Colorectal cancer incidence in individuals younger than 50, referred to as early-onset colorectal cancer (eoCRC), has doubled in many countries. Over the next decade, deaths due to eoCRC are expected to rise globally, with eoCRC accounting for over 20% of all colorectal cancers and becoming the leading cause of cancer-related deaths in 20-49 year olds. However, the factors leading to this increase are uncertain. The gut microbiome, which comprises millions of bacteria, fungi and viruses that are housed naturally within our digestive system, may influence the development of colorectal cancer, whereby some microbiota play a role in inflammation, DNA damage and production of cancer-promoting molecules. Recent studies have shown that there are specific genetic mutations associated with colorectal cancer risk, which occur more often in people of younger ages than in older ages. These mutations are also caused by the toxin called colibactin, which is produced by certain gut microbial bacteria. Our study aims to understand whether these bacteria, if present in early life, cause these mutations within our DNA (via colibactin production) and therefore increase the risk of eoCRC.

Height is a complex trait that is underscored by a combination of genetic and environmental factors. A large number of studies have defined the genetic basis of human height. Recent statistical genetics efforts have shown that ~40% of the variance in height can be explained by the combined additive effects of >10,000 individual variants. In this study, we will examine the utility of blood DNA methylation (DNAm) in capturing additional trait variance and in understanding the molecular architecture of height.

Chronic inflammation is a hallmark of ageing and age-related disease states. The effectiveness of inflammatory proteins such as C-reactive protein (CRP) in assessing long-term inflammation is hindered by it's high within person variability. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. This project will develop a series of DNAm predictors of CRP in the Generation Scotland Cohort and evaluate their performance in ALSPAC parents and children as well as several other UK based study populations.

Anxiety disorders (AD) are the most prevalent psychiatric condition in the general population worldwide, and it is estimated that between 6.57 and 13.54% of new fathers suffer from an AD (Leiferman et al., 2021), a considerably higher proportion than the prevalence for anxiety in men generally estimated by the World Health Organization (World Health Organization, 2017; range between 2.2 − 3.8%). The mental health of children is robustly associated with the mental health of their parents (Jami et al., 2021). In particular, children whose parents suffer from ADs, compared to children whose parents do not, have a higher risk of struggling with their mental health (e.g., Connell & Goodman, 2002; Micco et al., 2009; Lawrence et al., 2019). However, the specific role played by fathers in children's mental health difficulties has been under-investigated, and the particular risk posed by paternal anxiety for offspring mental health difficulties is not well understood.

Extreme heat (> 40°C heat) is becoming more and more commonplace in the UK meanging overheating in homes and buildings is a key risk. It is important to understand how this affects people’s physical and mental health, wellbeing and behaviour during heatwaves so that strategies can be developed to help people adapt.

Most research in the UK related to heat and health is focused on outdoor temperatures and population-scale health outcomes (e.g., mortality in South-West England) rather than people’s experiences and perceptions of heat, which varies between individuals and the buildings they live in.

We will fill these gaps by working with ALSPAC to develop and test a questionnaire that will ask participants about their experience and behaviour during a heatwave. The data collected from this plot will not be linked back to any ofther data but will help us to understand how heat might affect the health and wellbeing ofdifferent people, help to inform the development of early warnings and contribute to a fellowship application leading to more detailed research in ALSPAC.

In 2010, the American Heart Association (AHA) created ‘Life’s Simple 7 (LS7)’ – a risk score aimed at quantifying ideal cardiovascular health behaviours within large populations. This risk score consisted of seven modifiable factors known to influence cardiovascular disease; namely body weight, physical activity, diet, smoking, total cholesterol, glucose, and blood pressure. Over the last 12 years, LS7 has been shown to be effective in predicting a wide-range of future cardiovascular events in older cohorts, as well as the subclinical development of early cardiovascular risk in the young. In 2022, the AHA revised and updated this risk score to become ‘Life’s Essential 8 (LE8)’, adding sleep quality as a new modifiable risk factor for disease and altering definitions of what constitutes ‘ideal behaviours’ in many of the other risk factors. The comparability of this new score to LS7, however, and feasibility of using it in large population datasets to predict outcomes such as early changes in heart and brain health remains unknown.

