Proposal summaries
B467 - Prevalence of antimicrobial resistance in bacteria in healthy humans and identifying risk factors that are contributing to the carriage andpersistence of antimicrobial genes in human - 19/10/2007
No outline received
B573 - Preterm Birth Whole Genome Association Study - 16/10/2007
No outline received
B569 - Genetic and environmental influences on developmental trajectories of alcohol use misuse and related behaviours - 15/10/2007
No outline received
B574 - Variants in the cannabinoid receptor gene and their influence on alcohol and drug consumption - 10/10/2007
The CB1 receptor of the endocannabinoid system is known to modulate the endocrine hypothalamic-peripheral endocrine axes. Important advances have been made in our understanding of the endocannabinoid signaling system in various aspects of alcoholism and drug consumption. Alcohol increases the synthesis or impairs the degradation of endocannabinoids, leading to a locally elevated endocannabinoid tone within the brain. Elevated endocannabinoid tone might be expected to result in compensatory down-regulation of CB1 receptors or dampened signal transduction. Following release, endocannabinoids diffuse back to the presynaptic neuron where they act as short-range modulators of synaptic activity by altering neurotransmitter release and synaptic plasticity (Basavarajappa, 2007). Several small studies investigated a potential association between variants on the CNR1 gene and alcohol and/or drug consumption yielding inconsistent results (Herman et al. 2006; Racz et al. 2003; Schmidt et al. 2002; Zhang et al. 2004, Zuo et al. 2007).
We used data from the BWHHS study to evaluate whether two different single nucleotide polymorphisms of the CB1 receptor of the endocannabinoid system (CR1=rs1049353; CR2=rs2023239) are associated with obesity (2 variables), blood measures (9 variables), food intake (22 variables), drug consumption (6 variables) or mood (3 variables). There was no evidence that body mass measures, food intake or mood were related to genetic variants. However the results concerning alcohol and tobacco use are intriguing and merits further clarification.
Methods
Data from the ALSPAC study will be used to evaluate a potential association between variants of the CNR1 gene and alcohol consumption. We will genotype the two SNPs from the previous study (rs1049353; rs2023239) as well as to additional SNPs: rs806368 & rs12720071.The following data from the mother's forty seven month post-natal questionnaire will be investigated: alcoholic drinks (B22), own smoking (F4), passive smoking (D2, F5), drug/cannabis consumption (A3), being currently pregnant (A8).
The data will be analyzed using established statistical methods for genetic studies, primarily via regression models adjusted for potential confounding factors. Potential population admixture will be allowed for in the analysis. Genotyping will be done until end of November. Subsequently the analysis will be performed. The results will published in a scientific journal.
Significance
The ALSPAC study has considerable larger sample size than every other previous study on this topic. This candidate gene study will help to understand the role of the endocannabinoid system in the process of addiction. In addition,the study results are relevant regarding the application effects of cannabinoid (CB1) receptor antagonists. For instance a recent Cochrane review found that Rimobanant is helpful for quitting smoking (Cahill & Ussher, 2007).
B568 - The influence of the enviroment on face shape - 10/10/2007
No outline received
B592 - Predictive Value of Questionnaire Data for Assessing Atopic Status - 06/10/2007
Background: In epidemiological studies, questionnaire data are often used to determine atopic status of participants. When children are study subjects, the information on atopic status is provided by the parents. However, there does not appear to be a literature on the predictive value of a parent's report of allergies. To address this issue, questionnaire data regarding a child's allergy status need to be compared with objective data such as skin prick tests or specific IgE. In addition to obtaining both questionnaire and objective data, the temporal sequence is important for calculating predictive value.
Because of its prospective design, the ALSPAC cohort is ideal for addressing this question. Mothers were asked about their study child's specific allergies at ages 54 months and 81 months. At age 7 years, children attended Focus @7, which included skin prick testing.
Variables related to allergies and allergy symptoms will be used from earlier questionnaires (i.e., 54 months and 81 months) and compared with results of skin prick testing at age 7 years for children who attended the allergy clinic. Wheal size will also be considered. Predictive values of mother's responses at the 54 month and 81 month questionnaires will be calculated. Other variables that may influence a mother's report of child's allergic status will be considered, including mother's self-report of allergy and asthma, paternal allergy and asthma, mother's report of child's asthma, and child's history of wheezing and eczema at younger ages.
Again, I will not need to obtain any variables. All necessary variables were included in the dataset obtained for a project which will be submitted for publication by the end of December, 2007.
B567 - How common is CFS/ME at age 13 and what factors increase the risk of developing it - 03/10/2007
No outline received
B566 - An investigation of language-impairment and dyslexia associated SNPs within the general population - 03/10/2007
We are submitting this project proposal to obtain approval to analyse an additional gene for the project "An investigation of language-impairment and dyslexia associated SNPs within the general population".
