Proposal summaries

These are research proposals that have been approved by the ALSPAC exec. The titles include a B number which identifies the proposal and the date on which the proposals received ALSPAC exec approval.

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B807 - The measurement of polybrominated diphenylether flame retardants in samples of umbilical cord - 01/04/2009

B number: 
B807
Principal applicant name: 
Prof John Gordon Bell (University of Sterling, UK)
Co-applicants: 
Prof Jean Golding (University of Bristol, UK), Prof Anne O'Hare (University of Edinburgh, UK)
Title of project: 
The measurement of polybrominated diphenylether flame retardants in samples of umbilical cord.
Proposal summary: 

The hypothesis we would like to test is that children with autism, and perhaps those with other forms of developmental delay (DD), may have elevated body polybrominatd diphenylether (PBDE) concentrations, compared to typically developing (TD) controls. Using samples of umbilical cord tissue to measure PBDE leadings is highly relevant to what the foetus would have received from the mother via the placenta. In the first instance we would like to obtain 3 samples of cord tissue of varying mass, between 0.3 and 1.5g, so that we can find out what PBDEs we can measure in samples of this size. Hopefully we will be able to meaure most of the important PBDEs in these samples so that we could proceed with a funding application to measure samples from the different study groups described above.

PBDEs have been used as flame retardants in textiles, including carpets, curtains and household furnishings, as well as in plastics and computer components, since the mid-1980s, around the time that autism prevalence began to increase globally. While the causative factors involved in an individual becoming autistic are likely to be multi-factorial, the timing of PBDE introduction in homes and workplaces, their rapid rise in the environment since the 1980s and a parallel rise of PBDE concentrations in human tissues and fluids along with their known affects on metabolism makes them environmental factors that are very worthy of further investigation. Unlike many of the other neuroendocrine and elemental toxins such as dioxins, PCBs, Hg and Pb, that are all decreasing in the environment, PBDEs have risen rapidly over the same time frame as the recorded increased prevalence of autism. While around 43 PBDE congeners have been identified the contribution to overall tissue concentrations in humans is largely represented by 10 congeners namely PBDEs 28, 47, 49, 66, 99, 100, 153, 154,183 and 209. The measurement of tissue PBDE concentrations will be conducted using state-of-the-art analytical equipment including automated solvent extraction (ASE(tm)) and gas-chromatography/mass spectrometry (GC/MS). PBDEs have known endocrine disrupting activity including alteration of thyroid hormone concentrations [they deplete T4 levels and function, as well as reducing vitamin A (retinol)]. In addition, PBDEs stimulate pro-oxidant activity resulting in an increase in the oxidised/reduced glutathione ratio (GSSG/GSH). Increased GSSG/GSH ratio and antioxidant dysfunction have been reported in patients with autism. PBDEs induce hepatic cytochrome P450 IIB1 and 1A1 hepatic detoxifying systems. Possible impairments in this metabolic detoxification in individuals with autism and/or developmental delay might make these individuals more susceptible to elevated tissue levels of PBDEs. Perhaps the greatest concern of damaging effects of PBDEs relate to developmental neurotoxicity in mice and rats. These effects include disruption of spontaneous behaviour, impaired learning and memory, hearing and memory impairments and behavioural changes. The mechanisms for these affects on behaviour and cognition are unknown but may be associated with alterations to cholinergic receptors (Viberg et al., 2002).

Date proposal received: 
Wednesday, 1 April, 2009
Date proposal approved: 
Wednesday, 1 April, 2009
Keywords: 
Biological Samples
Primary keyword: 

B805 - Exploring and understanding the food practices of working families with younger children - 30/03/2009

B number: 
B805
Principal applicant name: 
Dr Rebecca O'Connell (University of London, UK)
Co-applicants: 
Prof Julia Brannen (University of London, UK), Dr Ann Mooney (University of London, UK), Dr Charlie Owen (University of London, UK)
Title of project: 
Exploring and understanding the food practices of working families with younger children.
Proposal summary: 

N.B. This research proposal is a response to a specific call from the ESRC/Food Standards Agency relating to the NDNS

Recent research suggests that the nation's diet will be more likely to improve if healthy eating policies take into account changing patterns of family life (Jackson & Pickering, 2009). This study aims to map and understand the effects of a major social change that research indicates affects the quality of children's diets, namely the rise of maternal/dual parental employment in the UK. The study will take as its starting point that children's nutrition and food practices take place not only in their homes but in a range of contexts. The study will interrogate the 2009 National Diet and Nutrition Survey (NDNS), the Health Survey for England (HSE) and the Avon Longitudinal Study of Parents and Children (ALSPAC) to examine in relation to diet the associations found in other studies between childhood overweight and parental employment. This secondary analysis will be followed by an intensive study of 48 working families sampled from the NDNS and selected according to (high and low) income level and the quality of children's diets. This part of the study will seek to provide explanations for statistical associations found (or not found) in the NDNS survey data. It will employ ethnographic methods, including interviews and photo elicitation, in order to understand the social processes which influence healthy and unhealthy diets of children both within and outside the home. The quantitative analysis of secondary data will hypothesise and examine associations between diet and parental employment status while the qualitative part of the study will inductively explore the contextual meanings of 'food use' in working families, the embodiment of food practices, and their embeddedness in different social contexts (inside and outside the home). The implications of the research for policy and practice include informing the design and evaluation of health interventions so that they may be tailored more effectively to the needs of employed families. Through its use of a variety of research tools the study will inform the methodology of future studies.

Background

Between 1995 and 2003, the prevalence of obesity among children aged 2 to 10 rose from 9.9% to 13.7% (Health Survey for England, 2006). As UK studies suggest, early childhood overweight is associated with the propensity for overweight and obesity in adulthood (Gardner et al., 2009). Given the lack of robust evidence concerning the effectiveness of interventions later in the life course (Summerbell et al., 2003), public policy is concerned with children's health (DH/DCFS, 2008a). Research has shown that some groups of children are at greater risk of being overweight and obese than others (Waldman, 2008): those from lower social economic groups (e.g. Kinra et al., 2000; Armstrong et al., 2003; Power et al., 2003; Stamatakis et al., 2005); and some ethnic minority groups (Health Survey for England, 2004; Rennie & Jebb, 2005; Law et al., 2007).

In addition, research evidence suggests an association between maternal employment and children's overweight status (Scholder, 2007; Hawkins et al., 2008). Analysing the Millennium Cohort Study, Hawkins et al. (2008) found associations between maternal employment and overweight among preschool children, a finding supported by some US research (e.g. Anderson et al. 2003; Crepinsek & Burstein, 2004). Specifically, Hawkins et al. found that children's likelihood of being overweight increased with the number of hours their mother worked per week. However, this finding was only significant among higher income families (annual income in excess of £33,000) (Hawkins et al., 2008). These results mirror US studies showing links between childhood overweight and maternal employment in highly educated, well off, white families (Fertig et al., 2003). These findings thus serve to complicate the general picture of a positive association between household income and children's weight (see e.g. Health Survey for England, 2006). Hawkins et al. (2008) hypothesise a link with diet, suggesting that longer maternal working hours may impede young children's access to physical activity and healthy foods. Analyses of ALSPAC suggest that the dietary patterns of children aged three (North & Emmet 2000) and seven (Northstone & Emmet, 2005) whose mothers were in paid employment were significantly associated with a 'junk' dietary component, although these studies do not explore diets in relation to working hours. In apparent contradiction, a survey by Sweeting & West (2005) of older children and their working parents (N=2,146) suggests a link between non-working mothers and poor diets : 63% of 11 year old children whose mothers were at home full-time were classed as eating "less healthily", compared to 52% of those whose mothers worked full-time. However, this latter analysis did not control for income and maternal education which are known to affect children's diets (Gregory et al., 1995; Northstone & Emmett, 2005).

Early nutritional experiences have both immediate and long term consequences not only for younger children's weight but also for their educational attainment and mental, social and economic wellbeing (NHS/HDA 2004; DfES, 2006; FHF, 2007; Feinstein et al., 2008; Golley et al., 2008). A possible link between parental employment and children's diet is important since the rise of maternal employment is one of the key recent social changes which has impacted upon children's lives in the UK (Layard & Dunn, 2009); the economic activity rate for women aged 16-59 rose from 59% in 1971 to 74% in 2007 (ONS, 2007; Walling, 2005). The most striking change in employment rates has occurred among mothers of young children (Berthoud 2007). In 2004, 57 per cent of women with a child of pre-school age were economically active compared with 55 per cent in 1997 (Aston et al., 2005); more than two thirds of working-age women with dependent children (68%) were in employment in the second quarter of 2008 (ONS, 2008).

However, these rises in parental employment have not been accompanied by any significant increase in public policy or workplace support for employed parents. Within the household, although recent studies have highlighted increases in men's care contribution to family life (e.g. Gershuny, 2001; O'Brien & Shemilt, 2003), including food provisioning (e.g. Drydon et al., 2009), gendered sociocultural expectations around carework have not kept pace with changes in parental employment patterns. Women remain disproportionately responsible for food work (Murcott, 2000; DeVault, 1997): the UK Time Use Survey suggests that in 2000 females spent roughly twice as much time as males on the activities of shopping, preparing food and washing up (ONS, 2000). Some US literature suggests that 'time poor' working families may face significant challenges in meeting the demands of feeding their families (e.g. Jabs et al., 2007). Parents' feeding decisions may represent attempts to reconcile competing symbolic and practical tasks. For example, whilst they recognise that some 'convenience' food is not 'healthy', mothers may find it helps them 'meet their priority of feeding their families in a time-scarce environment' (Jabs et al., 2007:24; Warde, 1999).

Theoretical approaches and methodologies

Research suggests that because parents play such a critical role in determining the diets of their children, as meal providers and role models (e.g.Wardle and Cooke, 2008), 'pressures on parents' food choices have great importance for the nutrition and health status of their children' (Devine et al., 2006: 2592). However, children exert their own pressures on parents (Norgaard et al., 2007), form their own preferences and practices and use food to forge (and reject) connection with others. Food is an important way in which people construct identities through consumption (Valentine, 1999), especially for children (e.g. James, 1998; Wills et al., 2008; James, 2008; James et al., forthcoming). In short, food practices are negotiated (DeVault, 1997; Jackson & Pickering, 2009:4). This study will be guided by such ideas and by a practice-based theory of family life (Morgan, 1996) in which children's agency is given due weight (Christensen, 2004). While home and family are of central importance in terms of feeding younger children and establishing eating patterns (Birch, 1998), they also interact with other environments (Bronfenbrenner, 1979) which provide food and influence food practices (NICE, 2006:149). School is a key eating environment for older children and when mothers or both parents work, for younger children nurseries, childminders, after school clubs, and the homes of friends and relatives are environments where a large proportion of the daily diet is consumed. Much of the limited supply of childcare in the UK is provided in the private sector by large companies or small businesses (private nurseries and childminding) where regulations around food consumption are limited (More, 2008), in contrast with the tighter regulations in schools (cf. Belot & James, 2009). A holistic view of children's nutrition and food practices is needed to understand the range of intersecting contexts in which children are nourished and their food practices nurtured.

