data from the Danish National Indicator Project (DNIP) that now contains detailed information on prior medical history, diagnostic methods (i.e. CT or MR scannings and severity by the Scandinavian Stroke Scale) and supplemental test, interventions and treatment during hospitalization on more than 4000 cases of hemorrhagic stroke after year 2001. Since other studies on this subject have had less than 100 cases of hemorrhagic stroke, results from this study will contribute to what is known in this area of research. However, an important issue is that the methods used to diagnose hemorrhagic stroke have changed during the given period due to the technical development and implementation of CT scannings in the 1990s. Since hemorrhagic stroke in most cases appear late in life, and given the age structure of the CSHRR, only a small number of cases in this cohort will have had the diagnosis made solely on the basis of a clinical examination.
The proposed research will be conducted at the Institute of Preventive Medicine. The group that will supervise the Ph.D. project has extensive experience in the area of researching long-term health consequences of childhood body size, has a successful history of collaboration, and is skilled in the statistical techniques required. The proposed research is feasible, as the data resource has been used for similar types of projects. With the support of the team, the proposed research is achievable within the timeframe of the Ph.D.
Statistical methods: Associations between birth weight, BMI and height at each age and hemorrhagic stroke will be investigated using Cox regression. Growth will be investigated using the life course analysis technique. Analyses will be conducted separately for men and women. Additionally, analyses will be conducted with the inclusion of birth weight to see if this changes the observed associations. Interactions between birth weight and body size in childhood will be investigated. The assumptions of the Cox regression model will be assessed as will the linearity of the associations. Sensitivity analyses will be conducted to examine the effect of diagnostic changes for hemorrhagic strokes.
Ethical aspects: The Danish Data Protection Agency has approved the use of the CSHRR for these studies
THE ALSPAC STUDY
The ALSPAC resource has a richness of detail that is incredibly valuable as it contains genetic and biological samples collected at multiple time points ranging from the prenatal period through to adolescence and young adulthood of the subjects, thus allowing the assessment of developmental trajectories and critical periods of development. The study recruited 14,541 pregnant women who resided in the former Avon Health Authority area of southwest England with an expected date of delivery between April 1991 and December 1992, resulting in a total birth cohort of 14,062 live births of whom 13,970 were alive at 1 year of age. These children have been followed, initially with questionnaires throughout childhood, and at regular annual clinic visits since the age of 7 years. The UK Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for ALSPAC, and there have been more than 850 articles published by February 2013; details of these can be found on the ALSPAC study website (enter the website here).
Information on weight and height, puberty, social background medical history for parents and grant parents and exposure to passive smoking, as well as health care examinations, multiple blood samples (including blood lipids) and cardiovascular health parameters (such as blood pressure and pulse rate, intima-media thickness, pulse wave, flow-mediated dilation and scan of the carotid arteries) is available for more than 5000 children.
Using information from ALSPAC, the current study will investigate the hypothesis:
* Childhood body composition and growth are associated with biological risk factors for hemorrhagic stroke
The proposed research will investigate these factors in the ALSPAC-children using the collected data and blood samples. Information from records of preceding measurements of height and weight, including birth weight will be used. Associations between body size and the known risk factors for hemorrhagic stroke such as hypertension, family history of stroke and diabetes will be examined. Associations with blood pressure will be investigated as well. Furthermore, associations of body size with the blood lipid-profile will be investigated. The study will examine both known and also more uncertain risk factors as the lipid profile will, in addition to the traditionally examined lipids like low density lipoprotein (LDL), total cholesterol, triglyceride and high density lipoprotein (HDL), include apolipoprotein B and apolipoprotein A-I which have been found to provide more useful information on the risk cardiovascular disease in adults than traditional lipids do. Also IGF-I levels, which have been hypothesized to promote structural integrity of cerebral arteries and thereby offering protection from hemorrhagic stroke, will also be examined.
It will thus be possible to investigate how different anthropometric parameters are biologically mediated to hemorrhagic stroke.
