It is proposed to collect data on individuals' political views and social attitudes such as altruism, or trust and broad measures of personality characteristics. It is hoped that this will allow a first glimpse at how our early environment and genetics, combine with current circumstances to determine our beliefs. We propose asking questions similar to those below. Ideally, all questions would be asked of both parents and their children. The collation of data on social attitudes would also be extremely worthwhile in itself. Using forms of question that have been widely used in other surveys will facilitate comparability with other surveys/studies. 1. Measures of Political Ideology a. Left-Right Scale question similar to used in Eurobarometer/WVS/BSA ) b. Libertarian-Authoritarian Scale - BSA 2. Political Behaviour Questions, E.G: a. Did you vote in the last general/European/local election? If so who did you vote for? b. Do you feel that one party tends to represent your views at the national/European/local level? If so which? c. Do you belong to a political party, trade union, environmental organisation, etc.? d. Have you engaged in any of the following types of political action? Boycotts/ Petitions/Rallies/etc. .3. More fundamental questions about political beliefs - belief in the power of government (Can government be an effective force for good, is government necessary, taxation is justifiable, progressive taxation is justified.) 4. Trust. Generally speaking, would you say that most people can be trusted or that you need to be very careful in dealing with people? Thinking just about people you know, would you say that most of them can be trusted...5. Other Social Attitudes (Altruism, Inequality-Aversion, etc.) , Religosity6. Big 5 personality traits - 44 or 10.

Investigate the role of antenatal dietary factors and blood levels of fatty acids in relation to the development of ADHD, DCD and dyslexia using data from ALSPAC. In addition we will investigate the role of these dietary factors on the continuous developmental traits of inattention and hyperactivity, motor coordination and reading skills. Measures of diet and fatty acids from ALSPAC used in this analysis will be: 1.Dietary data collected by food frequency questionnaire at 32 weeks pregnancy. 2. Maternal prenatal red blood cell fatty acids. 3. Duration of breast feeding assessed by maternally completed questionnaire at 6 months. 4. Child blood fatty acid levels available at birth (cord blood) and at 7 years. The final analysis will assess the role of fatty acids in the aetiology of children with complex overlapping difficulties in attention, poor motor coordination, poor reading skills, speech and language and social communication difficulties. The study will involve A.) a comprehensive literature review of all previous research looking at the role of fatty acids in the aetiology of ADHD, DCD and dyslexia B) Multivariate linear regression models will be used to analyse each of the dietary factors for the traits of attention, motor coordination and reading skills. C) Further analyses using multivariate logistic models will assess the role of these dietary factors in regard to (a) the extreme tail (10th centile) of each distribution, and (b) the diagnoses of ADHD, DCD and dyslexia.

Not available

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

AIMS

1. To estimate a twin model investigating the extent to which the covariance of PTSD and disordered eating is due to genetic and environmental influences.

a. It is hypothesized that additive genetic and unique environmental factors will significantly influence the variance of PTSD and disordered eating as well as their covariance.

2. To estimate a network model of genetic and psychosocial variables associated with PTSD and disordered eating among a sample of women.

a. It is hypothesized that many genetic and psychosocial variables will overlap with both PTSD and disordered eating.

3. To investigate whether maternal prenatal stress exposure is associated with offspring epigenetic changes and disordered eating.

a. It is hypothesized that maternal stress will be directly and indirectly associated with offspring disordered eating.

4. To investigate whether associations identified in Aim #3 apply to the etiology of substance use and depressive symptomatology as well as disordered eating.

a. It is hypothesized that both similarities and differences in DNA methylation patterns will be observed in the relations between maternal prenatal stress exposure and offspring disordered eating, substance use, and depressive symptomatology.

An overview of the study design to meet aims 3 and 4 can be found in the attached powerpoint file.

Background

The extent of copy number variation across the genome is still the subject of much debate although genome-wide maps of common copy number variation have now begun to emerge. Methods for detection and characterisation of both common and rare copy number variants are still far from perfect with no one approach to mining the genome optimal to detect all sizes of CNV. Consequently, there is still much to be learned about the extent and impact of this form of variation on human health and disease. Early studies of the role of common copy number variation in disease, including the Wellcome Trust Case Control Consortium (WTCCC) CNV project with which we were involved, suggest that much of this variation may already be well tagged by SNPs on the most recent genotyping platforms. However, rare and low frequency copy number variants, which are not expected to be tagged by common SNPs, have been shown to play a role in diseases such as autism and schizophrenia and the contribution of copy number variants to quantitative traits such as blood pressure and lung function is still largely unexplored. Algorithms have been developed that aim to utilise the raw allelic intensities from contiguous SNPs in SNP genotyping arrays to detect and quantify copy number variation. Although these detection approaches have raised substantial challenges, the most recent genome-wide SNP data allow improved detection of copy number through the inclusion of many more probes. Building upon recent experience and growing expertise in CNV analyses (1,2,3,4) and on data from other studies (listed in the following paragraph) which have approved collaborative CNV analyses we will undertake, we propose collaborative CNV studies of blood pressure & lung function together with ALSPAC investigators. These studies will help to gain the maximum benefit from newly available genome-wide association study data in ALSPAC, and will build upon the SNP association analyses that ALSPAC investigators plan to undertake.