A focus in some public health policy on individual consumer 'choice' has tended to confound food selection with preference, obscure the socio structural conditions in which food practices evolve and neglect the cultural and emotional factors that influence nutrition (Attree, 2006:67). Food plays important roles beyond providing sustenance, fulfilling non material cultural goals (de Garine, 2004:19) for adults and children (Alcock, 2007). It is an expression of care and identity (Kaplan, 2000). It is also political (Lien, 2004); food mediates power relations, including those based on age and gender (Murcott,1982,1983a; Charles & Kerr 1988). Understanding food practices requires approaches that go beyond rational-choice paradigms to confront 'habitus' (Bourdieu, 1977) - the situatedness of practices in everyday routines and social relations. Providing empirical data concerning the relationship between parental employment and children's diets and the embedded practices and processes which shape them, the proposed study will fill a clear gap in knowledge.

The main aims of the study are to address these key research questions:

* How does parental employment influence and shape family food practices in particular the diets of children (aged 1.5 to 10 years)?

* How do parents' experiences of negotiating the demands of 'work' and 'home' affect domestic food provisioning in families?

* What foods do children of working parents eat in different contexts - home, childcare and school - and how do children negotiate food practices?

The specific objectives of the study are:

1. To examine the relationship between parental employment status and the diets of younger children via secondary analysis of the 2009 NDNS Survey, the Health Survey for England (HSE) and the Avon Longitudinal Study of Parents and Children (ALSPAC)

2. To seek understandings of the food practices of children in working families, including families with high and low incomes and those whose children are classified on the NDNS as having 'healthy' and 'unhealthy' diets, by applying a range of in-depth qualitative methods

3. To develop the methodology in this area through the use of a multi-method research approach

4. To inform healthy eating advice for employed families, by presenting to policymakers and practitioners issues to consider for bringing about improvements in children's diets

Research design: A mixed methods approach

Hawkins et al., (2008:37) have suggested that '[f]urther research is needed to examine factors along the causal pathway between maternal employment patterns and childhood overweight, which can help inform policy and interventions. For example, little is known about differences in children's diet or physical activity levels by maternal employment status. Focussing on diet, this study will employ the different logics which underpin different methods (cf. Murcott, 1995:734; Brannen, 1992, 2005; Bryman, 1988; Greene et al., 1989). Through secondary analysis of survey data it will hypothesise and examine associations between diet and parental employment status. Through an anthropological and sociological approach it will inductively explore the contextual meanings of food use in working families, the embodiment of food practices, and their situatedness in different social contexts and practices. Together these approaches will help to provide a fuller picture (Brannen 2004; Mason, 2006).

Exploiting the knowledge and capacities of the multidisciplinary research team, the study will draw on a mix of disciplines (anthropology, sociology and social statistics) and research fields including the 'new social studies of childhood', family studies, childcare research and the study of food practices to achieve these objectives and complement the FSA's existing work in nutrition, dietetics and physiology. Its sample will aim to focus on families with at least one young child aged 1.5-10 years. The study will have four main phases. The timetable below is proposed based upon NDNS data becoming available in December 2009:

Phase 1: October - December 2009 Access to large scale data sets (NDNS, HSE, ALSPAC), identification of relevant variables, preparation of data set for analysis in Phase 2, design and piloting of qualitative research instruments for use in Phase 3.

Phase 2: November 2009 - Feb 2010 Secondary analysis of large scale surveys. To examine how parent employment relates to children's diets, secondary analysis will be carried out on the 2009 NDNS, the Health Survey for England (HSE) and the Avon Longitudinal Study of Parents and Children (ALSPAC), as all of these collect data on children's diet and mothers' employment. The NDNS is the only rolling UK survey to collect nationally representative and detailed dietary information on children and adults. So far, different waves have concentrated on specific age groups. A key advantage is that NDNS contains linked data on food, nutrient intake, nutritional status and contextual information on individuals. The first NDNS (1992/93) collected data on the diets of 1,340 children aged 1.5 to 4.5 and collected detailed data on the mother's hours of work. The third survey (1997) collected data for children aged 4 to18, with a full dietary record for 1,701 children; the survey asked about mother's employment, but only classified hours of work as full or part time. Some data have been analysed by social class (Gregory & Hinds, 1995), but not by mother's employment. Unfortunately, the sample sizes are quite small, especially for analysing sub-groups (Scientific Advisory Committee on Nutrition, 2008:21), such as employed mothers. Parental employment appears to have been asked in NDNS 2009.

HSE is an annual survey carried out on behalf of the NHS. The survey includes data on diet and nutrition for children and hours of work for mothers (although only full or part time). In 2007 there was a boost sample of children, so that a total of 7,504 children were included (Craig & Shelton, 2008b). The relation between diet and maternal employment has not been analysed. However, even a sample this size has limitations: as the survey report noted, while 'exploratory analysis indicated that there may be associations between a child's perception of how healthy they perceive their diet to be and how healthy their parents perceive their own diet to be... numbers of parent and child pairs ... are too small to produce reliable conclusions' (Craig & Shelton, 2008a: 292).

From the early 1990s ALSPAC followed approximately 14,000 children from birth into their teenage years. It collected detailed data at different age points on children and their families, including data on parental employment and on diet and nutrition (Emmett, 2009). This unique dataset provides opportunities to explore associations between employment and children's diets in a large sample across the childhood years. The level of detail on mothers' hours of employment varies at different points in time: at 47 months mothers were asked about employment, but not about hours of work; at 61 and 85 months mothers were asked about hours of work. However at 73 months mothers were not asked any questions about their employment. This study would look in detail at the effect of hours of work at different ages. Other studies have related diet and nutritional information for children and socio-economic data for adults: diet in 3-year olds (North & Emmett, 2000) and 4-year olds and 7-year olds (Northstone & Emmett, 2005) was analysed in relation to socio-economic factors, including mother's employment, although diets in relation to working hours was not examined.

These three datasets each has some information to contribute, but each has its limitations - in terms of sample size or in terms of details on hours of work. By analysing the data in combination, it should be possible to explore the relation between mother's hours of work and children's diet in more detail than has been done before. To identify a composite measure of diet quality using variables from the NDNS, HSE and ALSPAC datasets the advice of a public health nutritionist will be sought. The nutrition literature contains a wide variety of diet quality indices (Emmett, 2009; Kant, 1996) which have different advantages and disadvantages. The aim is to derive and interpret children's dietary patterns and assess their association with parental employment status using appropriate multivariate analysis techniques. The viability of the NDNS 2009 sample we wish to select will also be tested - single and dual parent earner households with children aged 1.5-10 years. Given the possible small sample size of the latter age group in the NDNS 2009 it may be necessary to carry out the analysis on all children in the survey who are under 18 years.

Phase 3: January - December 2010 Selection of participants, fieldwork and preliminary analysis of the qualitative study of employed parents and children's diet. The 2009 NDNS offers the most up to date analysis of children's diets and will provide the sampling frame for working families. This part of the project will seek to understand the relationship between parental employment and the food practices in which parents and their children aged 1.5-10 engage both in the home and in contexts outside the home. Forty eight dual and lone parent households and high and low income groups will be selected from the NDNS 2009 survey. The sample of households will be drawn from a number of urban and suburban areas in which these data are clustered in several different parts of England. To assist recruitment and thank participants for their time commitment, vouchers will be given to each household. Whilst we would hope to secure all 48 households in this way, we may need to be pragmatic if this is not possible. Further families will be found through snowballing from the selected NDNS participants. These participants will be screened for household employment and age of children, income and broad dietary indicators through completion of a short telephone interview (Casey et al., 1999). The diet data will be collected in the same format as in the NDNS to make the additional sample comparable. Four groups of working families divided by income level and by the quality of children's diets as assessed by the NDNS data will be selected:

(a) 12 households (one child aged 1.5-10) in which the child scores high on a composite measure of diet quality and where the parent /s they live with are employed and in low status jobs;

(b) 12 households (one child aged 1.5-10) in which the child scores low on a composite measure of diet quality where the parent/s they live with are employed and in low status jobs;

(c)12 households (one child aged 1.5-10) in which the child scores high on a composite measure of diet quality where the parent/s they live with are employed and in high status jobs;

(d) 12 households (one child aged 1.5-10) in which the child scores low on a composite measure of diet quality where the parent/s they live with are employed and in high status jobs.

Since the home is at the centre of family food practices the study will necessarily focus on food in the domestic domain. However, because other environments (workplaces, preschools, schools, after school clubs) interact with the home (e.g. Brannen & Storey, 1998; Burgess & Morrison, 1998), supplementing and influencing food practices within it (and vice versa), data will be collected from parents and children about food consumption in these contexts. Further, because food practices are embedded in social relations and social processes, they are not necessarily easily accessible to reflection (Eisner, 2008). The use of creative and visual methods facilitates investigating layers of experience that cannot easily be put into words (Gauntlett, 2007; Bagnoli, 2009). A flexible range of research tools (e.g. Mooney & Blackburn, 2003; Edwards et al., 2005) will be employed as appropriate to bring practices to the level of discourse and to address the contexts in which food is consumed. These will include 4 approaches: (a) in-depth semi-structured interviews with parents and children aged 1.5-10 that includes story telling with children; (b) drawing methods with children (e.g. Backett & Alexander, 1991; Backett-Milburn & McKie, 1999; Hill et al., 1996; Morrow, 2001); (c) a task based exercise in which family members will be asked to suggest working-family-friendly meal ideas for inclusion in a cookbook; (d) photo elicitation interview methods (PEI's) (Collier, 1967; Radley & Taylor, 2005) carried out by parents and children (Punch, 2002) in which they will photograph foods and meals (consumed in and outside the home) for discussion in the interview. Adopting this range of qualitative tools will enable choices to be made about the most appropriate methods for eliciting children's perspectives based on their maturity, competencies and preferences (Hill, 2006; Christensen & James 2000). Rather than only serving as 'records' of food eaten (as in a realist approach), photographs, drawings and storytelling will be employed to aid reflection (Harper, 1998, 2002; Pink, 2001) upon the meaning of food events to participants and the relevance and importance of different social, environmental and temporal contexts. Photography is a particularly appropriate method for achieving our objectives, not only because it may bring the public into the private (and vice versa; cf. Moss, 2001) but also because food is a material substance which appeals to several senses and is amenable to visual representation. Households will be visited twice. At the first visit, the PEI and other exercises will be explained to parent(s) and children; at the second visit, parent(s) and children will be interviewed, employing photographs, drawing, storytelling and the cookbook task as appropriate. Analysis of photographs is a collaborative process between participants and the researcher. As in qualitative research more generally, analysis is an iterative process in which emergent questions guide the collection of future data (Pink, 2004; Jenkings et al., 2008). Qualitative data analysis software (e.g. NVivo/NUD*IST/Atlas.ti) will be employed to assist in the inductive development of key themes, patterns and categories (Hammersley & Atkinson, 2007) specifically relating to the negotiation of domestic food provisioning and the experiences of participants relating to food practices across different sites.

