Children in single-parent and step-families have higher rates of problems in adjustment, education and health than those in non step-families, yet individual dfferences are marked. This programme of research is focused on the issue of which individuals are most vulnerable, to identify significant sources of risk and support in relation to the mental and physical health of children and parents.

HSB would like to purchase the data from the University after it has been collected.HSB would like to increase the amount of FY06 funds to increase the number of questionnaires (from 10,700 to 11,800) and the amount of work associated with pulling and shipping biologic samples from the University of Bristol to the NCEH lab for analysis.

In addition to the Tanner Scale questionnaire, from 2005, ALSPAC will supply biological samples; namely 150 maternal bloods, 150 maternal urines and 300 cord blood samples. This will be at an additional cost of $22,728 for 2007; $16,387 for 2008.

Background: The onset of puberty is difficult to ascertain using Tanner stages, which are subjective in nature. Especially when Tanner stages are self-reported by pre-teen children, questions of accuracy arise. The transition into puberty - represented by entry into Tanner Stage 2 - is especially difficult to determine. Since the outward sign of development reflect underlying changes in concentrations of reproductive hormones, an alternative method of detecting progression into puberty is to examine concentrations of relevant hormones. In pre-pubertal boys, testosterone levels are close of 0 nmol/L. It is only with the onset of puberty that blood concentrations rise and a distinctive pattern develops (Albertsson-Wikland 1997).

Purpose: Many of the boys in the study cohort have completed questionnaires indicating that they had reached puberty (Tanner Stage 2 or higher) as early as age 8. Using the blood hormone concentration, we will compare the self-reported pubertal stage to a more objective measure.

Description: We will examine testosterone concentrations measured by University of Bristol in 1000 (in total) previously collected blood samples of boys aged 7 through 10. Costs of this are included in Modified Line 005.

This sole-source contract is for the data collected during 2004 - 2008.

With regards to children with cerebral palsy, very little information about attainment of urinary continence is available. The long-term physical, psychosocial and financial burden of incontinence in the cerebral palsy patient is considerable and in order for the paediatrician to begin addressing these important issues further information regarding the normal attainment of bladder control in children with cerebral palsy has to be established. This is the aim of this study.

METHODS

The original study:

The data in this study originate from a previously published population based study (Scrutton and Baird 1997) which established a cohort of children with bilateral cerebral palsy born from 1989 to 1992 (inclusive) to mothers resident at the time of birth within the geographically defined area of the South East Thames Regional Health Authority (SETRHA) in south east England in order to monitor the children's hip development up to the age of 5 years using serial hip X-rays. It is for this reason that children with hemiplegic cerebral palsy are not included. The South East Thames Health Region at the time had a population of 3.65 million with 205 958 live births during the study period. A comparison of epidemiological data between SETRHA and England and Wales showed similarities between the two. For original methods of recruitment, details of ethical permission and consent, and diagnosis of cerebral palsy the reader is referred to the original paper (Scrutton and Baird 1997).

Present study:

For the purposes of this study, a questionnaire containing details of the child's attainment of bowel and bladder control by day and night, as well as parental concerns or presence of abnormal bladder and bowel symptoms, was used. This questionnaire was administered by physiotherapists to the parents of the children sometime after their third birthdays together with other information required for the original study at that time. The parents/carers were asked to post the questionnaire back to the investigators in a self-addressed envelope. Almost all were returned between the third and fourth birthdays, although one was returned at 5 years. After 5 years of age, a visit was carried out by the original authors, mostly in the child's home together with the parents. A number of parameters were obtained during this visit including confirmation of the diagnosis of cerebral palsy, the nature of the motor disorder including distribution (quadriplegia, diplegia, double hemiplegia and paraplegia) and type (hypertonia, ataxia, involuntary movements, hypotonia and ataxic diplegia after Hagberg 1985), learning level (as ascertained from other medical or educational sources), severity of disability and the age of attainment of bladder and bowel control by day and night. For funding and practical reasons these visits were carried out between 7 to 9 years of age. A closing visit questionnaire, including further continence data was completed some time after the age of 14 years (up to age 19 years) in this cohort, in a similar manner to the above. Whilst the stated aim of this study is to establish the age of attainment of bladder control in subjects with cerebral palsy, data on bowel control have been analysed simultaneously for two reasons: availability and therefore ease of analysis together with bladder data, and the fact that bowel and bladder control are physiologically and developmentally linked, and have been shown by previous authors to follow each other sequentially (Stein and Susser 1967, Largo and Stutzle 1977, Crawford 1989).

Definitions:

Cerebral palsy has been taken to mean all non-progressive disorders of movement and posture caused by a defect or lesion in the brain by 15 months chronological age, and not part of another syndrome which has a motor component. Those with syndromes including a high risk of skeletal or joint anomalies and children whose disorder had no clinical trunk or lower-limb involvement were also excluded. Each child's paediatrician provided written confirmation of the diagnosis at 5 years of age.

Bladder and bowel control was defined as being reliably continent with socially acceptable toileting even if help was required.

