Logistic regressions will be used to examine the association between stressful life events (SLEs) and OCD symptomatology. Additional logistic regressions will be conducted adjusting for sex, social economic status, depressive symptoms severity obtained from the SDQ at 81 months, maternal depression and marital status.

I will also investigate the impact of missing data using multiple imputation.

The link between psychosocial stress and eczema (aka atopic dermatitis) was identified at least a half-century ago when eczema was designated one the seven classic psychosomatic disorders.[1] The allostatic model of chronic stress proposes that dysregulation of normal homeostatic mechanisms may lead to chronic hyperarousal or hyporesponsiveness.[2] Mechanistic evidence comes from the field of psychoneuroimmunology linking the nervous system, endocrine system, and immune system.[3,4] Stress may also lead to disease-exacerbating behaviors related to diet, sleep, exercise, bathing practices, and treatment adherence.[5] In epidemiologic studies, self-reported stress levels have been shown to correlate with eczema incidence, and stress-reducing modalities have been found to improve eczema symptoms.[6,7]

Various factors are involved in a stress response and will be included in our analyses: exposure to a stressor, resilience/ the use of social supports, and the emotional and behavioral response.[2] We will also include family-related distress such as caregiver stress, maternal panic disorder or depression and family conflict because these have been reported to have immunological effects on younger subjects.[8]

Aim: To examine the association between stress and eczema.

Hypothesis: Higher rates of distressing life events, poor social supports, and psychological distress will each be associated with more persistent eczema.

All patients in the ALSPAC cohort with follow-up data available through age 18 will be included in a longitudinal cohort study. Because the relationship between stress and eczema is likely bidirectional,8 we will model the relationship between each measure of stress and repeated measures of eczema persistence using a marginal structural model and stabilized inverse probability-of-treatment weights to avoid conditioning on stress through its inclusion as a predictor in the outcome model.[9] We will have 90% power to detect an odds ratio as small as 1.23 at a 0.05 significance level in a design with 5 repeated measurements, assuming 15% eczema prevalence.[10,11] We will carefully evaluate missingness and will conduct sensitivity analyses using multiple imputations.[12,13] The results of this study promise to disentangle the individual experience of stress from group-level factors that may be associated with stress including race, socioeconomic status, and environmental factors.

This is a pilot study with the following research aims:

1.) Generation of NMR-based metabolomics data on Niemann-Pick Type C1 (NPC1) disease for identification of metabolic (diagnostic) markers for NPC1 disease at different ages.

2.) Development of methodology to facilitate future work on metabolomics of LCLs.

3.) Evaluation of a 700MHz NMR spectrometer with 1.7mm cryoprobe for metabolomics on mass-limited samples. This instrument is the first of its kind in the UK and offers significant potential for novel metabolomics research. A comparison will be made to data acquired on more standard NMR spectrometers (600MHz with 5mm nitrogen-cooled (Prodigy) probe).

Niemann-Pick type C disease is a complex disorder characterized by elevated cholesterol, glycosphingolipids and sphingosine in endosomal compartments. In the majority of patients lipids are stored due to a defective protein NPC1 a membrane spanning late endosomal protein. A minority (5%) of patients have mutations in a lumenal late endososmal protein NPC2. Although much is known regarding the clinical aspects of NPC disease, the cellular mechanisms leading to neurodegeneration are, to date, poorly understood, and the precise function of the NPC1 and NPC2 proteins remains unknown or speculative. NPC disease has one EMA-approved therapy (Miglustat) which is disease-modifying; however, new, additional therapeutic approaches are urgently required. In order to evaluate these, the identification of novel, clinically-relevant biomarkers for the monitoring of this disease and its progression are necessary.

IL-6 is an inflammatory cytokine with diverse roles in chromic inflammation and autoimmunity. It is thought to play a role in a diverse array of health outcomes, including auto-immune conditions, allergic conditions, brain diseases and even depression. Therefore, increased understanding of the mechanisms that influence it, and that it influences, could have far reaching health implications.

Aim: EWAS of interleukin-6 measured in the children at age 9, to identify CpG sites where methylation levels are correlated with IL-6 levels.

Aim : Our aim is to develop new methods for causal inference in the context of the Mendelian randomisation (MR) framework.