Statistical methods:
Longitudinal modelling of the relations between rates and patterns of growth in body weight and height from birth through adolescence and the pertinent potential biological mediators of the asscociation between birth-weight-childhood antropometrics and stroke risk will be carried out in collaboration with statisticians with particualr expertise in this type of analyses in Bristol and Copenhagen
Ethical aspects: Approval for the study was obtained from the ALSPAC ethics and law committee, and written informed consent and assent was obtained from both the parent or guardian and the child.
FUTURE ASPECTS
This PhD. study will, with the possible findings of childhood risk factors of hemorrhagic stroke, provide leads for future research aimed at targeted prevention already in childhood and clinical research within the areas of vascular disease.
B1540 - GWAS meta-analysis on childrens sleep problems - 28/03/2013
AIM:
To study the genetic basis of sleep problems in children (Caucasian ancestry only).
HYPOTHESES:
A GWAS meta-analysis on children's sleep problems will provide a powerful tool to reveal novel pathways and enhance our understanding on the architecture of these problems.
Family based and twin studies reveal high genetic heritability of sleep problems but so far, little evidence exists on particular genes and related pathways.
EXPOSURE VARIABLES:
No.
OUTCOME VARIABLES:
-Child Behavior Checklist (CBCL) : Scale Sleep Problems.
-Any other instrument with 3 or more comparable items to the above scale.
CONFOUNDING VARIABLES
- age, gender
B1539 - Joint effect of patterns of infant weight gain and breastfeeding on the risk of body mass index and obesity in childhood - 28/03/2013
Although the potential protective effect of breastfeeding on obesity has been studies extensively, the causal role is still discussed. In a previous analysis of the Avon Longitudinal Study of Parents and Children (ALSPAC) conducted by Dr. John J. Reilly and colleagues, weight gain in the first 12 months was associated with an increased risk of obesity at 7 years also after adjustment for a wide range of potential confounding factors, whereas an apparent protective effect of breastfeeding was reversed after adjustment (BMJ 2005).
It has been suggested that the observed association between longer duration of breastfeeding and lower risk of obesity might be explained by reverse causality. The concern is that more rapid weight gain in infancy induces breastfeeding cessation, and that the faster weight gain itself entrains later obesity. Only few studies have had sufficient data to model this bidirectional relationship and they show heterogeneous results. We propose to model the relation between weight and breastfeeding in infancy and the joint effect on obesity with relevant statistical methods, namely the g-computation formula that can account for the proposed bidirectional relation between infant weight gain and breastfeeding.
The research questions of this proposal are:
1) To investigate whether infant weight and weight gain predicts subsequent infant feeding.
2) To investigate the joint effect of patterns of infant weight gain and breastfeeding on body mass index and risk of obesity through childhood
Exposure: infant feeding at several occasions (breastfeeding, bottle feeding and complementary feeding)
Outcomes: child anthropometrics from birth through childhood
Covariates: maternal education, paternal education, family income, occupational social class, maternal age at childbirth, parity, maternal size, maternal smoking, sex of the child and gestational age.
B1538 - Genome-wide association study of deodorant usage - 28/03/2013
Background
The identification of genes involved in human behaviour is challenging. Genome-wide association studies (GWAS) have shown evidence of genetic contribution in relation to human traits including smoking behaviour and suicidal behaviour (http://www.genome.gov/gwastudies/). We have recently published a study showing a strong (P less than 10^-20) association between rs17822931, a functional SNP located in the ABCC11 gene, and deodorant usage (Rodriguez et al., 2013). A detailed analysis in ALSPAC showed a 5-fold over-representation of AA homozygous in categories of never using deodorant or using it unfrequently. Previous studies offer a biological basis for this association, since there are clear-cut differences in secretion of odour precursors dependent on rs17822931 genotype.
Two remarkable findings in relation to the behaviour of axillary deodorant use were that nearly 80% of European genetically non-odorous still use deodorant, whereas one in 20 individuals genetically odorous did not use it. This opens the possibility of a more complex scenario to explain the genetic basis of this human behaviour. To explore this possibility, an analysis of association at the whole genome level would therefore be required. However, a genome-wide analysis of genetic factors associated with deodorant usage has not been performed to date.