In 2010, the American Heart Association (AHA) created ‘Life’s Simple 7 (LS7)’ – a risk score aimed at quantifying ideal cardiovascular health behaviours within large populations. This risk score consisted of seven modifiable factors known to influence cardiovascular disease; namely body weight, physical activity, diet, smoking, total cholesterol, glucose, and blood pressure. Over the last 12 years, LS7 has been shown to be effective in predicting a wide-range of future cardiovascular events in older cohorts, as well as the subclinical development of early cardiovascular risk in the young. In 2022, the AHA revised and updated this risk score to become ‘Life’s Essential 8 (LE8)’, adding sleep quality as a new modifiable risk factor for disease and altering definitions of what constitutes ‘ideal behaviours’ in many of the other risk factors. The comparability of this new score to LS7, however, and feasibility of using it in large population datasets to predict outcomes such as early changes in heart and brain health remains unknown.

The association between maternal cardiometabolic markers and offspring cardiometabolic health has remained elusive. Barker et al. have postulated that the intrauterine environment and early-life development serve as potentially important determinants of cardiovascular disease (CVD) later in life. However, previous studies were constrained by limitations such as small sample sizes, short durations of follow-up, or inadequate control for confounding variables. Consequently, a systematic investigation of maternal gestational cardiometabolic biomarkers and their relationship with offspring cardiometabolic health in a large-scale cohort is warranted.

Repair of adult tissues involves a complex interplay of several key cell lineages and inevitably leads to formation of a fibrotic collagenous scar, whereas embryonic tissues heal perfectly without any resulting scar deposition. This dramatic difference in repair efficiency between embryonic versus neonatal/adult tissues has been instrumental is guiding us towards potential causes of scarring. Indeed, we now believe that one major driver of scarring is the wound inflammatory response which doesn't initiate until a transition period in fetal development which, in turn, coincides with the developmental onset of tissue scarring. This insight has led us towards further mechanistic cell and molecular studies in model organisms, such as mouse and zebrafish, which help us better understand the scarring process and how one might modulate the wound inflammatory response in order to improve or prevent scarring.

Whilst these approaches, motivated by comparing embryonic versus adult healing, have been fruitful, it is clear that scarring is a complex, multifactorial response likely driven by a number of interacting mechanisms. We would like to use a conceptually similar comparative approach to gain further insights into the fundamental cell and molecular mechanisms of scarring by analyzing differences in degree of scarring, not between embryo and adult, but rather across human adult populations since we know there is a range of “scarring phenotypes” from “minimal scarrer” to keloid scarring individuals. This use of human phenotypic variation in a population based, genetic association approach (genomewide association studies – GWAS), has the potential not only to yield gene variant correlates of scarring, but also to point towards specific biological contributions to wound healing. The use of natural human experiments (e.g. Bacillus Calmette–Guérin (BCG) vaccination wound healing, Caesarean section (C-section) wound scarring and examples of human disease related fibroses) has never before been used for identification of scarring genes, even though the approach has proven to be powerful for discovering genes associated elsewhere with a wide variety of complex health outcomes (www.ebi.ac.uk/gwas/). Furthermore, alongside a growing number of catalogues charting the results of human genetic association studies for health outcomes and intermediates there are tools able to consider (in frameworks of causal analysis) the existence of potentially causal and modifiable relationships between exposures of interest (e.g. inflammation, differential wound repair or scar) and health outcomes (e.g. wound healing, recovery, and disease).

Using human genetic data to help explore the potential of biological pathways contributing to health and disease in applied epidemiological designs is an approach that we have refined and developed and is an integrated approach to health research that has yielded important clinically relevant insights, but has also indicated opportunities (e.g. associated signaling pathways for targeting) to unify basic science approaches with human population based health data (see below).