We are proposing to include in our analysis the CNTNAP2 gene. This gene has recently been associated with language abilities in separate samples of individuals diagnosed with autism spectrum disorders. We have replicated the associations in our sample of families affected by SLI. This gene is located at 7q36 within the AUTS1 locus where several studies have mapped linkage to autism.
The panel of markers selected for the CNTNAP2 is listed at the end of the Appendix together to the other markers already approved for this project. The genotyping will be performed through the Sequenom system using the ALSPAC DNA samples we already have in our laboratory. Due to multiplex assays' constraints alternative markers might be selected to screen the listed genes. The statistical analysis we plan to perform is based on very standard single marker association approaches and will be very similar to what we conducted for the KIAA0319 gene.
B561 - Genetic contributions to childhood resilience - 01/10/2007
During the last decade, a revolution has taken place among clinical and developmental psychologists. Whereas the emphasis was formerly on continuity and stability over time, with earlier experiences uniformly shaping developmental trajectories, many researchers have come to recognise that individuals are not uniformly plastic, so that some are more susceptible than others to influence. In perhaps the most widely cited demonstration of this, Caspi and colleagues showed in a retrospective study in New Zealand that individual differences in a specific genetic allele determined which children would be adversely affected by depriving early life experiences, whereas children without this allele emerged apparently unscathed from similarly debilitating experiences. The clarity of this finding quickly made believers of many researchers who had hitherto viewed with scepticism decades of scholarship on risk and vulnerability by such researchers as Rutter, Gottesman, and Masten, but empirical demonstration of the nature, extent, and limits of susceptibility to influence (both vulnerability and its obverse, strength in the face of adversity) has been limited. The goal of the proposed research is to examine multiple possible sources (both genetic and environmental) of these individual differences and an array of developmental outcomes using a large, representative, and rich data set collected by the ALSPAC team.
For many years (and with differing degrees of emphasis at different times on either side of the Atlantic) students of child development have recognised that psychological and behavioural development are neither predetermined nor infinitely malleable, although infants appear to be born with marked congenital individual differences. Child psychiatrists such as Thomas and Chess devoted their careers to illustrating the impact of such inborn temperamental attributes on children's developmental trajectories, whereas psychologists such as Rothbart have sought to understood the physiological bases of the major dimensions of temperament that have been identified (Rothbart & Bates, 2006). Students of temperament and behaviour genetics have thus emphasized the importance of biogenetic predispositions and have sought to unpack the ways in which experience might, in combination with congenital individual differences, shape children's development, by promoting stability over time (i.e., 'the child is father to the man'), leading some children to develop more poorly than anticipated, or ensuring that some children prosper, doing better than originally expected. To some extent, progress has been impeded by measurement difficulties, particularly by the challenge of making sense of differences between temperamental appraisals provided by parents (reflecting their subjective perceptions of the child) and those obtained through more objective and systematic observational and physiological means.
In addition, the focus has largely been on the temperamental factors that place some children at greater risk of developing behaviour problems, including serious psychological disturbances-especially because they are "difficult" or "irritable"-- and upon the stability of individual differences, that is, the degree to which children remain difficult across infancy, childhood and adolescence. By contrast, considerably less attention has been paid to such positive characteristics as cheerfulness, perseverance, the capacity to love and be loved, or resilience that might presage positive outcomes; and even less empirical work has focused upon the extent to which-and the reasons why-children's characteristics change. Even though developmental psychologists have shown more interest in the positive side of life than have clinical psychologists, investigating such topics as the origins of empathy, prosocial behaviour, and social skills, few researchers have explored why some children change from negative to positive developmental trajectories and vice versa.
Although it is seductive to assume that those most positively or negatively disposed early in life remain that way as they age, new findings reported by Sharp, Croudace, and Goodyer (2007) caution against such potentially simplistic reasoning. Not only were optimistic 7- to 11-year-olds more likely to change their orientations than peers who had an initial 'neutral' orientation, but those who initially scored highest on optimism scored highest on psychopathology two years later. Clearly, one cannot presume that continuity always characterises the process of human development, including positive development.
Attachment theory has played a particularly important role in shaping understanding of the ways in which early experiences (notably, the quality of parental behaviour and of infant-parent interaction) influence the quality of the close, emotional relationships that infants form to each of their attachment figures and which, in turn, help shape children's later social relationships and approaches to other challenging tasks and experiences. Over the last 40 years, and especially since Ainsworth developed the Strange Situation Procedure (SSP) to assess the security of infants' emotional ties ('attachments') to their mothers, fathers and other caregivers, developmental psychologists have made considerable progress in illuminating the origins and predictive implications of individual differences in child development, even those measured very early in life.