Phase 4: Jan 2011-September 2011. Analysis, writing up and raising methodological questions for future research including the NDNS survey. The fourth phase will involve integrating the data and results generated from the secondary analysis of NDNS, HSE and ALSPAC and from the qualitative study. The ways in which the different data sets will be integrated will be considered from the outset of the study (Greene et al 1989; Brannen 1992, 2005; Bryman, 2006). Mixed methods can provide for an articulation between different layers and types of explanation - macro and micro - each of which cannot be fully explained without reference to the other (Kelle, 2001). However, it is recognised that translation of research questions across different methods of data collection changes their significance and is likely to affect responses and create problems of interpretation. The two layers do not map on to each other readily; they are different forms of explanation albeit they may complement one another (Bryman, 2007; Murcott 1995). We may expect to find some dissonance (Perlesz & Lindsay, 2003) between findings generated by different methods, e.g. reports of the nature of diets in the survey and what is said in the interviews. On the other hand, we may expect the two analyses to complement each other, e.g. explanations for dietary habits may not be viewed in relation to health or quality issues. The analysis of the NDNS and the qualitative study will provide guidance for future research about the value of a mixed method approach for this area of research, which methods and which survey/interview questions are useful and for which purposes.

Date proposal received: 
Monday, 30 March, 2009
Date proposal approved: 
Monday, 30 March, 2009
Keywords: 
Social Conditions
Primary keyword: 

B801 - Determination of the affect of a complex CNV region on Chr 12 on various psychological variables of the ALSPAC cohort - 30/03/2009

B number: 
B801
Principal applicant name: 
Prof Anthony J Brookes (University of Leicester, UK)
Co-applicants: 
Title of project: 
Determination of the affect of a complex CNV region on Chr 12 on various psychological variables of the ALSPAC cohort.
Proposal summary: 

Copy number variation (CNV) represents a significant proportion of human genomic variation and it is increasingly becoming clear that CNV is involved in phenotypic variation and disease (Itsara et al, 2009). We are interested in understanding the relationship between copy number variation at loci critical to development, growth and disease. Our current region of interest focuses on a genomic domain spanning genes important for pluripotency, energy utilisation and the immune response. Our analysis of the current genome build reveals part of this region to exist mainly as an ancient (pre-simian) tandem duplication, with corresponding gene duplications. SNP genotyping across this interval in a case control study demonstrated association with rheumatoid arthritis and also revealed hints for CNV (Lorentzen et al, 2007). Due to its complexity and limited LD with surrounding DNA the region is not detected using current genome wide SNP technologies, and therefore targetted CNV analysis is required. Assays for CNV within the tandem duplication were developed based on an adaption to the paralogous ratio test (PRT)(Armour et al, 2007). In these assays the relative number of copies between the tandem repeats is assessed using oligonucleotide primers that amplify simultaneously from both repeats. During this analysis we discovered that either repeat can be duplicated or deleted, thereby representing a complex CNV. From these investigations we have developed an accurate copy number counting assay and demonstrated a significant association between rheumatoid arthritis and copy number of this tandem duplication. This region is of substantial interest as, in addition to the association with RA, it has been implicated in a number of disorders through the data from the rat genome database including QTLs related to insulin resistance and heart disease. Mouse models determine that homozygous nulls for this gene are lethal whereas heterozygous null are related to insulin resistance and increased body mass. Furthermore, changes in protein levels of one of the genes within the CNV in humans has been linked to cancer, insulin resistance and Alzheimer's disease. Given the wide range of disease associations and the role pluripotency, energy transfer and immune response plays in growth and development it is likely that changes in copy number at this region will have an impact on various underlying biochemical measures. Therefore it would be prudent, in addition to traditional case control studies that we are planning, to examine the role of copy number in relation to various endophenotypes. For this the highly characterised ALSPAC cohort is ideal.

For this purpose we have designed and assessed a number of assays based on the paralog ratio test (PRT). These assays allow the assessment of copy number between the repeats, and thereby can indicate which of the two repeats are changing in copy number. The PRT is relatively unique among copy number counting methods in that it requires very little DNA to produce accurate counting. It would therefore be feasible to rapidly genotype the entire ALSPAC cohort with multiple assays using 100 ng DNA, including repeats.

The results of these assays would then be analysed in relation to various biochemical and physiological measures listed below.

Date proposal received: 
Monday, 30 March, 2009
Date proposal approved: 
Monday, 30 March, 2009
Keywords: 
Genetics, Psychology
Primary keyword: 

B804 - Contribution of ALSPAC lung function data to international consortium on lung function reference values - 24/03/2009

B number: 
B804
Principal applicant name: 
Prof John Henderson (University of Bristol, UK)
Co-applicants: 
Title of project: 
Contribution of ALSPAC lung function data to international consortium on lung function reference values.
Proposal summary: 

An international concortium led by Janet Stocks, UCL and funded initiallly by Asthma UK, has produced reference equations for spirmoetry from childhood through to adult life (www.growing lungs.org). This project is an extension of this work utilising large collections of lung function data from cohort and cross-sectional studies to refine the current reference equations. ALSPAC has greater than 7000 measurements fo spirmoetry in 8 year olds and a further 4000 from 15 year olds that will be a valuable addition to the resource and wil be appropriately credited in publicatiosn arising from this work.

Data required are spirometry measurements form Focus@8: FEV1, FVC and mid expiratory flows (FEF 25-75) and child's sex, height and weight on day of measurement. No other identifying information will be sent.

Date proposal received: 
Tuesday, 24 March, 2009
Date proposal approved: 
Tuesday, 24 March, 2009
Keywords: 
Respiratory
Primary keyword: 

B803 - Evaluation of a novel atopic dermatitis susceptibility variant in the ALSPAC cohort - 24/03/2009

B number: 
B803
Principal applicant name: 
Dr Young-Ae Lee (Masaryk University, Europe)
Co-applicants: 
Prof John Henderson (University of Bristol, UK)
Title of project: 
Evaluation of a novel atopic dermatitis susceptibility variant in the ALSPAC cohort.
Proposal summary: 

Atopic dermatitis (AD or eczema) is a chronic inflammatory skin disorder and a major manifestation of allergic disease. In the industrialized countries, the prevalence of AD is approximately 15 % with a steady increase over the past decades1. Genetic and environmental factors interact to determine disease susceptibility2, and family and twin studies indicate that the genetic contribution is substantial3. The molecular mechanisms underlying eczema are not fully understood. Skin barrier defect as well as systemic and cutaneous immune dysfunction in response to allergens or bacterial products are thought to play an important role4.

We conducted a genome-wide association study in 939 individuals with AD and 975 controls as well as 270 complete nuclear families with 2 affected siblings. SNPs consistently associated with AD in both discovery sets were then investigated in two additional independent replication sets totalling 2637 cases and 3957 controls. Highly significant association was found with rs7927894 on chromosome 11q13.5 (Pcombined = 3.1 x 10-10). Approximately 13% of individuals of European origin are homozygous for the risk allele, and their risk of developing AD is 1.47 times that of noncarriers5.

The objective of this study is to evaluate this novel eczema susceptibility variant at the at the general population level in the ALSPAC cohort in order to

1) replicate the initially reported association with eczema.

The ALSPAC cohort (n=7000) carries sufficient power to replicate the original finding:

Under the assumption of a moderate odds ratio of 1.3 and a disease prevalence of 10%, the power to detect an association is 94%.

2) assess the population-attibutable risk of this variant for eczema.

in contrast to the affected families and cases/controls used in the GWAS, the ALSPAC cohort will enable us to estimate the population attributable risk fraction (PARF) which indicates the proportion of cases in the population attributable to the rs7927894 risk allele.

3) evaluate this variant for association with other atopic disorders.

Interestingly, this variant has also been reported to be a risk factor for Crohn's Disease6, extending the number of overlapping risk variants for different chronic inflammatory diseases and highlighting the importance of shared molecular pathogenic pathways. The ALSPAC cohort will allow us to test this variant for association with other atopic disorders including asthma, and hayfever. An association analysis with Crohn's Disease may be attempted. However, due to the expected low prevalence of Crohn's disease, the ALSPAC cohort may not carry sufficient power to yield conclusive results.

4) evaluate epistatic effects between this variant and Filaggrin loss-of-function mutations.

Loss-of-function mutations in the filaggrin gene are strongly associated with eczema7,8. We have detected an epistatic effect between rs7927894 and the filaggrin loss-of-function mutations in the German Multicenter Allergy Study (MAS 90). However, only 871 of the original 1300 MAS children were available for genetic studies. The ALSPAC cohort is significantly larger than the MAS cohort and will allow us to replicate this finding and to estimate the effect size more accurately.

Reference List

1. Taylor, B., Wadsworth, J., Wadsworth, M., & Peckham, C. Changes in the reported prevalence of childhood eczema since the 1939-45 war. Lancet 2, 1255-1257 (1984).

2. Cookson, W. The alliance of genes and environment in asthma and allergy. Nature 402, B5-11 (1999).

3. Schultz, L. F. Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J.Am.Acad.Dermatol. 28, 719-723 (1993).

4. Bieber, T. Atopic dermatitis. N.Engl.J.Med. 358, 1483-1494 (2008).

5. Esparza-Gordillo, J. et al.A common variant on chromosome 11q13 is associated with atopic dermatitis. Nature Genetics in press (2009).

6. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat.Genet. 40, 955-962 (2008).

