In a current project, we are trying to identify genetic factors associated with pubertal traits in Chilean Children. We are also interested on how genetic ancestry affects these traits. In order to know whether our results on Chileans are unique, we need to replicate the same analyses using a European cohort like ALSPAC.

Stuttering is a complex communication disorder, characterized by dysfluent speech, that can have a profound effect on an individual’s social and mental wellbeing. Up to 11% of children commence stuttering by 4 years of age. Whilst stuttering resolves for many, a third will develop a persistent stutter. Stuttering interventions are effective for some in the preschool years; yet, there are no effective treatments for older children, adolescents or adults, and it is not possible to predict who will develop persistent stuttering. The exact causes of stuttering are still unknown, but genetic factors play an important role.

We hypothesize that common genetic variation makes a substantial contribution to the risk of stuttering and propose that this is most effectively investigated by undertaking a genome-wide association study (GWAS), using a large population-based sample of people who stutter (PWS), recruited via an online questionnaire. Crucially, so far there is no published GWAS for stuttering, a clear gap in our genetic understanding of this disorder.

We are building a global collection of PWS, recruiting adults and children through a concerted media recruitment campaign. Alongside our efforts to recruit PWS directly, we are building a global network of cohorts with information on stuttering via the GenLang Consortium. We intend to combine data from both approaches, in a large-scale GWAS meta-analysis.

Understanding the genetics of stuttering will provide insights into the underlying biology, potentially leading to stratification of stuttering into clinically relevant subtypes, targeted treatment and drug targets. This will lead to better health and socioeconomic outcomes for PWS.

Arsenic, cadmium, lead, and mercury (As, Cd, Pb, Hg), are toxic elements with no known biological functions. Long-term exposure to these elements is possible through the food chain, water contamination, and air pollution depending on local conditions. Arsenic appears to impair neurocognitive performance but not behavioural outcomes (Tolins et al, 2014), and the impacts on language or motor development are less clear. There have been few studies to date of cadmium and neurodevelopment (Rodriguez-Barranco et al, 2013), although previous work within ALSPAC found no association with motor skills (Taylor et al, 2018). Mercury at high-doses is known to delay neurodevelopment (Grandjean & Herz, 2011), but the evidence for an effect at more realistic low-levels is unclear. The strongest evidence of harm during childhood from heavy metals is exposure to lead which has been reliably linked to impaired cognitive, behavioural, and motor development (Sanders et al, 2009). For each of these elements there is a potential to strengthen the evidence base through the use of genetic methods unbiased from confounding factors, and to examine less-studied neurodevelopmental outcomes.

Thyroid dysfunction is one of the most common clinical problems among pregnant women. Before the onset of foetal thyroid function in mid gestation, the foetus is completely dependent on the maternal supply of thyroid hormones, which play a crucial role in the foetal growth and development. The increased requirement of thyroid hormones by approximately 50% during pregnancy is a challenge for the maternal thyroid glands. Our recent systematic review and meta-analysis showed that maternal thyroid dysfunction is associated with neurodevelopmental disorders, such as attention deficit hyperactivity disorder and epilepsy. However, the association between maternal and offspring thyroid dysfunction were only investigated in single studies. The major disadvantage of existing studies included limited sample size and unavailability of confounding variables. This project aims to evaluate the association between maternal and offspring thyroid dysfunction in an individual cohort of larger sample size, with appropriate adjustment for confounding factors. It is expected that the results may provide insights on the clinical practice in handling thyroid dysfunction in pregnant mothers and their offspring.

Partly because of perceived health benefits and environment concerns, vegetarian/vegan diets have become increasingly popular around the globe in recent years. Despite the possibility of low intakes of some nutrients such as protein, omega-3 fatty acids, vitamin D, vitamin B12, iron, calcium, zinc, and choline, evidence suggests that vegetarians have generally better long-term health than their omnivorous counterparts. Pregnancy is a special period in the lifecourse, when foetal development requires increased nutrient intakes and accelerates nutritional depletion, and adequate and balanced nutrition is critical for both maternal and foetal health. Two reviews have suggested that appropriately planned and well-balanced vegetarian/vegan diets during pregnancy may be considered safe for the women and their fetuses. However, little is known about whether these diets will have longer-term effects on offspring health throughout childhood. Vegetarianism is highly socially and culturally patterned, so there is a need to carefully control for confounding to infer causal effects. This PhD aims to study associations between maternal vegetarian diet and offspring health across several domains and to attempt to infer which associations are likely to be causal. It also aims to study the role of DNA methylation and circulating metabolites as mediators of any effects.