We are interested in the metabolites data set because we believe it is interesting from both a methodological and biological point of view. MR being an instrumental variable method, it makes strong and untestable assumptions about the effect of genetic variants on measured variables, the 'no pleiotropy' assumption being the most restrictive (Didelez V. et al, 2010).. But one might ask whether it is possible to relax this assumption, and if so with what consequences. When the number of genetic variants and measurement increase, can it be replaced by a different set of assumptions that might be more believable in a biological context. See for example (Silva R and Evans R., 2014) and (Kang et al. 2014) who make assumptions about the strength of the confounders and the number of invalid instruments. To that end, we intend to model all variables together, a method sometimes called "network Mendelian randomisation" (Burgess S. et al, 2014). In particular, we will use recent developments in the fields of matrix recovery and graphical modelling in order to infer the effect of the confounders and identify some of the pleiotropic pathways (Candes E. et al. 2009, Chandrasekaran V., 2011). According to our power analysis, we expect to uncover 60% of the causal links at a false discovery rate of 5 %, and this in the presence of arbitrarily strong confounders. Thanks to simulations for a wide range designs, we have confirmed that our FDRs are well calibrated.

Infertility is a significant health problem worldwide, estimated to affect approximately 1:6 couples of reproductive age. Whilst reports of global declines in semen quality are controversial, the increasing prevalence of male subfertility stands as uncontested fact: male factor is now the leading cause of fertility problems, and accounts for almost half of all cases. Exposure to environmental toxicants, such as heavy metals, organic solvents and pesticides, as well as lifestyle choices, including obesity and poor diet, drugs (prescribed medication and otherwise) and smoking are all suggested to be contributory causes to male subfertility, but effects are poorly defined. Unexplained poor sperm motility (asthenozoospermia) is the commonest clinical abnormality in subfertile males, yet our limited knowledge of the exact workings of spermatozoa mean that this problem is incompletely understood, neither do we know how to correct it. Incredibly, there is no drug that a subfertile man can take, nor that can be added to his sperm in vitro, to improve sperm motility. Couples instead rely on Artificial Reproduction Technology (ART), such as IVF, which is expensive, invasive and not without risk. Nonetheless, year-on-year, ART is increasingly utilised worldwide. In order to tackle a global health problem, there is clearly a need to better understand the pathological processes affecting male reproductive health.

Sperm motility, calcium and CatSper

Sperm motility is arguably the most important characteristic to impact on male fertility. Increase and fluxes in intracellular calcium [Ca2+]i are fundamental to the regulation of sperm motility and function, including changes in direction, hyperactivation and chemotaxis. [Ca2+]i is regulated by at least two processes: mobilisation of Ca2+ stored in the sperm neck region and/or movement into the cell via Ca2+ permeable ion channels and transporters, mainly CatSper channels. CatSper channels are essential for male fertility and are present in the flagellum of human sperm. Landmark studies have demonstrated Ca2+ entry into human sperm in response to progesterone (a product of cumulus cells) is via CatSper channels. CatSper channels are also activated by organic molecules that apparently evoke chemotaxis, and it has therefore been proposed that this ion channel acts as a polymodal chemosensor integrating multiple chemical cues from the female reproductive tract to elicit functional responses to direct sperm towards the egg.

Environmental exposures

Xenobiotics are any alien molecules that are foreign to mammalian biological systems. Such substances include pesticides, herbicides, cosmetics, preservatives, cleaning materials and pharmaceutical products, and have worked their way into our lives in a variety of forms. Even though awareness of the biological risks of chemical toxicity has increased considerably in recent years, the majority of these chemicals have long half-lives and can still be detected in the environment decades after their release. Xenobiotics may have direct or indirect effects on sperm motility and function, including interference with physiological CatSper responses, which subsequently manifests as male subfertility. For example, dichlorodiphenyldichloroethylene (DDE) is an organochlorine pesticide, an endocrine disruptor and known reproductive toxicant to certain species of birds due to thinning of their eggshells. DDE is fat soluble, and tends to build up in the fat of animals. Due to its stability in fat, DDE is rarely excreted from the body, and body levels tend to increase throughout life. In vitro exposure to DDE affects functional sperm parameters and we have demonstrated that it activates CatSper at environmentally relevant concentrations.

Trans-generational reproductive impact

For many disease states it is now recognised that the risk of disease in adult life is determined by a combination of genetics, the intra-uterine environment, childhood exposures and adult lifestyle, but the impact of each of these components on sperm parameters and male fertility is largely unknown. The impact of environmental factors on the epigenome and male fertility, and significance of epigenetic changes/aberrations (often hypermethylation) in assisted reproduction are beginning to be understood. However, identification of the respective contribution of genetic and timecourse environmental exposures to male reproductive capacity in adulthood is not only very limited, but also very challenging, particularly due to the difficulty of obtaining data on multiple factors throughout life.

Aims

By utilising the Avon Longitudinal Study of Pregnancy and Children (ALSPAC) cohort, we aim to address the contribution of genetic and timecourse environmental exposures to male reproductive capacity in adulthood. This cohort is a huge resource and has the fantastic potential to provide prospective longitudinal data, allowing not only quantification of relative contributions of various elements, but the potential to identify critical timepoints and how these associations change with progression from fetal life, childhood, adolescence and into adult life.