7. Palmer, C. N. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat.Genet. 38, 441-446 (2006).

8. Brown, S. J. & McLean, W. H. Eczema genetics: current state of knowledge and future goals. J Invest Dermatol 129, 543-552 (2009).

Concept Specific measure Person Source Time point(s)

eczema Doctor's diagnosis of eczema child questionnaire Age 0-5 years

Age 6-10 years

Age greater than 10 years

eczema eczema child Physical exam Age 0-5 years

Age 6-10 years

Age greater than 10 years

asthma Doctor's diagnosis of asthma child questionnaire Age 0-5 years

Age 6-10 years

Age greater than 10 years

asthma asthma child Physical exam Age 0-5 years

Age 6-10 years

Age greater than 10 years

hayfever Doctor's diagnosis of hayfever child questionnaire Age 0-5 years

Age 6-10 years

Age greater than 10 years

hayfever hayfever child Physical exam Age 0-5 years

Age 6-10 years

Age greater than 10 years

atopy Elevated spec. IgE or Skin Prick test child evaluation Age 0-5 years

Age 6-10 years

Age greater than 10 years

Chronic inflamm. bowel disease (IBD) Doctor's diagnosis of IBD child questionnaire ever

Date proposal received: 
Tuesday, 24 March, 2009
Date proposal approved: 
Tuesday, 24 March, 2009
Keywords: 
Skin
Primary keyword: 

B802 - Investigating the relationship between IL-6 and bone mass accrual in childhood - 24/03/2009

B number: 
B802
Principal applicant name: 
Dr Jon Tobias (University of Bristol, UK)
Co-applicants: 
Title of project: 
Investigating the relationship between IL-6 and bone mass accrual in childhood.
Proposal summary: 

(No proposal received).

Date proposal received: 
Tuesday, 24 March, 2009
Date proposal approved: 
Tuesday, 24 March, 2009
Keywords: 
Bones
Primary keyword: 

B799 - Parallel longitudinal model of childhood depression and BMI LINKED TO B0659 - 23/03/2009

B number: 
B799
Principal applicant name: 
Dr Jon Heron (University of Bristol, UK)
Co-applicants: 
Title of project: 
Parallel longitudinal model of childhood depression and BMI (LINKED TO B0659).
Proposal summary: 

(No outline received).

Date proposal received: 
Monday, 23 March, 2009
Date proposal approved: 
Monday, 23 March, 2009
Keywords: 
Depression
Primary keyword: 

B800 - The Impact of Prolonged Infertility on Parenting - 20/03/2009

B number: 
B800
Principal applicant name: 
Dr Catherine Pearlman (Yeshiva University, USA)
Co-applicants: 
Title of project: 
The Impact of Prolonged Infertility on Parenting.
Proposal summary: 

Previous studies have small samples with small or no control groups. ALSPAC's vast data will allow for a larger sample of women who have experienced prolonged infertility. The data also provides for control groups. Due to the large numbers of variables present in the data, it will be possible to screen out for a variety of variables that might skew the data. For example, age of mother, ethnicity, socioeconomic status, and other variables. To date I have not found other studies that use the length of time of being infertile as a variable. Using the ALSPAC data, this will be possible. Instead of focusing on the type of technology used to become pregnant, I will focus on how the length of time trying to conceive influences subsequent parenting.

Date proposal received: 
Friday, 20 March, 2009
Date proposal approved: 
Friday, 20 March, 2009
Keywords: 
Parenting, Fertility/Infertility
Primary keyword: 

B798 - Understanding the lifestyle molecular and genetic pathways that link womens reproductive function to healthy ageing LINKED TO B1193 - 15/03/2009

B number: 
B798
Principal applicant name: 
Prof Debbie A Lawlor (University of Bristol, UK)
Co-applicants: 
Prof Naveed Sattar (University of Bristol, UK), Prof Scott Nelson (University of Glasgow, UK), Prof Kate Tilling (University of Bristol, UK), Dr Caroline Relton (Newcastle University, UK), Dr Jon Tobias (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK)
Title of project: 
Understanding the lifestyle, molecular and genetic pathways that link women?s reproductive function to healthy ageing (LINKED TO B1193).
Proposal summary: 

Aims and objectives of the programme

Broad aims of programme

The aims of the programme are to (i) understand the mechanisms that underlie the associations of women's reproductive characteristics (age at menarche, menstrual patterns, follicular activity, fertility, pregnancy and age of menopause and menopausal changes) with later risk for chronic complex diseases and their risk factors (obesity, hypertension, dyslipidaemia, hyperglyaceamia, insulin resistance, type 2 diabetes, coronary heart disease, stroke, osteoporosis, depression, breast density and breast cancer); (ii) to understand the role of women's reproductive health in healthy ageing and (iii) to determine the mechanisms for the intergenerational transmission of patterns of women's reproductive, cardiovascular, metabolic, skeletal and mental health.

The programme will bring together existing funded work of the PI and co-applicants that is concerned with pregnancy related changes and future cardiovascular, metabolic and bone health in offspring and mothers (project grants from US NIH, MRC, Wellcome Trust & BHF). In the first phase we will focus primarily on consolidating the work from these different projects (objective 1 of the first 5 years) in order to obtain a comprehensive picture of how pregnancy related changes affect a wide range of future health related outcomes in mother and offspring. In addition in the first 5 years we will obtain detailed repeatedly assessed phenotypic data (hormonal, vascular, metabolic, bone and DNA methylation changes) on a cohort of women (the mothers) as they go through the menopausal transition (from age 47-52 years). These new data will be used to address objectives 2-7 below and will provide the evidence based for understanding how oestrogen deficiency and menopausal changes influence ageing in general and specifically vascular, metabolic and muscular-skeletal ageing. With subsequent renewal of the programme , after the first 5 years, we would focus on the daughter's menstrual pattern, follicular activity and emerging fertility, as well as linking data on the mother's breast density from routine mammography and mental health outcomes to the main dataset.

Specific objectives of the first 5 years

We will:

1. Determine the extent to which pregnancy related weight gain, vascular and metabolic changes are related to the mother's and her offspring's future reproductive, vascular, metabolic and muscular-skeletal health.

2. Determine the pattern of changes in glucose, insulin, lipids, blood pressure, total and truncal fat and bone mineral density as women go through the menopausal transition and distinguish whether there is a specific menopausal effect over and above age related changes in these phenotypes.

3. Determine the hormonal, genetic, molecular and lifestyle pathways that underlie variation in age at menopause and variation in changes in vascular, metabolic and bone phenotypes over the menopausal transition.

4. Determine the association of different patterns of change in glucose, insulin, lipids, blood pressure and total and truncal fat over the menopausal transition with variation in postmenopausal carotid intima media thickness.

5. Establish the role of DNA methylation in determining the timing and magnitude of menopausal changes.

6. Determine the pattern of global and gene-specific (e.g. ESR1) DNA methylation patterns as women go through the menopausal transition.

7. Determine the consequences of menopause- related DNA methylation changes with respect to subsequent changes in vascular, metabolic and muscular-skeletal health.

Data requirements and new data collection

Objective 1 above will use existing data or data currently being collected (e.g. mums clinic and 17+ clinic fasting blood samples and assays) and brings together agreed work of the PIs in ALSPAC as funded by existing grants (NIH; MRC; BHF).

The remaining objectives will be addressed by collection of new data from a subgroup (~3000) of the ALSPAC mothers who fulfil the following criteria:

Age 47-49 years at start of new clinics (September 2010)

No previous history of hysterectomy or bilateral oophorectomy

Not known to have undergone natural menopause

Mothers fulfilling these criteria will be invited to attend annual clinics over a 4 year period (4 clinics in total) at which the following will be completed:

1. Completion of menstrual cycle & hormonal use questionnaire

2. Taking of a fasting blood sample

3. Measurement of weight, height, waist circumference and blood pressure

4. DXA scan - total & hip

The grant will request funds to complete the following on the blood samples:

1. Repeat assessment (at each clinic) of sex hormones, glucose, insulin and lipids

2. Global and gene specific DNA methylation patterns.

Date proposal received: 
Sunday, 15 March, 2009
Date proposal approved: 
Sunday, 15 March, 2009
Keywords: 
Epigenetics
Primary keyword: 

B796 - Metabolic syndrome in adolescents Associations with dietary intakes circulating 25-hyrdroxyvitamin D and IGF-1 - 05/03/2009

B number: 
B796
Principal applicant name: 
Dr Kirstin Newby (Boston University, USA)
Co-applicants: 
Title of project: 
Metabolic syndrome in adolescents: Associations with dietary intakes, circulating 25-hyrdroxyvitamin D and IGF-1.
Proposal summary: 

The prevalence of metabolic syndrome (MetS) has been estimated anywhere from 2% to 9.4% for US

adolescents and varies depending on the definition used (1-3). A more recent report based on the National

Health and Nutrition Examination Survey (NHANES 1999-2002) estimated the prevalence of MetS as

high as 23% for overweight/obese children aged 12-18 years (4). MetS components in childhood are

carried into adulthood (5, 6). With the growing obesity epidemic and the positive relationship between

obesity and MetS (7), research aimed at understanding the risk factors for MetS in children is needed and

is likely to have important public health implications.

Diet is a known risk factor for MetS, although contributions of individual dietary components to MetS

remain relatively ambiguous for children and adolescents. In particular, associations between dairy intake

and MetS remain unclear, although several studies, mainly in adults, suggest a protective effect crosssectionally

(8-10) and prospectively (11, 12). The Coronary Artery Risk Development in Young Adults

(CARDIA) study, a 10-year prospective study, reported a lower incidence of MetS (OR: 0.28; 0.14-0.58)

among overweight individuals consuming the highest compared with the lowest dairy category (12).

Little information exists regarding this relationship in children and adolescents. A recent cross-sectional

study observed a decreased likelihood of MetS with higher frequency of dairy, fruit, and vegetable

consumption in children aged 6-18 years living in Iran (13).

Calcium and vitamin D are two major nutrients found in dairy products that may play a protective role

against MetS (10, 14-16). Serum 25-hydroxyvitamin D is used to assess overall vitamin D status. A few

population-based studies have found inverse associations between 25(OH) D and MetS (17, 18). Data

regarding the relationship between calcium, vitamin D, and MetS are limited for children. However, a

cross-sectional study of 217 obese children aged 7-18 years found that vitamin D insufficiency was

associated with several MetS risk factors including higher BMI and systolic blood pressure and lower

HDL-cholesterol concentrations (19). Therefore, examining the potential relationship between dietary

calcium, serum vitamin D and MetS may be important in understanding the associations.