Aim
To conduct a (GWAS) in relation to deodorant usage in ALSPAC
Approach
We will perform a standard GWAS using genome-wide SNP data and phenotypic data already available in ALSPAC. Our proposal does not require the generation of new additional data.
Reference
Rodriguez S, Steer CD, Farrow A, Golding J, Day IN. 2013. Dependence of Deodorant Usage on ABCC11 Genotype: Scope for Personalized Genetics in Personal Hygiene. J Invest Dermatol. 2013 Jan 17. doi: 10.1038/jid.2012.480.
B1535 - Comparison of methods to relate GWG to child BMI at age 7 - 28/03/2013
There is increasing emphasis in medical research on fetal and childhood antecedents of chronic disease risk, and how these interact with other exposures throughout the lifecourse to influence later-life conditions (1). Answering questions about the relative importance of speed, magnitude and timing of growth, behaviour and health status for longer-term outcomes requires appropriate analyses of longitudinal data. For example, to understand how maternal weight gain during pregnancy (gestational weight gain, GWG) influences later cardiovascular disease risk for the child, we might seek to describe relationships between GWG and BMI at age 7, and how any relationships are mediated through birthweight and changes in weight during childhood.
Analysis of lifecourse data poses several statistical problems (2). Analysis of a repeated outcome must account for dependencies between multiple observations on the same person: methods to do this (e.g. multilevel models, (3) (4)) are now widely available in standard statistical software packages (e.g. Stata (5)). Within-individual variation may vary over time (e.g. absolute measurement error in weight will be larger in later childhood than at birth) and there will usually be dropout due to non-response, death, illness, emigration, etc. Where several repeated measures are used as exposures in one regression model for a later-life outcome, standard regression models may be affected by their multicolinearity. Disentangling the genuine associations between GWG, birth weight and later outcomes is important; a negative correlation between birth weight and later cardiovascular risk would imply a public health focus on increasing average birth weight, whereas if the relationship were largely between subsequent growth and later cardiovascular risk, this would imply a focus on minimising excess weight gain in children (6).
We consider methods for relating growth (exemplified here by GWG) to later outcomes (here, BMI at age 7). Methods to be used include: SITAR (7); multivariate multilevel growth models (8); latent class models (9); mediation models (10)including structural equation models (11) and lifecourse models (12). We propose to use the associations between GWG, birthweight, childhood growth and BMI at age 7 in ALSPAC as an example dataset on which to compare these statistical methods.
B1479 - The determinants of child/adolescent well-being and psychological resilience - 28/03/2013
There is a growing body of literature that has analysed cross-sectional data which shows that there is a strong relationship between the current characteristics of the individual and their wellbeing. However, policymakers need to know about how these characteristics arose in order to determine the point in the life-cycle when interventions would be most cost effective. To answer this question, a life-course model is needed that captures in a quantitative way the impact of different influences (at different points in time) upon subsequent wellbeing.
Our previous research has identified that adult life satisfaction is mainly dependent on seven other contemporaneous dimensions of a person's adult characteristics. These are a person's education, employment, and earnings, plus their mental health, physical health, family status and criminal records. However, our central interest is in how these seven measures are determined and thus on how we can influence them (and thus wellbeing). We know that both a person's family background and childhood development will be important. But, little is known about the relative importance of specific components of a person's family background and childhood development. There is also little understanding about the timing of when these components begin to matter. Our primary research aims to address both of these areas.
Thus, in our primary research project, we will first test the hypothesis that a person's family background and childhood development affect adolescent mental health, by responses to Strenghts and Difficulties Questionnaire (SDQ), the Short Mood and Feelings Questionnaire (SMFQ) and by the Development and Wellbeing Assessment (DAWBA), mainly through their effect on our seven other contemporaneous dimensions. If our hypothesis is confirmed, we will then seek to isolate the causal effect of a number of specific components of a person's family background and childhood development, which are caused by exogenous mechanisms such as the raising of the school leaving age (RoSLA) and life events, to identify their relative importance and also how they interact with time.
