To explore the relation between childhood sexual behaviour and adolescent sexual behaviour, and possible mechanism underlying this relationship (e.g., the roles of childhood gender-typed behaviour, childhood victimisation, childhood and adolescent intimate friendships, and pubertal development).

Middle childhood--conventionally defined as between 6 to 11 years of age--provides rich contexts in which sexual orientation might develop. It nurtures intimate same-sex friendships [1], and coincides with adrenarche--a potential biological catalyst for the emergence of sexual attraction [2]. Sexual behaviour (e.g., masturbation) in middle childhood may be related to adolescent sexual orientation in at least 2 ways: The pleasure resulting from genital stimulation during adrenarche may involve same-sex friends in intimate interactions, which may lead to adolescent same-sex sexual attraction and activities.

Also, childhood gender atypicality may be involved in the link between childhood sexual behaviour and adolesent sexual orientation: for example, gender atypicality in middle childhood may increase victimization, which could be associated with increased childhood sexual behaviour, perhaps to offset negative emotions [3]; in addition, childhood gender atypicality is directly linked to same-sex sexual orientation [4].

Aims: To compare performance of existing methods for cell mixture adjustments in analysis of DNA methylation in cord blood and children's blood

Hypothesis: When the reference samples do not match with study samples, reference free methods are more robust than reference based methods.

Variables:

Total cholesterol

HDL-cholesterol

LCL-cholesterol

Triglycerides

Methylations measured on Illumina 450k methylation array (under ARIES project) as well as covariates including Age, Sex, BMI, Smoking, SEP measures

The main aim of this study is to test the hypothesis that females gain genetic benefits for their offspring through mate choice. Whilst it is known from work on non-human animals that mate choice can result in improved growth and survival of offspring (e.g. Petrie 1994) the possibility that human mate choice can affect subsequent fitness-related traits of children has not been investigated. We aim to specifically test this possibility using data collected for the ALSPAC study.

If females are gaining genetic benefits for their offspring from mate choice we can predict that disruption of the mate choice process will result in a lack of genetic benefits and thus poorer offspring growth and health. It is known that from the laboratory that use of the contraceptive pill at the time of mate choice can result in the alteration of female mate preferences such that females are more likely to prefer individuals that are more Mhc similar to themselves (Roberts et al 2008; Alvergne & Lummaa 2010). Mhc similarity between biological parents can lower the degree of heterozygosity at the Mhc in children such that they are less able to combat disease. We would like to test whether such mate choice disruption has any real world consequences. We aim to do this by:-

1) comparing health of children for a sample of women who chose their biological fathers whilst taking the pill with that of a sample of women who intitiated oral contraceptive use after meeting the biological fathers of their children.

2) comparing the degree of MhC similarity between mothers and fathers in a group of women who met their partners whilst using oral contraceptives with another group of women who started using oral contraception after making their mate choice.

3) comparing the degree of heterozygosity at the Mhc in the children of mothers who chose their partners whilst on the pill with those from mothers who did not.

Identifying genetic and epigenetic markers for fetal growth variation is important for both perinatal and adult health. Imprinted genes, which show parent-of-origin, specific, monoallelic expression, play key roles in fetal growth. There have been several genome-wide association studies to link genetic variants with birth weight, although none of them assumed parent-of-origin inheritance pattern, mainly because it requires large family cohorts to impute parental origin of the variants. As a recent collaborative project with the ALSPAC, we have shown that the maternal inheritance of a single copy number variant (repeat sequence 1: RS1) in the promoter of imprinted PHLDA2 gene to be significantly associated with increased birth weight and head circumference1. We hypothesise that there will be more genetic variants associated with fetal growth to be identified if parental origin of the allele is taken into account. Therefore, we would like to carry out a genome-wide search for genetic variants in assocition with fetal growth considering parental origin effects. Importantly, monoallelic expression of imprinted genes is controlled by differential DNA methylation established during gametogenesis. We propose to carry out a study using existing genomic, epigenomic, expression and phenotypic data at the ALSPAC to find genes important in fetal growth using a parent-of-origin model.