AIMS:

Health-risk behaviours - here including alcohol, tobacco, drug use, risk taking and antisocial behaviour - are prevalent in early adulthood and highly comorbid. They constitute a major public health challenge impacting individuals, families and society. Identifying environmental risk factors causally associated with health-risk behaviours is crucial to design effective interventions.

The main objective of the proposed research project is to identify environmental risk factors causally associated with health-risk behaviours in emerging adulthood. To achieve this aim, the project will build on advances in genetics, using DNA information to strengthen causal inference.

The project will largely build on already collected data and, pending on funding may include additional data collection regarding health risk behaviours and environmental risk in early adulthood.

The project will investigate three major questions:

1. Comorbidity between health-risk behaviours: We will test whether the observed comorbidity within health-risk behaviours is due to underlying causal relationships or arises from genetic and environmental confounding (for instance alcohol use and antisocial behaviour).

2. Magnitude and consequences of gene-environment correlations: We will examine gene-environment correlations by looking at genetic influences on environmental risk factors (e.g. neighbourhood safety). We will then test to what extent the relationship between risk factors and health-risk behaviours may arise from shared genetic influences.

3. Early and concurrent environmental predictors: We will build on the longitudinal feature of the datasets to examine how early and concurrent risk-factors predict health-risk behaviours. We will contrast conventional analyses and classical techniques to examine causality with analyses using DNA information to strengthen causal inference.

Background

The face is a biological display of our identity and controlled in the most part by genes.1-3 There is consistent facial concordance between identical twins,4 identifiable facial features within families,5 geographic populations,6 and the sexes,7 and finally distinctive facial features associated with particular genetic conditions.8,9 This suggests that inter-individual variation in craniofacial morphology is primarily determined by genetic variation.

Studies of craniofacial heritability are performed on twin and parent-offspring databases and provide insight in the relative contribution of genetic and environmental effects on craniofacial parameters.4,5,10,11 Heritability studies allow the focus on those facial parameters displaying a strong genetic component as well as acknowledging possible environmental influences. Most if not all studies on craniofacial heritability start from sparse descriptions of facial shape using a limited set of manually indicated landmarks. Variation in these landmarks is then comprised using principal component analysis or by measuring geometric features such as distances, curvature, ratios and/or angles. Subsequently, for each principal component or geometric feature separately a heritability score is computed using correlations between parent and offspring or between twins. However, sparse representations typically overlook salient features of facial shape. Furthermore, heritability studies today do not investigate co-inheritance between different geometric features. Doing so would allow subdivision of facial shape into modules (multiple landmarks and measurements grouped together) of co-inheritance, that when analyzed as groups could reveal higher levels of inheritance.

Research Aim

The aim of this proposal is to perform a spatially-dense analysis of facial heritability and co-heritability starting with Fathers and offspring data available within ALSPAC. The study outcome is two-fold. In a first instance a spatially dense view on facial heritability per landmark will be provided. In a second instance, a subdivision of facial shape into modules of co-inheritance will be provided. Subsequently, the benefit of such a modularization will be tested in a limited association study between facial shape and known craniofacial genes based on BRIM.12

Background: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterised by deficits in social interaction and repetitive and stereotyped interests and behaviours. The aetiology ot ASD comprises known genetic factors [1,2] and increasing evidence suggests a role for intrauterine environmental factors, such as exposure to maternal smoking during pregnancy [3]. Maternal smoking during pregnancy has been associated with other adverse perinatal outcome such as lower birth weight and higher risk of other neurodevelopmental disorders such as attention deficit hyperactivity disorder [5], therefore smoking during pregnancy is a biologically plausible hypothesis in the aetiology of autism but the evidence is still inconsistent. Epigenetics is one potential mechanism linking intrauterine exposures and postnatal outcomes. DNA methylation changes induced by the prenatal exposure could affect genes that are implicated in the aetiology of ASD and therefore DNA methylation could be a causal mediator for the increase risk of ASD. A recent study in the ALSPAC has shown that maternal smoking is associated to DNA methylation changes across the genome, including the replication of genes that were found in other cohorts and new targets [6]. Although an association between maternal smoking in pregnancy and autism might be plausible, there is much inconsistencies in studies to date. In particular, when investigating causal effects in observational studies there is the possibility of unobserved and residual confounding and a way to overcome this issue is by using genetic variants as proxies for the exposure as in a Mendelian Randomization framework [7]. GWAS studies have observed robust associations between smoking and a locus on chromosome 15 involving the CHRNA3 gene, as well as associations in other genes such as BDNF [8].

Aim: We aim to investigate the causal relationship between maternal smoking during pregnancy and childhood's autistic traits and whether this is mediated via DNA methylation changes at birth.