In our second project, we would like to investigate the early determinants of psychological resilience which can be broadly defined as the person's ability to withstand exogenous negative shocks in life. There is a growing body of literature over the last decade on the causes and consequences of human's psychological resilience, especially people's ability to bounce back from significant bad life events (Rayo and Becker, 2007; Graham and Oswald, 2010; Perez-Truglia, 2012). This recent surge of interest is fuelled by the releases of new longitudinal evidence of hedonic adaptation to negative life events, including adaptation to unemployment, disability, and bereavement (Clark et al, 2008; Oswald and Powdthavee, 2008). Yet little is known, either by economists or psychologists, why certain individuals are better than others at bouncing back from a bad life event and why they are initially hurt less by such a shock.
Thus, in our second project, we wish to test the hypothesis that a person's psychological resilience can be determined early on in childhood. To do this, we would first need to measure the emotional trauma from bad shocks in their life events. We would then try to find the important determinants of this estimated measure of psychological resilience in children. We believe our research using ALSPAC data can provide us with new scientific evidence on whether or not the components of long-term well-being (e.g., individual's ability to cope with bad life shocks) are determined early on in childhood, or more specifically before the child was born.
Finally, in our third project we wish to use the ALSPAC data to develop a dynamic factor model of child and adolescent well-being. More precisely, we wish to look at the development of cognitive, non-cognitive and health capabilities in a dynamic framework where abilities are the result of parental environments and investments at different stages of childhood and adolescence(Cunha et al, 2010). We believe that the unique wide range of cognitive, non-cognitive and health measurements in the ALSPAC data will allow us to refine our current understanding of the dynamics of child development.
References:
Clark, A.E., Diener, E., Georgellis, Y. and Lucas, R.E. 2008. Lags and leads in life satisfaction: a test of the baseline hypothesis. Economic Journal, 118(529), F222-F243.
Cunha, F., J.J. Heckman, and Susanne M. Schennach (2010) "Estimating the technology of cognitive and noncognitive skill formation" Econometrica, Econometric Society, vol. 78(3), 883-931, 05.
Graham, L. and Oswald, A.J. 2010. Hedonic capital, resilience and adaptation. Journal of Economic Behavior & Organization, 76, 372-384.
Oswald, A.J., and Powdthavee, N. 2008. Does happiness adapt? A longitudinal study of disability with implications for economists and judges. Journal of Public Economics, 92(5-6), 1061-1077.
Perez-Truglia, R. 2012. On the causes and consequences of hedonic adaptation. Journal of Economic Psychology. In press
Rayo, L. and Becker, G.S. 2007. Evolution efficiency and happiness. Journal of Political Economy, 115(2), 302-337.
B1532 - Limb Length in Children An Epidemiological Study of Growth in Northern Europeans - 18/03/2013
Aim:
To assess change of leg length over time in the skeletally imature population, inorder to accuratley assess growth remaining when planning epiphyseodesis.
B1528 - Does increased bone turnover explain the link between cardiovascular disease and osteoporosis - 18/03/2013
Aims
This project will, which will form the basis of an Arthritis Research UK Clinical Research Fellowship for Anupama Nandagudi, will use the mother participants in ALSPAC to investigate whether increased bone turnover explains the link between CVD and osteoporosis:-
(i) Using a cross sectional design, we will confirm that carotid intimal thickness (cIMT) is associated with hip BMD, as measured in the first mothers' clinic comprising predominantly premenopausal women, independently of shared risk factors.
(ii) We will investigate whether cIMT is related to bone turnover, as assessed by beta-CTX measured on blood samples obtained at the same time funded by this fellowship, and whether any association observed explains that between cIMT and hip BMD as described in (i).
(iii) Using a prospective design, we will determine whether cIMT is related to pQCT parameters as assessed at the distal and mid radius in the second mothers' clinic two years later. In particular, we will determine whether these associations involve phenotypes suggestive of increased bone resorption, and if so, whether these relationships are explained by associations with beta-CTX as described in (ii).