Higher circulating levels of IGF-1 have been associated with risk of certain types of cancer such as

prostate cancer (20, 21), whereas lower levels have been related to other chronic conditions such as

obesity and MetS (22, 23). In several studies, IGF-1 has been positively associated with dairy and milk

intake (24-26). Rich-Edwards et al (27) reported results from two pilot studies examining associations

between milk intake and IGF-1 as follows: 1) Mongolian children showed significant increases in IGF-1

and other factors with whole milk intake over 1 month, and 2) girls living in Boston showed small

increases in IGF-1 when consuming lowfat milk compared with a vegetable-based milk substitute over a

1 week period; these findings were not statistically significant. Rogers et al (26) found that milk and

dairy intakes were associated with IGF-1 and its binding protein (IGFBP-3) concentrations for all

children and for boys after adjustment. These associations were no longer statistically significant after

additional adjustment for protein intake, suggesting that protein may be an important mediator in this

relationship. In that study, dairy intake was positively associated with leg length in boys but not in girls,

and it appeared that IGF-1 played a role in this relationship as the association was attenuated after

adjustment. The mechanism by which IGF-1 is related to milk consumption is not fully understood.

Possible explanations include the high protein content of milk and dairy (26, 28) and/or constituents in

milk that may not be degraded/deactivated during digestion, such as growth hormones used in milk

production (27). More research is needed to identify the exact mechanism by which milk intake increases

IGF-1 and other growth factors. A recent population-based study of 6,810 British subjects found that

serum 25(OH)D and IGF-1 concentrations were inversely associated with MetS. However, associations

with IGF-1 were not statistically significant for participants with the lowest vitamin D concentrations,

indicating that both need to be considered in future research studies (22). Research projects that consider

all of the nutrients and factors discussed above are needed, especially in child and adolescent populations.

Date proposal received: 
Thursday, 5 March, 2009
Date proposal approved: 
Thursday, 5 March, 2009
Keywords: 
Diet, Metabolic, Nutrition
Primary keyword: 

B791 - Investigation of population prevalence and health consequences of structural genetic variants using genome-wide SNP data - 03/03/2009

B number: 
B791
Principal applicant name: 
Dr Tom Gaunt (University of Bristol, UK)
Co-applicants: 
Dr Ruth Newbury-Ecob (University of Bristol, UK)
Title of project: 
Investigation of population prevalence and health consequences of structural genetic variants using genome-wide SNP data.
Proposal summary: 

We propose an analysis of the prevalence and health consequences of genetic variants that are not single nucleotide polymorphisms (SNPs). These include deletions, duplications, variations in copy number and translocations of parts of the genome, up to and including the duplication or deletion of whole chromosomes (monosomy, trisomy etc). Specific examples are: duplications/deletions of parts of genes such as the Haptoglobin duplicon (HP gene) and growth hormone receptor exon 3 insertion/deletion (GHR gene), large chromosomal alterations such as Prader-Willi syndrome (deletion of part of chromosome 15) and changes in chromosome number such as Klinefelter's syndrome (XXY, an additional sex chromsome), triple X syndrome (XXX, an additional sex chromosome) and Down's syndrome (three copies of chromsome 21). These types of genetic variation are not directly measured by current genome-wide SNP arrays, but can be inferred from the raw data, and present the opportunity to gain added value from existing data.

Experimental plan:

* Existing raw genotyping data from Illumina SNP genotyping performed at the Wellcome Trust Sanger Institute will be used

* Raw fluorescence data will be analysed for reductions or increases in total fluorscence across a number of genomically adjacent SNP tests (representing loss or gain of the DNA sequence containing those SNPs

* "Extended homozygosity" (regions where many SNPs appear to have two copies of one allele, rather than two different alleles) will also be identified - some of these will represent deletions

* Pairwise Hardy-Weinberg equilibrium will be used to identify distortions in genotype frequencies that might represent a "null allele" in the sample

* All identified variants will be "phenome-scanned" (i.e. tested against a range of phenotypes representative of all data available), and/or specifically analysed (if they affect a single gene for which the function is known). Whilst numbers may be small, the aim is to identify whether a genetic variant causes individuals to be in the "tail" of the population distribution for particular phenotypes

* Population frequencies of variants, and potentially differences in break-points, will be estimated. Further testing of DNA for breakpoint location and fine mapping is beyond the scope of the current application, but may be requested in the future

For phenotypic analyses a representative range of phenotypic data will be needed. We ask the committee to approve "all" phenotypes, as genomic analyses will inform the phenotypes to analyse on a case-by-case basis, and as such phenotype choice will be iterative. In each case we would wish to compare relevant phenotypes for those individuals with a genetic variant to the phenotype distribution or frequency in the rest of the ALSPAC cohort.

Date proposal received: 
Tuesday, 3 March, 2009
Date proposal approved: 
Tuesday, 3 March, 2009
Keywords: 
Epigenetics , Genetics
Primary keyword: 

B793 - Association of childhood socioeconomic position at birth with adiposity and metabolic markers at age 9 and 15 - 25/02/2009

B number: 
B793
Principal applicant name: 
Prof Debbie A Lawlor (University of Bristol, UK)
Co-applicants: 
Dr Laura Howe (University of Bristol, UK), Dr Bruna Galobardes (University of Bristol, UK), Prof John Deanfield (University College London, UK), Prof Naveed Sattar (University of Bristol, UK), Professor Aroon Hingorani (University College London, UK), Prof George Davey Smith (University of Bristol, UK), Prof Andy Ness (University of Bristol, UK)
Title of project: 
Association of childhood socioeconomic position at birth with adiposity and metabolic markers at age 9 and 15.
Proposal summary: 

Adverse childhood socioeconomic position is associated with increased coronary heart disease (CHD) risk in later life,(1,2,3) and it has been suggested that this may, at least in part, be mediated by adiposity and its associated adverse metabolic and vascular changes. As well as being associated with future risk of CHD, individuals from poorer socioeconomic backgrounds in childhood have also been found to be more obese, more dyslipidaemic and more insulin resistant in adulthood than those from higher socioeconomic groups.( 4,5) Greater BMI and obesity in childhood and early adulthood have been shown in two very large studies to predict CHD risk in adulthood,( 6,7) but it is unknown whether this association is because of the tracking of BMI from childhood to adulthood (in which case interventions to prevent/treat obesity in adulthood might be an appropriate option) or whether permanent changes in metabolic and vascular function occur in childhood as a result of greater adiposity (in which case interventions in childhood would be paramount). A major problem with life course studies that identify associations of risk factors in childhood / early adulthood (socioeconomic position or BMI in the examples above) with future risk of adult diseases such as CHD, is that by definition the populations being studied experienced their childhood at least 5-6 decades ago and the relevance of these findings to contemporary populations of children, who live in very different circumstances, is unclear.

If the association of childhood adverse socioeconomic position with adult CHD risk from older birth cohorts is at least in part because those from poorer backgrounds in childhood were more obese and therefore experienced adverse metabolic consequences which resulted in long-term damage and increased susceptibility to future CHD risk, and if socioeconomic differentials in contemporary children were likely to have similar long term effects on future CHD risk, then one would expect to find socioeconomic differentials in adiposity and its associated adverse metabolic outcomes in contemporary cohorts of children.

Studies in contemporary populations of children from high income countries have shown socioeconomic differentials in adiposity, with those from more deprived socioeconomic backgrounds being more adipose.( 8,9) For example, in the European Heart Health Study children aged 9 and 15 from Denmark (high income country) whose parents were least well educated and who came from houses with the lowest income had larger waist circumferences and skinfold thicknesses and greater BMI than those from more educated parents and higher income families, though in two lower income countries (Estonia & Portugal) associations were in the opposite direction.(8) In that study socioeconomic differentials in lipids (HDLc, LDLc and triglycerides) and circulating insulin were in the directions that one would anticipate from the associations with adiposity, but few other studies have been able to examine socioeconomic differentials in a wide range of metabolic markers in a contemporary population of children. Of particular relevance to this application, it has also been show in ALSPAC that there is a clear social gradient (based on head of household social class at birth) of fat mass (with children of higher social class having a lower fat mass), but no gradient in lean mass.(9) Comparing these results to published studies using BMI the authors concluded that social inequalities in childhood obesity may have been underestimated in previous studies.(9) Our aims here are to extend that work by looking at other adiposity markers within ALSPAC and also metabolic and vascular risk factors. The lead author of that published paper (Andy Ness) is a co-applicant on this application and we would be happy to involve others who worked on those data on the papers that result from this application.

The aim of this proposal is to examine the association of socioeconomic position at birth with adiposity and metabolic markers in childhood at age 9.

Our specific objectives are:

1. Determine the magnitude of the association of head of household occupational social class, maternal educational attainment and parental educational attainment (as determined at birth) with BMI, waist circumference and DXA assessed fat mass at age 9.

2. Determine the magnitude of the association of head of household occupational social class, maternal education and paternal education (at birth) with blood pressure and circulating levels of insulin, HDLc, LDLc, triglycerides, apolipoprotein, adiponectin, leptin, CRP and IL6 at age 9.

3. To determine whether any associations in objective 2 are mediated by adiposity measurements.

In a second paper we would like to build on this first paper (whatever the findings) by completing the following objectives:

1. Determine the magnitude of the association of head of household occupational social class, maternal educational attainment and parental educational attainment (as determine at birth) with BMI, waist circumference and DXA assessed fat mass at age 15.

2. Determine the magnitude of the association of head of household occupational social class, maternal education and paternal education (at birth) with blood pressure and circulating fasting levels of insulin, HDLc, LDLc, triglycerides, apolipoprotein at age 15.

3. To determine whether any associations in objective 2 are mediated by adiposity measurements.

The rationale for this second paper is that the association of childhood BMI/obesity with future CHD risk (as shown in two very large study populations (6,7)) strengthens with older age at BMI assessment, suggesting that later childhood/early adulthood may be a more important risk period and/or that tracking of obesity into adulthood might be an important mechanism for the association of childhood adiposity with future CHD risk. There is also some evidence that the associations of childhood socioeconomic position with adiposity and metabolic and vascular risk factors increase with age. In the European Heart Health Study point estimates are larger at age 15 than 9 but the sample size it too small to determine whether these differences are statistically robust.

Our rationale for treating these as two separate papers is that (a) we believe there is sufficient data for two papers each with distinct and clear messages, with the second clearly building on the first; (b) the measurements at age 15 were on fasting samples, whereas those at 9 were not, and at age 9 a wider range of measurements (including leptin, adiponecting and markers of inflammation) have been completed than at 15 and we do not wish to distract from the messages of the paper by having in one paper to discuss these differences in detail (they will be discussed in the second paper).