Definitions of learning level, severity of disability and type (Hagberg 1989)/distribution of motor disorder are defined and classified according to the Gross Motor Function Classification System (GMFCS).

RESULTS

The results of bladder and bowel continence attainment will be presented in a longitudinal manner together with details of any abnormal patterns which will be discussed. The data collected at three years and eight years of age have already been analysed and analysis of the data available at 16-19 years of age is currently awaited. The only available control comparison group is a series of international studies which are for the large part retrospective, cross-sectional and not population based and neither are they collected from a British population with a similar birth date.

We have performed a large genome-wide association study in a few thousand ankylosing spondylitis patients and need to replicate several promising genetic associations. Although we have genotyped putatively associated SNPs in a new sample of cases, we need to obtain genotype data from a similarly sized european control sample on ~100 candidate SNPs. Since both cohorts have been genotyped on the Illumina 317K SNP chip, the ~1700 ALSPAC individuals for whom genome-wide SNP data is now available would be an obvious choice. Note that we are requesting a small number of candidate SNPs (i.e. ~100 SNPs) NOT the entire genome-wide dataset.

Variation in fasting glucose concentration (FPG) is important for human health. In the normal range FPG is associated with risk of type 2 diabetes and ischaemic heart disease independently of obesity. In pregnancy maternal FPG concentration is an important independent determinant of birth weight in non-diabetic mothers. There is evidence that the regulation of FPG has a strong genetic component.

The main regulator of FPG concentration is the enzyme glucokinase. Our preliminary data shows that common variants in the promoter region of the glucokinase gene are associated with FPG and fetal growth. The minor allele at GCK-30, present in 30% of the UK population raises FPG by0.06 mmol/l (0.04-0.11), p = 0.003; and, when present in the mother, birth weight by 64g (25-102), p = 0.001. We have next shown that variation, further upstream (rs3757840) of the gene, and with no obvious functional role, has a similar, but independent effect on FPG.

In this project we propose to test comprehensively the hypothesis that common genetic variation in GCK alters FPG and birth weight. We will use the latest approaches for capturing the important variation across a gene together with DNA resources from 28,799 mother-child pairs. This approach will establish, if our hypothesis is true, a definitive genetic component to the aetiology of normal variation in FPG and birth weight.

Having identified a possible interaction between a maternal Nrf2 SNP and prenatal paracetamol exposure on asthma risk, we would like to carry out further genotyping to confirm additional gene*paracetamol interactions.These include an additional Nrf2 SNP; GCL (relevant to glutathione synthesis); Melatonin receptor MTNR1b (melatonin is a powerful antioxidant linked to paracetamol toxicity); CYP2E1 (relevant to paracetamol toxicity).

Treatment for mental illness often focuses on changing cognitive patterns (for example, cognitive behavioural therapy). There is much evidence to suggest that cognition is different in those with mental illness but whether change in cognition is a causal risk factor has not yet been established. Classic observational studies of cognitive patterns and mental illness do not get around the problems of reverse causation and residual confounding. That is to say that the change in cognition might instead emerge as a result of the mental illness, or both might be the result of other unmeasured factors.

One way to get around this is using Mendelian randomisation. Here we take genetic variants associated with the trait of interest: cognition and use them to naturally randomise individuals to levels of the exposure. Therefore, analogous to a randomised control trial, we can make conclusions about whether or not the relationship is causal. In this study, we will be looking at the cognitive traits of emotion recognition, working memory, cognitive styles and impulsivity. This research could inform the development of cognitive training tasks as interventions for mental illness.

Socioeconomic disparities in health across the life-course are well-documented, long-standing, and consequential. Research suggests that a significant proportion of the social gradient in health is due to SES differences in health-risk behaviors. Scholarship investigating the underlying mechanisms whereby lower SES increases health-risk behavior points to the mediating role of risk-increasing (or ‘riskogenic’) psychosocial schemas. Specifically, evidence suggests that social context and experiences in development, which are patterned by one’s social position, calibrate psychosocial orientations, including impulsivity or self-control, sensation seeking, and hostile views of relationships, which influence health-risk behaviors and health outcomes. Although the past decade has seen a spate of published GE-health research, few studies have focused on the role of G-E interplay in shaping psychosocial schemas as mechanisms through which SES adversity shapes health disparities. This project will investigate the effects of SES adversity on changes in psychosocial schemas, conceived as socially-calibrated and genetically-influenced endophenotypes which link SES adversity to increased health risk-behaviors. Additionally, although we know that social experiences “get under the skin” to have enduring effects on health outcomes, we lack knowledge on the biological pathways through which such effects persist. Thus, second, and more innovatively, we will engage with the nascent field of social epigenetics to examine DNA methylation (DNAm) as a biological mechanism through which SES-adversity calibrates psychosocial schemas. In this project, we will investigate the DNAm patterns underlying psychosocial adaptations to SES adversity that increase health-risk behaviors, building on work that identifies DNAm as an important molecular underpinning of experience-dependent changes in cognitions, decision-making, and behavior.