(iv) Whether shared genetic risk factors also contribute to the relationship between CVD and osteoporosis will be examined as follows:-
a. We will investigate whether genetic markers for cIMT as identified in recent GWA studies are also related to hip BMD, pQCT variables and/or beta-CTX.
b. We will determine whether genetic markers for bone phenotypes identified in recent GWA studies are also associated with cIMT.
c. We will determine whether associations between cIMT and bone outcomes observed above are explained by shared genetic risk factors which we identify.
d. Whether associations between cIMT, bone phenotypes and genetic factors which we find can be replicated in other populations with equivalent genotypic and phenotypic data will be investigated based on other cohorts (eg Young Finns, Twins UK).
Hypothesis
Prevalent subclinical CVD predicts future fractures and bone loss (1). As well as shared risk factors, this may reflect common pathological mechanisms such as increased bone turnover, which is the subject of the present proposal
Exposure variable
Subclinical CVD as reflected by cIMT as measured at the first mothers' clinic
Outcome Variables
Hip BMD (first mothers' clinic)
Beta-CTX (first mothers' clinic)
Trabecular BMD, as measured by pQCT at the distal radius (second mothers' clinic)
Cortical bone parameters, as measured by pQCT at the mid-radius (second mothers' clinic)
Confounders
Lifestyle risk factors (smoking, HRT use, physical activity, alcohol)
Constitutional risk factors (BP, BMI, fat mass (including intramuscular fat mass as measured by pQCT), age of menopause)
Blood measures (CRP, IL-6, LDL, VLDL, HDL, leptin, adiponectin)
References
(1) Uyl D, Nurmohamed MT, van Tuyl LHD, Raterman HG, Lems WF 2010 (Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; A systematic review of the association between cardiovascular disease and osteoporosis. Arthritis Research and Therapy 13 (1) Article Number: R5.
B1527 - Contributions of genetic and environmental factors to muscle density - 18/03/2013
Background
There is increasing interest in the contribution of sarcopenia to frailty and ageing, but research in this area is hampered by the lack of accurate non-invasive measures of muscle function. Though a number of assessments related to muscle function are available, including tests of muscle strength, and functional assessments such as timed chair raise and 'get-up-and-go', objective imaging-based techniques are very limited. Measurement of lean mass, for example by DXA scanning, provides one potential option, based on evidence that this is related to muscle strength and physical activity. However, the overall amount of muscle provides limited information as to its function, suggesting the need for other imaging modalities. One such candidate is pQCT-based measurement of muscle density. However, rather than muscle function, it may be that this primarily provides a measure of intramuscular fat. Consistent with this suggestion, we recently reported a relatively strong inverse correlation between muscle density and total body fat mass (1). A similar relationship was reported between muscle density and insulin levels, consistent with the fact that intramuscular fat deposition is thought to represent an initial step in the development of insulin resistance.
Aims
In the present proposal, we aim to address the hypothesis that muscle density as measured by pQCT provides useful information about muscle function, which is independent of estimates of fat mass/insulin resistance. This will be investigated by examining whether muscle density (adjusted for fat mass) is related to relevant environmental factors such as physical activity, or to genetic factors unrelated to obesity (this research programme will also link in with a parallel project involving Celia Gregson using the Hertfordshire cohort, intended to examine relationships between equivalent pQCT-derived measured of muscle density and findings from muscle biopsies).
Methods
Outcome variables:
Muscle density and cross sectional area as measured by tibial pQCT at 15.5 and 17.5 clinic visits.
Exposures:
Moderate and/or vigorous physical activity, based on Actigraph measures at age 15.5 years, as previously used to examine relationships with other pQCT-derived variables at age 15.5 (2).
High impact activity, based on Newtest monitors at age 17.5 years, as previously used to examine relationships with other pQCT variables at age 17.5 (K Deere et al, JCEM, In Press).
Genome-wide genetic markers, imputed to the latest version of hapmap, as used in our recent GWAS studies of other pQCT parameters in our pQCT consortium (3) (discovery cohorts: ALSPAC, GOOD, Young Finns; replication cohorts: Mr Os, Hertfordshire, EMAS; second meta-analysis centre: University of Gothenberg).