B559 - An investigation into the association between prenatal diet height body composition and IGF levels and subsquent cancer risk using a Mendelian randomization approach - 01/10/2007
Outline
Height, body composition and IGF levels have all been shown to be associated with cancer risk, in particular breast and prostate cancer. The extent to which nutrient availability in the prenatal period affects these phenotypes and subsequent cancer risk is largely unknown. Genetic variation can influence dietary intake and metabolism of nutrients, thus affecting exposure to specific dietary components, such variation will be exploited in this project. The advantage of this method is that associations between genetic polymorphisms and height, body composition and IGF levels are not subject to the problems of measurement error, recall bias and confounding.[i] The use of genes as surrogates for measuring exposures in epidemiology has been termed Mendelian Randomisation, and is gaining recognition as an important research tool, marked by the establishment of an MRC Centre for Causal Analyses in Translational Epidemiology at the University of Bristol.
Suitable candidate genes include those which are; a) associated with nutrient intake, such as the lactase gene, polymorphisms of which determine lactose intolerance and therefore milk intake[ii] b) involved in nutrient metabolism, for example the MTHFR gene which is involved in the metabolism of folate,[iii] c) important in the transport and intern
B558 - The structure and origins of schizotypal personality traits in adolescence - 01/10/2007
No outline received
B557 - Electronic patient records and database research - 28/09/2007
Aims
1. Obtain consent for and establish mechanisms of linkage between ALSPAC study participants and routine sources of health and social data to enable enrichment of the study database and cost-effective prospective follow-up.
2. Investigate challenges to linkage based epidemiological research and follow-up of population-based cohorts and develop generalisable solutions to these problems
3. Demonstrate the value of linkage-based research through a series of exemplar projects on key health and social outcomes in young adulthood.
4. Establish a training programme to share these methods and insights with other researchers.
B560 - Pilot study of ALSPAC hearing data at age 11 work towards grant application - 27/09/2007
The aim of the pilot work is to support an application for the proposed 17+ clinic. The following data are required for preliminary analyses:
1. Hearing threshold and hearing questionnaire data collected at the Focus11+ clinic.
2. Sex of child
3. Social status of child
The following analyses will be performed:
1. Comparison of the frequency distribution of hearing threshold at 11 years with the data currently being collected at age 15 years.
2. Comparison of the frequency distributions at age 11 and 15 with similar data from the 1958 cohort study
3. Estimation of the percentage of children with a permanent hearing loss at age 11 years
4. Effect of sex and social status on hearing thresholds at age 11
The results of these analyses will be used as part of a grant application, and may also be written up for publication.
B555 - The association between social functioning social cognition and psychosis-like symptoms in the ALSPAC birth cohort - 20/09/2007
Aims
1/ To examine the cross-sectional association between social functioning, as measured by the SCDC at age 13 and the presence of PLIKS at age 13 yrs
2/To examine the strength PLIKS, as measured at age 13, as a predictor of poor social functioning at age 15 years.
3/To examine the role of social cognitive ability, as measured by the Emotion Triangles Test, at age 13, as a mediator, in the above association.
4/To examine how social functioning and social cognition as measured at age 13, predict the future development of PLIKS, as measured by questionnaire at ages 14 and 16 years.
B556 - Relation of adverse psychosocial enviroment to childhood obesity and early puberty as markers of future breast cancer risk - 19/09/2007
Objectives/aims:
- To establish whether markers of adverse psychosocial environment (such as adverse socioeconomic circumstances and stressful life events) are associated with biochemical markers of cortisol metabolism (fasting cortisol levels and urinary excretion of total cortisol metabolites at age 8), central fat patterning (by waist circumference and DXA), and earlier timing of thelarche and menarche (by questionnaire).
- To establish whether these associations are modified by level of physical activity and energy intake.
In addition to providing a test of our proposed stress-body fat-puberty model, the proposed study also has the potential to inform the scientific basis of targeted interventions to reverse the childhood obesity epidemic .
B552 - Meta-analyses of genetic association studies of psychiatric disorders - 17/09/2007
No outline received
B514 - Association between common variants in the adiponectin gene APM1 or ADIPOQ and childhood growth body composition adiponectin levels and insulin sensitivity - 15/09/2007
No outline received
B554 - Sexually transmitted infections and sexual behavior in an adolescent cohort - 14/09/2007
Sexual health is an important component of physical and mental health. In the UK, rates of teenage pregnancy are among the highest in western Europe and sexually transmitted infections (STIs) such as chlamydia are common in teenagers and young adults. Sexual behaviour is a normal part of human development and it is crucial to understand the factors that influence sexual health and behaviour through this development process in adolescence to guide suitable public health interventions to improve sexual health.