Plan for completing work

1. DAL will put dataset together

2. DAL, LH & BG will agree analysis plan

3. LH will complete initial analyses with input from DAL & BG

4. LH will draft initial paper with input from DAL & BG

5. Other applicants on this proposal (and others they suggest as appropriate) will comment on draft and further revisions

References:

1. Galobardes B, Lynch JW, Davey Smith G. Childhood socioeconomic circumstances and cause-specific mortality in adulthood: systematic review and interpretation. Epidemiol Rev. 2004;26:7-21.

2. Galobardes B, Lynch JW, Davey Smith G. Is the association between childhood socioeconomic circumstances and cause-specific mortality established? Update of a systematic review. J Epidemiol Community Health. 2008 May;62:387-90

3. Galobardes B, Davey Smith G, Lynch JW. Systematic review of the influence of childhood socioeconomic circumstances on risk for cardiovascular disease in adulthood. Ann Epidemiol. 2006 Feb;16:91-104.

4. Davey Smith G, Hart C. Insulin resistance syndrome and childhood social

conditions. Lancet 1997;349:2845.

5. Lawlor DA, Ebrahim S, Davey Smith G. Socioeconomic position in childhood and adulthood and insulin resistance: cross sectional survey using data from the British women's heart and health study. BMJ 2002; 325:805-807

6. Baker JL, Olsen LW, Sorensen TI. Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med 2007;357:2329-2337

7. Bjorge T, Engeland A, Tverdal A, Smith GD. Body Mass Index in Adolescence in Relation to Cause-specific Mortality: A Follow-up of 230,000 Norwegian Adolescents. Am J Epidemiol 2008;168:30-37

8. Lawlor DA, Harro M, Wedderkopp N, Andersen LB, Sardinha LB, Riddoch CJ, Page AS, Anderssen SA, Froberg K, Stansbie D, Davey Smith G. The association of socioeconomic position with insulin resistance among children from northern (Denmark), eastern (Estonia) and southern (Portugal) Europe: findings from the European Youth Heart Study. BMJ 2005;331:183-86.

9. Ness AR, Leary S, Reilly J, Wells J, Tobias J, Clark E, Davey Smith G, the ALSPAC Study Team. The social patterning of fat and lean mass in a contemporary cohort of children. International Journal of Pediatric Obesity 2006; 1:1, 59-61

Data required

1. SEP at birth (exposure) - occupational social class mother & father; education mother; education father

2. Adiposity measurements at age 9 (outcome 1): month and year of clinic; age of child at clinic; weight; height; waist circumference; DXA fat mass & lean mass from 9 year clinic

3. Metabolic and vascular measurements at age 9 (outcome 2): BP, lipids, insulin, adiponectin, leptin, CRP, IL6 from samples taken at 9 year clinic

4. Adiposity measurements at age 15 (outcome 1, second paper): month and year of clinic; age of child at clinic; weight; height; waist circumference; DXA fat mass & lean mass from 15 year clinic

5. Metabolic and vascular measurements at age 15 (outcome 2, second paper): BP, fasting lipids, insulin and glucose from samples taken at 15 year clinic

6. Potential confounding factors: Maternal and Paternal age at birth, ethnicity, maternal parity, maternal smoking in pregnancy, paternal smoking around time of birth/pregnancy, maternal pre-pregnancy BMI, paternal BMI around time of birth/pregnancy; child's sex.

Date proposal received: 
Wednesday, 25 February, 2009
Date proposal approved: 
Wednesday, 25 February, 2009
Keywords: 
Metabolic
Primary keyword: 

B794 - Psychosocial aspects of maturation family functioning and substance use in adolescence - 24/02/2009

B number: 
B794
Principal applicant name: 
Dr Marianne van den Bree (University of Cardiff, UK)
Co-applicants: 
Dr Katherine Shelton (University of Cardiff, UK), Dr Jon Heron (University of Bristol, UK)
Title of project: 
Psychosocial aspects of maturation, family functioning and substance use in adolescence.
Proposal summary: 

Aim: To identify whether pubertal timing moderates longitudinal associations between parent substance use, parent-child relationship quality and adolescent substance use.

Background: Early initiation of substance use has been associated with a more rapid progression to heavier use and abuse (Spear, 2000), has short- and long-term health implications (van den Bree, 2005) and can impact on individual and others' welfare through associations with increased risky behaviour (Patton et al., 2004). Understanding the psychosocial risk mechanisms that lead some adolescents to earlier initiation and heavier use of substances is arguably central to reducing the existing public health burden presented by frequent and/or excessive drinking and smoking. The quality of family relationships, parents' own substance use and the timing of pubertal maturation relative to one's peers are risk factors for substance use in adolescence. The potential interplay between these risk factors in influencing the use of cigarettes and alcohol in early to mid-adolescence is not well understood.

Children from homes characterised by poor family functioning and by parents own heavy substance use are at increased risk of substance use (Hawkins, Catalano & Miller, 1992; Engels et al., 2004). Family relationships that are non-supportive or characterised by conflict can undermine adolescents' ability to regulate their behaviour in a goal-oriented way, with self-regulation linked in turn to substance use (e.g. Brody & Ge, 2001). On the other hand, adolescents who smoke or drink regularly may incur parents' disapproval that in turn is linked to decreased expressions of warmth and affection by parents and increased conflict (Shelton et al., 2008).

The timing of the pubertal transition (compared to same-sex, same-age peers) is theorised to be an important determinant of the relationship between pubertal maturation and psychopathology (Graber et al., 1997). Early maturing adolescents may be more prone to experiencing difficulties because they are less well prepared for pubertal change (Peskin, 1973). Early pubertal timing is associated with the increased use as well as abuse of substances (e.g. Graber et al., 1997; Lanza & Collins, 2002; Orr & Ingersoll, 1995). Other studies, however, have also shown that late-maturing males begin to drink earlier and to smoke more than on-time maturing males (Graber et al., 1997; (Bratberg et al., 2007).

Early maturation is theorised to sensitise children to variations in parent mood and behaviour, which heightens risk for psychological adjustment problems (e.g. Ge et al., 2002). In addition, while pubertal maturation has been associated with negative emotions among adolescents, this emotionality may be partly attributed to parents who are not perceived to be sensitive to the adolescent's needs (Paikoff & Brooks-Gunn, 1991). Findings suggest a potential disparity between parent and adolescent expectations about the timing of developmental tasks in the families of off-time maturing boys and girls.

While previous research has independently identified early maturation, parent substance use and parent-child relationship quality as risk factors for adolescent substance use, it is not clear how domains of family functioning might interact with the timing of pubertal development to influence use of cigarettes and alcohol. In our analyses based on Addhealth data we found that the longitudinal association between parent-child relationship quality (assessed in 1995) and alcohol use (assessed one year later in 1996) was stronger for early than late maturing girls, in addition, we also found gender differences in the moderating influences of pubertal development on the associations between relations with the parents and adolescent substance use (Shelton and van den Bree, submitted).

The aim of the proposed research is to investigate in ALSPAC the transactional nature of longitudinal associations between the quality of parent-child relations, parent substance use and adolescent cigarette and alcohol use and to assess whether any such relationships are moderated by the timing of pubertal maturation as well as to further explore potential gender differences.

Analyses will involve structural equation models using maximum likelihood estimation in LISREL (Joreskog & Sorbom, 1996).

Data which we would like to use for this project are:

103 months of life (frequency of use of different alcoholic beverages)

115 months of life (parental awareness of child alcohol use)

140 months of life (parental awareness of child alcohol use)

157 months of life (frequency of use of different alcoholic beverages)

8 Years old Ever drunk without permission (antisocial behaviour questionnaire)- personal interview

10 Years old Ever drunk without permission (Antisocial behaviour questionnaire)- personal interview

11 Years old Got very drunk (sensation seeking questionnaire) - personal interview based

13 Years old Several question related to alcohol use, frequency of use, pattern of use, binge drinking, getting drunk, age started, usage by friends.

14 Years old Several question related to alcohol use, frequency of use, pattern of use, binge drinking, getting drunk, age started, usage by friends .

15 Years old Several question related to alcohol use, frequency of use, pattern of use, binge drinking, getting drunk, age started, usage by friends.

115 months of life (parental awareness of child cigarettes use)

140 months of life (parental awareness of child cigarettes use)

167 months (cigarettes use attitude) - questionnaire based

8 Years old Ever smoked - personal interview based

10 Years old Ever smoked - personal interview based

13 Years old Several question related to cigarettes smoking, frequency of use, pattern of use, age started, usage by friends.

14 Years old Several question related to cigarettes smoking, frequency of use, pattern of use, age started, usage by friends.

15 Years old Several question related to cigarettes smoking, frequency of use, pattern of use, age started, usage by friends.

Parental reports

97 months of life Cigarettes use/ Partner smoking/ Alcohol use

110 months of life Drug use/ Partner smoking/ Partner drinking

134 months of life Cigarettes use/ Partner smoking

145 months of life Cigarettes use/ Partner smoking/ Partner drinking

97 months of life Parent to child interaction (Enjoyment)

Partner's parent to child interaction (Parental enjoyment)

Parent to parent interaction (aggression, affection)

110 months of life Partner's parent to child interaction (Parental enjoyment)

Parent to parent interaction (activities together, satisfaction, rows, warmth, authority)

145 months of life Partner's parent to child interaction (Parental enjoyment)

Parent to parent interaction (activities together, satisfaction, rows, warmth, authority)

169 months of life Parent to child interaction (Parental involvement in child social life and parental awareness)

Timing of variables of pubertal development SPECIFIC CHILD BASED QUESTIONNAIRE "Growing and Changing" (including Tanner assessments).

Date proposal received: 
Tuesday, 24 February, 2009
Date proposal approved: 
Tuesday, 24 February, 2009
Keywords: 
Social Conditions, Substance Use
Primary keyword: 

B785 - Pilot study of Bisphenol A concentrations - 19/02/2009

B number: 
B785
Principal applicant name: 
Dr David Melzer (Peninsula College of Medicine, University of Plymouth, UK)
Co-applicants: 
Title of project: 
Pilot study of Bisphenol A concentrations.
Proposal summary: 

(No outline received).