Identifying the genetic determinants of lung function and blood pressure may lead to the identification of potentially modifiable intermediate phenotypes which can be targets for public health interventions. Analyses of CNV association with blood pressure and lung function will be undertaken to further the understanding of the genetic architecture of these traits. SNP association studies have demonstrated that very large sample sizes are necessary to detect variants with small effect sizes. The inclusion of 9000 ALSPAC individuals will substantially boost the power of our planned study (which currently includes data from adults in the Busselton Health Study (n ~1500, with 3600 expected in 2011) and the British 1958 Birth Cohort (n ~8000), children from the Raine study (n ~1500) and children & young adults from the Cardiovascular Risk in Young Finns Study (n ~2450)).

In a subset of individuals, robust findings from these analyses may be validated (either by experimental assay or by direct genotyping of tag SNPs if available), and followed up with breakpoint sequencing to fine-map the precise genomic location of the CNV. If it would appear appropriate and scientifically beneficial to include any ALSPAC participants at this stage, then this will be subject to a separate application.

Approaches

Louise Wain will work closely with Dave Evans or Nicholas Timpson in order to undertake the analyses as discussed below. In the first instance, the analyses would need to be run by Louise Wain, but the project aims also to develop this capacity at the University of Bristol. The analysis could be undertaken on the high performance cluster at the University of Bristol if, for example, Louise Wain were offered visitor status (or using a similar new £2m facility in Leicester, as you prefer). An alternative would be the provision of secured log in access to Bristol servers remotely. What ever the preferred mechanism, we would propose that Louise visits Bristol for regular meetings with a named ALSPAC investigator. This will be supplemented by project progress reports shared and discussed as required with all named co-applicants from both the University of Bristol and the University of Leicester.

Analysis of CNV using using SNP chip data requires the use of the raw X and Y intensities and/or derivatives of these (log R ratio and B allele frequency). Due to the inherent noisiness of this data, a key stage in the process of generating CNV genotype calls will be quality control (QC) and definition of a suitable filtering strategy (2).

Quality control (QC) will be applied to each dataset to exclude outlying samples on the basis of the SNP genotype data (e.g. those with substantial missing genotype data, or showing ancestral differences in principal components analysis (PCA)) or intensity data (large standard deviations of genome-wide intensity measures and subsets of samples that might have been processed differently identifiable as likely batch effects by PCA). There are several algorithms available for detecting and measuring copy number variation in SNP genotyping data (e.g. QuantiSNP and PennCNV which are based on Hidden Markov Models) using the raw allelic intensities or derivations thereof. Raw CNV calls will be subject to further rigorous QC with filtering thresholds defined by simulation and sensitivity analyses undertaken to evaluate the consequences of the filtering strategy chosen on the downstream association testing.

CNVs will be tested for association with blood pressure variables, SBP and DBP, and lung function variables, FEV1 and FEV1/FVC, using linear regression. In addition, previously published CNV maps will be used to define boundaries of common CNVs and these CNVs will be tested for association using methods such as CNVtools. Validation will be undertaken in selected subsamples from these studies.

Additional benefit

The CNV methods, or calls used, could be applied to the study of a wide range of additonal phenotypes in ALSPAC and the experience of these kinds of analyses will benefit analysts involved in ALSPAC.

Genotype data required

This project requires the intensity data for each SNP and non-polymorphic probe on the array (log R ratio and B allele frequency, and raw X and Y intensities if possible).

References:

1. L. V. Wain, J. A. Armour, M. D. Tobin, Lancet 374, 340 (Jul 25, 2009).

2. L. V. Wain et al., PLoS One 4, e8175 (2009).

3. N. Craddock et al., Nature 464, 713 (Apr 1, 2010).

4. H. M. Blauw et al., Hum Mol Genet 2010, 10 (Aug 10, 2010).

The complete project (submitted for a Wellcome Trut Intermediate Clinical Fellowship) includes an international collaboration with other birth and adult cohorts. This outline refers to the analysis that will be carried out with Alspac data.

AIMS

The purpose of this research is to describe the magnitude of inequalities in asthma phenotypes throughout the life course, identify the mechanisms that underlie them and thus provide means of reducing the burden of disease, both overall and in terms of contributing to avoidable health inequalities, due to this condition. The specific aims are:

1) Describe the socioeconomic inequalities in wheezing, asthma phenotypes, atopic makers, lung function and bronchial responsiveness in childhood and/or adolescence in Alspac.

2) Describe the life course socioeconomic inequalities in asthma phenotypes across generations: parents and offspring.

3) To determine the major causes of different socioeconomic patterns in asthma phenotypes identified in objectives 1 and 2.

4) Invetigate the role of health selection in asthma inequalities: determine whether asthma phenotypes influence socioeconomic position in children (schooling)

5) Investigate the role of health services role in asthma inequalities in children.

Project outline:

A genome-wide association study of ADHD using antisocial behaviour as an index of heterogeneity

Introduction

ADHD is a highly heritable disorder that is of unknown pathogenesis (Stergiakouli & Thapar, 2010; Faraone et al, 2005). ADHD shows clinical as well as aetiological heterogeneity and the presence of antisocial behaviour (ASB) in children with ADHD is known to be an important marker of heterogeneity. It indexes greater clinical severity, poorer outcome, persistent problems in adulthood, stronger association with neurocognitive deficits and higher familial and genetic loading. Previous candidate gene studies have also suggested that the presence of ASB indexes heterogeneity (Langley et al, 2010).

In our ADHD programme grant we set out to identify ADHD susceptibility genes and also test for the effects of comorbid conduct disorder symptoms.

We have recently completed the genome-wide association study in a well-characterised sample of 727 children with DSM-IV/III-R diagnosed ADHD and 5,081 controls. We have tested for association between 1) SNPs and ADHD, 2) SNPs and Conduct disorder in children with ADHD.

The impact of breast feeding on BMI growth trajectories among FTO gene carriers