The ALSPAC cohort is representative and extremely well characterised from before birth. The ALSPAC children are now teenagers, and this offers a unique opportunity to study adolescent sexual behaviour and adverse sexual health outcomes, including sexually transmitted infections. Sexual activity has been measured at age 11, 12, 13+, 15+ and factors affecting relationships between the individual and his/her environment have been measured across the life-course. We propose to repeat the sexual activity questionnaire at the age 17+ clinics and in addition, collect biological samples to test for current and past chlamydia and human papillomavirus (HPV) infection. These infections are common and important in terms of public health policy given the recent introduction of the National Chlamydia Screening Programme and imminent HPV vaccine introduction. Using this data, we will describe the sexual behaviour and prevalence and incidence of chlamdyia and HPV in teenagers, and identify risk factors for adverse sexual health outcomes. By doing so, we aim to identify potentially modifiable behaviours/ factors that can be used to develop sexual health interventions for young people.
Aims:
- To describe the sexual behaviour of ALSPAC participants attending the age 17+ clinics
- To establish the prevalence of current and past infection with chlamydia in ALSPAC participants attending the age 17+ clinics
- To establish the prevalence of current and past infection with HPV in ALSPAC participants attending the age 17+ clinics
- To measure associations between sexually transmitted infections with current and past sexual behaviour and other risk taking behaviours
- To establish early-life influences and predictors of adverse sexual health outcomes
Methods:
We propose to engage the cohort in the next round of clinics at age 17+ years. Participants attending the clinics will be invited to complete a computer assisted self-interview (CASI) on 'romantic relations' and other relevant risk behaviours, particularly substance use. The romantic relations questionnaire was first introduced at the age 11+ clinic and to maintain consistency between assessments we will retain this questionnaire. However, we will also assess whether further questions should be added, for example, to allow direct comparisons with NATSAL. Participants will be invited to give blood and first catch urine samples which will be used to test for active and past infection with chlamydia and HPV (see below). In addition, informed consent will also be sought to test stored samples collected in the age 15+ and 13+ clinics.
These data will be analysed to describe the age-specific sexual behaviour and the incidence and prevalence of HPV and chlamydia. We will then identify risk factors for HPV and/or chlamydia infection over life course and associations with other risk taking behaviours. Predictor variables from biological, individual, family, peer, social and cultural domains will be considered for inclusion in regression models.
B551 - Early origins of coronary heart disease Application of the Illumina50k chip to the Avon Longitudinal Study of Parents and Children - 14/09/2007
No outline received
B490 - Determination of FT1 abundance in ALSPAC sample lysate - 14/09/2007
Project outline:
The recent swathe of genomewide analyses, which are essentially acephalous scientific experiments testing all available genetic variants for association with common disease traits, has thrown up a series of apparently novel pathways for further analysis. One of these is that of the FTO locus of chromosome 16 which has been shown now to have a association with T2D driven entirely by its robust associaion with fat mass (Zeginni et al Science 2007, Frayling et al Science 2007). As yet, neither the driving force behind this association, nor its biological foundation have been elucidated.
Returning to the work of Remy & Michnick (Molecular and Cellular Biology) and personal experience alongside Pof Jeremy Tavare, Prof Holly recalled that the adjacent locus to FTO, AKTIP (seen below)fundamentally involved in the insulin signalling pathway. This protein has been observed to enhance the PKB mediated recruitment of GLUT4 to the cell surface and hence the action of IGF1, IGF2, and consequent responsiveness to insulin.
Whilst not the actual site of association
Observed by Zeginni and Frayling, the
protein (FT1) encoded by AKTIP
may well lie in the 5' promoter of the
FTO locus, possibly having an impact on
the expression pattern and profile of the
locus concentrated on by these new
reports.
In efforts to verify this, a simple
experiment can be performed which can
enable one to assess the relative
abundance of this protein (FT1) in the
lysate of spent samples (here derived from
the ALSPAC cohort. With genotypes
already collected for this cohort, one simply
requires samples of cell pellets for examination via the use of FT1 antibody which has already been developed and delivered to Bristol (and lab in question here) by Remy and Michnick. This experiment will employ simple western blotting approaches for the examination of FT1 protein levels (measured in a semi-quantitative manner) in individuals organised by their respective FTO genotype. Under the hypothesis that the FTO locus is exerting its observed metabolic association through its interaction with the FT1 locus, one may anticipate a genotype specific difference in the yield of FT1 by this approach.