Date proposal received: 
Thursday, 19 February, 2009
Date proposal approved: 
Thursday, 19 February, 2009
Keywords: 
Iodine, Biological Samples
Primary keyword: 

B784 - An analysis of the mathematics achievements of hearing impaired children in primary school - 19/02/2009

B number: 
B784
Principal applicant name: 
Terezinha Nunes (University of Oxford, UK)
Co-applicants: 
Title of project: 
An analysis of the mathematics achievements of hearing impaired children in primary school.
Proposal summary: 

The ESRC-RNID project has two aims: (1) to provide a large scale survey of deaf children's numeracy achievements in primary school, analysing the relationships between background variables and achievement; (2) to investigate longitudinally the connections between different aspects of numeracy achievement (number knowledge, spatial knowledge, knowledge of number facts, word problem solving) and cognitive competencies (the understanding of some logical principles; working memory) that are strong predictors of hearing children's mathematics achievements, after controlling for the effects of general intelligence. The focus of the project is on attainment at Key Stages 1 and 2.

Both aims will produce original contributions to knowledge. (1) A survey of deaf primary school children's mathematics is urgently needed.The last extensive U.K. survey of deaf children's mathematics achievement that described the attainments of school leavers was carried out by Wood et al. (1984) and showed that deaf children lag behind their hearing peers by 2 to 3.5 years in mathematics attainment.Due to changes in educational provision (e.g. access to BSL) and technology (use of computers and calculators), audiological interventions (better hearing aids and cochlear implants), and progress in knowledge of how deaf children learn, previous surveys may not reflect present achievements. The inclusion of data already available for the ALSPAC study would strengthen the database for this ESRC-RNID project. (2) Research on deaf children's mathematics learning (Nunes et al., 2008) shows that they underperform in mathematics in relation to their level of non-verbal intelligence; when non-verbal intelligence is controlled for, hearing children still perform significantly better than deaf children in a variety of measures of numeracy and cognitive competencies (logical reasoning and working memory). However, it is not known how well the cognitive measures predict deaf children's mathematics learning. This project will analyse whether these cognitive measures predict deaf children's mathematics learning longitudinally as well as they predict hearing children's learning (Nunes et al, 2007).Tymms et al. (2003) found that the school-entry measures that predict hearing children's performance in Year 2 do not predict the performance of profoundly deaf children. This may have been due to their small sample size. It would be very important to attempt to attempt to replicate and understand these results, if they are replicated.

The data available in ALSPAC would provide an initial analysis of some of these aspects, namely:

  • the importance of background variables (SES and mother's education);
  • the performance of deaf children in comparison to that of hearing children, controlling for SES and mother's education;
  • the importance of age of diagnosis;
  • the performance of deaf children in comparison to that of hearing children, controlling for cognitive factors (performance IQ and working memory)
  • the connections between mathematical reasoning, working memory, knowledge of number facts and visual-spatial organisation and mathematics attainment.

The analysis of the connections between the cognitive factors and mathematics attainment would not be possible in terms of a longitudinal prediction because the children's Key Stage 1 results precede the focus@8 assessments, which contain the relevant cognitive variables, and there may be very few children with hearing loss taking Key Stage 2 assessments (often they are not included in these assessments).

It is likely that there are many more deaf children who have received cochlear implants currently in school than those included in the ALSPAC sample. A careful description of the mathematics attainment of children who did not receive an implant could be used at a later point by professionals interested in analysing the effects of implantation on children's attainment. If the report provides detailed information, it could be used in a meta-analysis for comparison with children who had cochlear implants.

Variables relevant for this analysis

The predictors relevant for this analysis are measures of SES and maternal education, age of diagnosis, and the cognitive measures, which include assessments of the children's:

a) mathematical reasoning (Year 4);

b) knowledge of arithmetic (a sub-test of the WISC);

c) working memory (backward digit span), short-term memory (non-word repetition and forward digit span) and attention (Coding and two Digit Span tasks from the WISC and the scale within the Strengths and Difficulties Questionnaire);

d) general intelligence (Weschler Intelligence Scale for Children: WISC);

e) Key Stage 1 and 2 Maths results.

These variables are included in the dataset which T. Nunes, P. Bryant and K. Sylva are currently analysing for a previously approved DCSF project, with the exception of the age of diagnosis of the child's hearing impairment. This information will be obtained from the earliest age at which there is an entry of hearing impairment for the child and compared to later entries (to avoid including children who had temporary impairments due to illness, for example).

Date proposal received: 
Thursday, 19 February, 2009
Date proposal approved: 
Thursday, 19 February, 2009
Keywords: 
Education, Hearing
Primary keyword: 

B786 - Replication of the association of a functional gene-network with intelligence - 18/02/2009

B number: 
B786
Principal applicant name: 
Dr Danielle Posthuma (Vrije Universiteit, Amsterdam, Europe)
Co-applicants: 
Ms Dina Ruano (Leids Universitair Medisch Centrum (LUMC), Netherlands , Europe)
Title of project: 
Replication of the association of a functional gene-network with intelligence.
Proposal summary: 

Introduction

Using an existing IQ GWAS dataset, we have analyzed the combined effect of genes in the same functional gene-networks in the variation of human intelligence. Our functional gene-networks were defined based on biological knowledge and the combined analysis was done by developing a novel datamining and analysis procedure.

Method

The novel data-minining and analysis procedure has been implemented in a tool-chain, to be used on a computer cluster. The tool-chain has been run on the SARA supercomputing cluster in Amsterdam to collect, transform, and analyze the relevant data.

Findings to be replicated

After correction for multiple test analysis one of the analyzed functional gene-networks revealed association. The set of genes included in the associated network is currently under embargo, until the conclusion of replication studies.

Replication cohort

We would like to replicate our result using the GWAS data form the ALSPAC study.

Replication requirements

We will need to have access to the IQ scores of all individuals and to the genotypes of 265 SNPs that were obtained using the Illumina 317k platform. These 265 SNPs are present in genes that are contained in the functional gene-network that we have found to be associated to intelligence in the IQ GWAS dataset previously analyzed.

Replication method

The tool-chain developed by Dr. Dina Ruano will be made available to Dr. Beate Glaser of ALSPAC for use in the replication result. The tool-chain will be applied to the replication cohort by Dr. Glaser. The results of the replication will be supplied to Dr. Ruano for further analysis and for publication.

Intellectual property

The tool-chain made available by Dr. Ruano will be used only for the replication study and will remain the intellectual property of VUmc.

Publication plan

A paper has been prepared on the original findings, including the applied method. The intention is to add the replication results to this paper before submission.

Date proposal received: 
Wednesday, 18 February, 2009
Date proposal approved: 
Wednesday, 18 February, 2009
Keywords: 
Gene Expression, Genes
Primary keyword: 

B787 - Investigating the role of novel glycaemic trait variants in fetal and childhood growth - 13/02/2009

B number: 
B787
Principal applicant name: 
Prof Mark McCarthy (Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), UK)
Co-applicants: 
Dr In?s Barroso (Wellcome Trust Sanger Institute, London, UK), Prof George Davey Smith (University of Bristol, UK), Dr Dave Evans (University of Bristol, UK), Prof Tim Frayling (Peninsula Medical School, University of Plymouth, UK), Dr Rachel Freathy (Peninsula Medical School, University of Plymouth, UK), Prof Andrew Hattersley (Peninsula Medical School, University of Plymouth, UK), Dr Inga Prokopenko (Wellcome Trust Centre for Human Genetics, UK), Dr Nic Timpson (University of Bristol, UK)
Title of project: 
Investigating the role of novel glycaemic trait variants in fetal and childhood growth.
Proposal summary: 

We propose to test the following hypotheses:

1) Fetal genotype and maternal genotype are associated with fetal growth measures (birth weight, birth head circ, birth length).

2) Fetal genotype and maternal genotype ar associated with measures of growth in infancy and childhood (height, weight, BMI, fat mass etc).

3) Child's genotype is associated with intermediate traits related to Type II diabetes including fasting insulin, fasting glucose and insulin secretion and related metabolic traits (in the subset of offspring with OGTT data).

Date proposal received: 
Friday, 13 February, 2009
Date proposal approved: 
Friday, 13 February, 2009
Keywords: 
Nutrition, Growth
Primary keyword: 

B789 - Do early life experiences influence the development of myopia in adolescents Analysis of data from the ALSPAC cohort - 10/02/2009

B number: 
B789
Principal applicant name: 
Miss Cathy E M Williams (University of Bristol, UK)
Co-applicants: 
Dr Clare Gilbert (London School of Hygiene and Tropical Medicine, UK), Dr Jez Guggenheim (University of Cardiff, UK), John Sparrow (University of Bristol, UK), Prof Yoav Ben-Shlomo (University of Bristol, UK)
Title of project: 
Do early life experiences influence the development of myopia in adolescents? Analysis of data from the ALSPAC cohort.
Proposal summary: 

People who are short sighted (myopic) have blurred vision for distant viewing, but clear vision for near, and this occurs because their eyes grew too long during childhood and early adolescence. Myopia is becoming more common, and can lead to loss of vision in middle and from degenerative and other changes. Studies show that "nature and nuture" are both important in the development of myopia and the "epidemic" of myopia in Asian children is attributed to as yet little understand factors associated with urban living. As it is becoming increasingly realized that what happens to individuals early in life, indeed, even before they are born, can influence later disease risk, we plan to analyse data collected from a cohort of children when they were aged 15 years who have been followed up regularly since they were born. To our knowledge this will be the first study of myopia during children to use the "life course" approach to analysis although data from the 1958 birth cohort (who are now middle aged) is ongoing, providing a very useful comparative study.

Background: The World Health Organization (WHO) estimate that 153 million people worldwide are visually impaired from uncorrected refractive error, 8 million of whom are blind. The report suggests that 12 million school-age children (5-15 years) are visually impaired from uncorrected refractive errors, and population based surveys undertaken using standard methods and techniques suggest that 90-95% of visual impairment in this age group is due to myopia. Uncorrected myopia is, therefore, a major public health problem.

The following 4 components of the eye determine its refractive status: axial length (AL), corneal curvature, anterior chamber depth, and the thickness, curvatures and internal refractive indices of the lens. After birth the eyes grow in all dimensions, increasing almost threefold in volume by the time adult size is reached. Eye growth is exquisitely controlled so that in most people the AL of the eye increases in tandem with changes in corneal curvature and dimensions of the lens so that the image of distant objects remains focused on the retina. Evidence from laboratory, animal and clinical studies suggests that growth of the cornea and lens are largely controlled genetically whereas AL is influenced at least in part, by visual stimuli. How the visual system detects and adapts to blur, and how this is then translated into altered growth is not known. However it is known that emmetropisation is an active and dynamic process which persists throughout childhood and adolescence, involving an image-processing feedback mechanism in the retina which ultimately influences growth of the sclera. Failure or perturbation of emmetropization can give rise to myopia. The plasticity of this process has been demonstrated in animal experiments in which eye growth has been manipulated by lid closure, diffusers and plus or minus lenses but there is considerable species variation. It seems reasonable, therefore, that changes in the environment in children may also modify eye growth.