Aim:Life course epidemiology is the study of how exposures during gestation, childhood, adolescence and adulthood influence later health and wellbeing. Analysis of data from across the life course enables us to examine the dynamic ways in which variables of interest change and interact across a person's life span, determinants of these changes, and how the pattern of change relates to later health. A key focus within life course studies is analysis of mediation, i.e. the chain of intermediate processes that links an exposure to an outcome. Well-executed mediation studies are a crucial next step for the field of life course epidemiology. They represent an opportunity to increase understanding of pathways and mechanisms by studying the causal chains that explain exposure-outcome associations. Mediation analysis can therefore provide aetiological insight and identify potential intervention targets. In recent years, the epidemiological literature has given much more consideration to some of the statistical issues in mediation analysis than was the case previously; epidemiologists are now much more likely to give careful thought to mediator-outcome confounding and the potential resultant collider bias, and methods are now available that allow for exposure-mediator interactions or for situations where a confounder of the mediation-outcome association is caused by the exposure. Counterfactual theory has been used to show that the 'total' effect of an exposure on an outcome can be decomposed into the 'natural' direct and indirect effects, and methods for identifying these effects have been developed. However, several challenges remain. In this proposal, I will address 2 key issues in mediation analysis: 1) mediation analysis with repeated measures data, and 2) causal mediation analysis using Mendelian Randomization (MR), and will apply appropriate methods to address the following 2 questions of public health importance in the field of adiposity and cardiometabolic health:i) Whether the trajectory of growth and development affects cardiometabolic health independently of final attained adiposity.

Aims

The general aim of the project is to contribute to the characterization of the genetic risk factors for NVP and BF through genome wide association meta-analyses, in order identify genetic variants influencing these traits and to develop predictive models of which women are more prone to develop NVP and to breastfeed. The results of these studies will help inform the design and translation of more individualized reproductive health interventions.

The aims of the analyses of ALSPAC data are:-

(1) To determine the incidence of anxiety (clinical levels and any anxiety symptoms) in this cohort

(2) To determine the incidence of anxiety (clinical levels and any anxiety symptoms) in this cohort

(3) To determine the course of anxiety symptoms over time

(4) To estimate and quantify the impact of early-onset anxiety on current and later social, health and economic outcomes, adjusting for confounders.

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In the IMAGEN sample of 2000 adolescent sample from the European cohort, we have detected a strong association between SNP rs16958736 (of VPS4A gene) and the activation of striatum (i.e. caudate, putamen and nucleus accumbens) in 'large win' vs 'no win' contrast of Monetary Incentive Delay (MID) task with P=1.30E-7. A following haplotype analysis then found that the same haplotype that was associated with the activation of striatum was also in association with the hyperactivity (ADHD) assessment from SDQ questionnaire. Meanwhile, in Drosophila, we found that both over-expression and knock-out of VPS4A could alter the frequency of locomotion activity of flies. By searching in the literatures, we then found that VPS4A encodes an ATPase which is involved in trafficking of G protein coupled receptors (GPCRs), including dopamine and noradrenaline. We therefore hypothesize that VPS4A may influence synaptic plasticity through regulating signalling at the dopaminergic and noradrenergic synapse.

In another paper, we have detected the SNP rs2067499 from THRB (Thyroid Hormone Receptor B) in strong association with ACC (anterior cingular cortex) and INS (insula) with P=1.19E-7, the same SNP was then found with significant association with ADHD assessment from SDQ with P=0.014. We propose that a mild resistance to TH (Thyroid Hormone) is associated with increased ACC-INS connectivity and results in ADHD-symptoms by enhancing sensitivity to external and internal stimuli.

Aims and Hypotheses

The project therefore plans to investigate whether low birth weight, and rapid early growth (0-2 years), in addition to asthma, early transient wheeze and maternal smoking, are associated with the development of specific obstructive pulmonary function abnormalities in adolescence.

We have hypothesised that there is an association with low birth weight/IUGR and the development of reduced pulmonary function; that there is also an association between rapid growth during 0-2 years and reduced pulmonary function; and that asthma may mediate this. In addition, the project plans to look at whether low birth weight explains the association between maternal smoking and reduced function.