Confounders: age, gender, height, weight, subcutaneous fat area (pQCT), lean mass, fat mass.
1. Sayers A, Lawlor DA, Sattar N, Tobias JH. The association between insulin levels and cortical bone: findings from a cross-sectional analysis of pQCT parameters in adolescents. J Bone Miner Res. 2012;27(3):610-8. Epub 2011/11/19.
2. Sayers A, Mattocks C, Deere K, Ness A, Riddoch C, Tobias JH. Habitual levels of vigorous, but not moderate or light, physical activity is positively related to cortical bone mass in adolescents J Clin Endocrinol Metab. 2011;In Press.
3. Paternoster L, Lorentzon M, Vandenput L, Karlsson MK, Ljunggren O, Kindmark A, et al. Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone. PLoS Genet. 2010;6(11):e1001217.
B1525 - GWAS of diarrhoea during first years of life - 18/03/2013
Background and hypothesis:
Diarrhoea, as defined by the World Health Organization (WHO), is the passage of loose stool by an individual, at least three times a day, or more frequently than normal. It usually lasts less than 7 days and it can course with or without fever and vomiting. It is most commonly caused by intestinal infection that is transmitted faecal-orally, and infants and pre-school children have higher risk of infection. Children up to age 3 have an average of one to two episodes per year, with peak incidence between the ages of 6 and 23 months.
In the first 5 years of life, approximately 70% of diarrhoea cases are caused by viruses (40% Rotaviruses and 30% others such as Noroviruses and Adenoviruses), 20% by bacteria (Campylobacter spp, Yersinia spp, Salmonella spp, Shigella spp or pathogenic Escherichia coli) and 5% by parasites (Lamblia spp, Cryptosporidia spp or Entamoeba histolytica).
Infection depends on the pathogen strain and on the host genetic background. Heritability for early childhood diarrhoea in Brazil has been estimated in 54%. Histo-blood group antigens (HBGAs) are genetically determined glycoconjugates present in mucosal secretions, epithelia and on red blood cells, and are recognized as susceptibility and cell attachment factors for gastric pathogens like Helicobacter pylori, Noroviruses and Rotavirus.
We performed a preliminary GWAS on diarrhoea in INMA (N=700 children, diarrhoea yes/no during the first year of life based on questionnaire data), and among the top hits (p value ~ 10.E-06), we identified SNPs on one of the HBGA genes.
Aim:
We aim to to perform a genome-wide association (GWA) study meta-analysis on diarrhoea during first years of life.
Exposure variables:
-GWAS data imputed with 1000G project
Outcome variables:
-Diarrhea with or without doctor visit, interview or doctor diagnosis at age 1-1.5y
-Diarrhea with or without doctor visit, inerview or doctor diagnosis at age 2-2.5y
-Diarrhea with doctor visit, interview or doctor diagnosis at age 1-1.5y
-Diarrhea with doctor visit, interview or doctor diagnosis at age 2-2.4y
Confounding variables:
-Sex
Variables needed for exclusions:
-Preterm (less than 37 completed weeks of gestation)
-Congenital anomalies, where known (e.g. Down's syndrome, trisomy 18)
-Stillbirth
-One of sibling/twins or correction
-Non-European ancestry
Maybe in further steps other covariates will be needed (breastfeeding, day care attendance, siblings at birth...)
B1533 - FLG genotyping in ALSPAC children - 14/03/2013
Proposal submitted to the MRC centenary award (presided over by George Davey Smith):
Filaggrin (FLG) genotyping to enable FLG+/- stratified analysis to identify FLG*SNP interactions in eczema.
Lavinia Paternoster (PI)
Filaggrin null mutations have been established as a major risk factor for eczema. Several low frequency loss-of-function mutations have been identified which result in skin barrier defects and are associated with increased risk of ichthyosis, eczema and asthma. Originally two mutations (R501X and 2282del4) were identified and used in genetic association studies. However, recently published data on a European population shows that whilst using these two mutations will classify ~13% of the population as FLG mutation carriers, including a further two loss of function mutations (R2447X and S3247X) will classify an additional ~4% of the population as carriers.