There is compelling evidence from twin, family and association studies, and epidemiological research that myopia is a complex disease. However, the rapidly increasing incidence in SE Asia can only be explained by exposure to environmental risk factors that are new or where exposure at the population level is greater and/or more intense. Changes in behaviour and life style consequent to urbanization have been implicated but there are controversies surrounding which elements in childrens' environments are the more important. To date all studies have been either cross sectional or relatively short-term longitudinal studies in which standard multivariate statistical methods have been used. The latter cannot take account of the sequence and timing of the different exposures which are likely to be critical in the development of myopia.

The ALSPAC birth cohort enrolled 14,000 children born in Avon in 1991/92. The cohort have had eye examinations at different time points (see below) and there is a wealth of other data on relevant exposures (e.g. socioeconomic status of parents prior to enrolment and throughout the study; birth weight; breast feeding; early growth; parental myopia; close work; outdoor activities; intelligence etc). We will use the life course approach to analyses which will be the first time these methods will have been used in myopia research in children although we understand that data from the 1958 birth cohort are being examined in this manner. The following data on myopia and ocular dimensions are available from the ALSPAC cohort:

* undilated (ie without cycloplegic drops) autorefraction at ages 7, 10, 11 and 15 years. The prevalence of myopia (defined as less than 1.5D to take account of non-dilation) increased from 1.5% at the 7-year clinic (n=8003 right eyes) to 3.6% at the 10-year (n=7467 right eyes) and 4.9% at the 11 -year (n=6730 right eyes) clinics; 5500 attended and were autorefracted at the 15-yr clinic (data in preparation for analysis).

* vision related questionnaire data at 7 years and clinical examination at 7 years which included eye examination and the following measurements: LogMAR visual acuity, contrast sensitivity, stereo acuity, motor fusion; ocular alignment, eye preference, subjective accommodation.

* 2900 participants also have data on axial length and corneal curvature from the 15-year clinic

* Up-to-date optometric records for approximately 3000 participants who came to the 15-year clinic, and their siblings and parents

* Opportunistic autorefraction of approximately 2500 parents of the study participants who came to the 15-year clinic.

Date proposal received: 
Tuesday, 10 February, 2009
Date proposal approved: 
Tuesday, 10 February, 2009
Keywords: 
Vision
Primary keyword: 

B788 - Comparison of human and mouse quantitative trait loci - 10/02/2009

B number: 
B788
Principal applicant name: 
Dr Jonathan Flint (University of Oxford, UK)
Co-applicants: 
Prof Chris Ponting (Wellcome Trust Sanger Institute, London, UK), Dr Martin Goodson (Wellcome Trust Centre for Human Genetics, UK), Prof George Davey Smith (University of Bristol, UK), Dr Nic Timpson (University of Bristol, UK)
Title of project: 
Comparison of human and mouse quantitative trait loci.
Proposal summary: 

We are requesting the P values for each marker from genomewide analysis of available samples in a number of ALSPAC phenotypes. We need the genome-wide set of P-values to compare with a similar set of measures obtained in a study of mouse complex phenotypes. Our justification for wanting to carry out this comparison is as follows:

Genetic mapping of disease models in rodents has long been expected to help with the identification of genes involved in human illness. Yet, while this is true for models that arise from abnormalities of a single gene, leading to new insights into diverse conditions such as obesity (leptin), susceptibility to infectious disease (toll receptors) and mental retardation (lissencephaly), the approach has been far less successful for phenotypes with a complex genetic basis. In a few instances common genes have been found: variants in CTLA4 increases risk of autoimmune disease in humans and a mouse model of type 1 diabetes (Ueda et al. 2003); a copy number variant in the same susceptibility gene (Fcgr3) contributes to immunologically mediated glomerulonephritis in humans and rats (Aitman et al. 2006).

The conservation of many physiological processes between the two species suggests that variation at genetic loci might be shared, and there is some evidence that this is so. Paigen and colleagues used linkage results to argue that more than half of human atherosclerosis QTLs are located in regions homologous to mouse QTLs (Wang et al. 2005a). However human linkage results are notoriously unreliable and, as Risch and colleagues pointed out, concordance is unlikely given that the genetic effect in humans depends on disease allele frequencies and such allele frequencies are unpredictable (Risch et al. 1993). The lack of power in human linkage studies compromises their use in comparison with the mouse findings. Furthermore, while the mapping of complex traits has proved to be an effective technique, delivering many thousands of quantitative trait loci (QTLs) its power is not matched by high resolution. The large confidence intervals into which both mouse and human QTLs were mapped made it difficult to exclude the possibility that overlap was coincidental.

Two developments allow us to revisit the question of the overlap between mouse and human QTLs, First, the advent of adequately powered genome-wide association studies in humans, which map genetic effects at high resolution, has proved to be a robust method for QTL identification (McCarthy et al 2007, Nature Reviews Genetics) Second, progress in mapping QTLs at high resolution in mice has yielded a map of over 900 QTLs for 100 phenotypes, each mapped to approximately 3 Mb (Valdar et al. 2006a). This was achieved using a quasi outbred population of mice, the heterogeneous stock (HS). While HS mouse QTLs are not mapped to the same resolution as is obtainable in human association studies, we hypothesize that it should be possible to perceive overlap between data sets.

In order to test this idea, we need a large set of data comparable to that mapped in the HS. All of our data, genotypes and phenotypes are freely available online (http://gscan.well.ox.ac.uk). We wish to compare the distribution of the mouse QTLs to the distribution of P-values found in human GWAS studies. Our mouse data set contains the following phenotypes that we wish to compare with the GWAS data from ALSPAC, Table 1 (appendix).

To carry out our analyses we need the P values for each marker. We do not need the individual genotypes, nor the individual phenotypes. We need the result of the analysis of association for every marker in the genome.

Date proposal received: 
Tuesday, 10 February, 2009
Date proposal approved: 
Tuesday, 10 February, 2009
Keywords: 
Genetics, Genes
Primary keyword: 

B790 - Genomewide association studies into circulating levels of adiponectin - 09/02/2009

B number: 
B790
Principal applicant name: 
Dr Nic Timpson (University of Bristol, UK)
Co-applicants: 
Dr Brent Richards (McGill University, ROW), Prof George Davey Smith (University of Bristol, UK)
Title of project: 
Genomewide association studies into circulating levels of adiponectin.
Proposal summary: 

Insulin resistance is a highly heritable trait and predisposes to both type 2 diabetes (T2D) and coronary heart disease (CHD). Whilst genome-wide association approaches have revealed multiple variants reproducibly associated with either T2D or CHD few of these variants are shared at a biological level. Additionally, there are no common variants yet reported to be reproducibly associated with biochemical measures of insulin resistance. Using serum adiponectin levels as a surrogate biomarker of insulin sensitivity, we aim to perform a meta-analysis of 3 genome-wide association studies and sought replication of our findings in 5 additional cohorts (including the ALSPAC children with non-fasting adiponectin levels measured at age 9).

Insulin resistance is a quantitative trait that predisposes to, and predicts independently, adverse metabolic and cardiovascular outcomes such as type 2 diabetes (T2D) and coronary heart disease (CHD)(1-3). Although factors such as obesity, diet and exercise importantly influence insulin resistance there is compelling evidence that it is strongly influenced by hereditary factors(4), yet few genetic determinants of insulin resistance have been described and none of these have been found to alter risk of T2D and CHD.

The precise mechanism through which insulin resistance has adverse impacts on metabolic and cardiovascular outcomes is as yet unclear and, indeed, may differ depending on the particular downstream pathology. Thus, while impaired insulin action per se may contribute directly to hyperglycemia, it has been suggested that the compensatory hyperinsulinemia that inevitably accompanies insulin resistance in the non-diabetic individual may have adverse consequences on the vasculature and liver that could predispose to athero-thrombosis(5, 6). However the precise quantification of insulin resistance in the epidemiological setting is challenging; "gold standard" measures of insulin resistance require technically demanding hyperinsulinemic clamp studies employing stable isotopes to dissect hepatic effects of insulin from those on muscle and fat, and such studies have consequently rarely been performed in populations large enough to generate meaningful information through genome wide association (GWA) studies(7).

We plan to undertake a large-scale meta-analysis of GWA studies (n = 14, 733) of circulating adiponectin levels in the hope that this will reveal common genetic variants that might at least in part explain the heritability of insulin resistance. Given the importance of insulin resistance as a precursor of both T2D and CHD, we anticipated that the identification of genetic variants associated with circulating adiponectin levels might be exerting their effects through an influence on insulin sensitivity/resistance and that such variants might therefore modulate the risk of T2D or CHD, or indeed both.

1. Chen, K.W., Boyko, E.J., Bergstrom, R.W., Leonetti, D.L., Newell-Morris, L., Wahl, P.W., and Fujimoto, W.Y. 1995. Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM. 5-Year follow-up of initially nondiabetic Japanese-American men. Diabetes Care 18:747-753.

2. Beck-Nielsen, H., and Groop, L.C. 1994. Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 94:1714-1721.

3. Meigs, J.B., Wilson, P.W., Fox, C.S., Vasan, R.S., Nathan, D.M., Sullivan, L.M., and D'Agostino, R.B. 2006. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab 91:2906-2912.

4. Laws, A., Stefanick, M.L., and Reaven, G.M. 1989. Insulin resistance and hypertriglyceridemia in nondiabetic relatives of patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 69:343-347.

5. Despres, J.P., Lamarche, B., Mauriege, P., Cantin, B., Dagenais, G.R., Moorjani, S., and Lupien, P.J. 1996. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 334:952-957.

6. Semple, R.K., Sleigh, A., Murgatroyd, P.R., Adams, C.A., Bluck, L., Jackson, S., Vottero, A., Kanabar, D., Charlton-Menys, V., Durrington, P., et al. 2009. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest.

7. Howard, G., O'Leary, D.H., Zaccaro, D., Haffner, S., Rewers, M., Hamman, R., Selby, J.V., Saad, M.F., Savage, P., and Bergman, R. 1996. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation 93:1809-1817.

Date proposal received: 
Monday, 9 February, 2009
Date proposal approved: 
Monday, 9 February, 2009
Keywords: 
Genetics
Primary keyword: 

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