Research over the last decade has demonstrated that alongside genetic factors, childhood adversity plays a vital role in the development of psychiatric illnesses. Several meta-analyses have shown robustly that childhood adversity is a cross-diagnostic risk factor, increasing rates of depression and anxiety to schizophrenia and borderline personality disorder. Despite this association, the biological processes underlying this phenomenon are not well understood. Without this knowledge, development of effective therapeutics is impossible. The precise effects of childhood adversity on function per se (e.g. cognition, emotion, social function) are not well known. The aim of this research is investigate the links between adverse childhood experiences and later function, identifying domains which are most affected (both in psychiatric and clinically well populations). These domains will then be explored further using translational animal models and more focused human studies, uncovering underlying biological mechanisms and leading to novel treatment options for people affected by childhood adversity.

Not all individuals exposed to childhood adversity will develop psychiatric illness, and genetics is likely to play a role in determining susceptibility vs. resilience. The role that genetics plays in moderating the effects of childhood adversity on function will therefore also be explored.

It is well established that cardiovascular disease (CVD) begins in childhood. Impairments in vascular function occur before the structural changes of CVD present in the arteries and the progression of CVD is related to CVD risk factors, such as cardiorespiratory fitness, physical activity, body composition and blood markers, in youth. Therefore, there is great interest in understanding how exposure to early lifestyle factors could be related to CVD risk in children and adolescents. Our current project utilising the ALSPAC data (B3455) is investigating the associations between early exposure to cardiorespiratory fitness and body composition with measures of arterial structure and function. However, physical activity and sedentary time are additional important markers of health, and warrant exploration for their potential associations with arterial structure and function at an early age.

Existing paediatric data examining associations between physical activity and/or sedentary time with measures of arterial structure and function are limited by small sample sizes and a subjective assessment of physical activity. Therefore, the current models are unable to account for a suitable number of confounding variables. Also, most studies have used cross-sectional design, and those which are longitudinal have a maximum follow up period of two years. Moreover, independent relationships of physical activity and sedentary time with arterial structure and function, may be altered by an existing interaction between physical activity and/or sedentary time.

Recent experimental data in prepubertal children has shown that the decline in arterial function during prolonged sitting can be prevented by performing 10 minutes of moderate intensity exercise each hour. There is evidence on the interaction between physical activity and/or sedentary time and traditional CVD risk factors, such as body composition and blood markers, in children and adolescents. However, there is a scarcity of data at a population level that examines how sedentary time and physical activity interact in children and how this relates to direct measures of vascular function and structure. Therefore, this project aims to examine the cross-sectional and longitudinal relationships between the early life exposure to physical activity and sedentary time with vascular function and structure from childhood to adulthood, while controlling for traditional CVD risk factors and cardiorespiratory fitness.

Stark inequalities in health already exist in the UK, with people from lower socioeconomic backgrounds suffering from greater levels of ill health across multiple domains. The covid-19 pandemic potentially threatens to worsen these health inequalities. The ‘lockdown’ changed people’s behaviour radically, but the socioeconomic differences in these experiences are not well understood. Some groups of society may have increased health-promoting behaviours – for example, engaging in more physical activity and preparing more food within the home. Other groups may have experienced adverse changes in health-related behaviours – for example, smoking more or consuming more alcohol in response to the stress and anxiety induced by the pandemic. It is possible these differences are socioeconomically patterned, and could therefore worsen pre-existing inequalities. Another key factor likely to influence patterns of behaviour change during the pandemic is household/family structure. For example, parents with children and individuals shielding or living with a household member who was shielding may have been less able to engage with health-promoting behaviours.

Data from the Office for National Statistics demonstrate that between 23rd March and 5th April 2020, 27% of the UK workforce were furloughed due to the COVID-19 lockdown. Many others lost jobs, or had working hours and income reduced. The adverse financial and employment consequences of the covid-19 lockdown are concentrated in already vulnerable groups of society – they are more likely to be experienced by people in insecure or low-paid jobs. The young adults in ALSPAC are in the age groups most likely to have been affected by furlough, job losses, and loss of pay or hours (https://www.resolutionfoundation.org/publications/young-workers-in-the-c...). Detailed pre-pandemic data from the ALSPAC cohort offers the opportunity to better understand which groups of society were more likely to be impacted financially by the lockdown. We will explore whether SEP, adverse childhood experiences, pre-existing mental health problems, obesity, smoking, alcohol use, shielding or living with a household member who was shielding, and family structure are associated with greater likelihood of adverse financial changes during covid-19, and hence whether the lockdown is likely to exacerbate health challenges for these groups.

As part of our commitment to DPUK (https://www.dementiasplatform.uk/) we are developing a trial dataset to be classified using the DPUK ontology and for the variable list to be uploaded to the DPUK data portal. Further developments may take place if hte trial proves successful.