We recently carried out a large-scale GWAS meta-analysis within the EAGLE consortium, where we identified three novel loci for atopic dermatitis. Two of these variants were located near genes that play a role in epidermal differentiation and proliferation (OVOL1 and ACTL9), whilst one was in KIF3A within a cytokine cluster of genes with previous evidence of immune-related and inflammatory functions (including associations with asthma and psoriasis). These findings highlight the importance of both skin-barrier and immune related genes in the aetiology of eczema. We hypothesise that there are likely to be important interactions between these two pathways, in that genetic variants within inflammatory/immune-related genes might only predispose to eczema if there is also dysfunction in skin barrier pathways. Due to the large number of tests carried out, analyses often lack power to detect interactions between genetic variants, but we plan to focus on interactions between FLG and known eczema and atopy variants.
Proposed Analysis: We propose genotyping the 4 FLG null mutations in the EAGLE cohorts and then carry out FLG+/- stratified analyses for the known eczema (and other atopy) hits to identify interactions between each SNP and FLG. Each cohort will carry out the analyses and provide summary data to Bristol for meta-analysis.
Pilot results: In ALSPAC we have already genotyped two of the four FLG variants (i.e. R501X and 2282del4). Preliminary analyses show evidence for an interaction between FLG and one of the known eczema hits (rs2897442, in KIF3A), showing an association only in those individuals with a FLG mutation (FLG+ OR=1.75, 95%CI 1.22 to 2.50, p=0.002 compared to FLG- OR=1.08, 95%CI 0.96 to 1.21, p=0.212; interaction p-value =0.014). We also find some evidence for an interaction between atopy SNP rs2252226 (FCER1A) and FLG, with this SNP also only showing association amongst individuals with a FLG mutation (FLG+ OR=1.50, 95%CI 1.11 to 1.98, p=0.008 compared to FLG- OR=0.96, 95%CI 0.87 to 1.07, p=0.475; interaction p-value=0.005). This gene also has a role in immune response.
It is expected that genotyping the additional two FLG variants in ALSPAC will increase power to detect interaction (by improving classification of people into FLG+ and FLG- strata). We also plan to use the other EAGLE cohorts to replicate this finding and carry out a meta-analysis of all FLG*known atopy hit interactions.
This resource will subsequently be used to carry out a genome-wide test for FLG interactions amongst the EAGLE cohorts and could be used in the analysis of other conditions, such as asthma. More thorough genotyping of the FLG mutations will also enable us to investigate properly whether the GWAS signal seen in this region can be completely explained by known FLG mutations.
B1531 - Metabolomic analysis of the affects of the rs174575 FADS2 polymorphism - 14/03/2013
AIMS
This study aims to use mass spectrometry (MS) to identify differences in metabolites between individuals who are homozygous for either the major or minor allele of FADS2. Using MS to identify metabolites will enable a snapshot of the physiological state to be captured and compared between genotypes.
HYPOTHESES
The FADS genotypes have been implicated in a range of outcomes including cardiovascular and metaboloic disease risk, neurological conditions and IQ. FADS2 is a delta 6 fatty acid desaturase involved in the synthesis of omega-6 and omega-3 fatty acids. It is thought that the enzyme from the FADS2 minor allele is less effective at producing derivatives of the fatty acid pathway and thereby there is an increase in precursors left un-metabolised. This infers that the metabolic profile will differ between FADS2 genotypes. PLS regression will be used to examine the metabolites most associated with variation in the outcome (the phenotype or genotype).
EXPOSURE VARIABLE
rs174575 FADS2 polymorphism either individuals homozygous for the major allele (CC) or homozygous for the minor allele (GG)
OUTCOME VARIABLE
Mass spectra from QStar XL QqTOF Mass spectrometer
CONFOUNDING VARIABLES
Age, gender, lean mass, fat mass. The main purpose of the project is to pilot MS methodology, additional variables may be added at a later date.