Chronic Obstructive Pulmonary Disease (COPD) is a complex, heterogeneous and prevalent disease with a high socio-economic burden whose underlying biological mechanisms are unknown. It is now well established that about half of the patients with COPD never achieved a normal lung function early in life, and there is increasing evidence that some COPD risks may derive from early life factors in this setting it is highly likely that respiratory diseases are the end result of a set of different dynamic environmental-gene interactions that can occur during the entire life span of an individual (time). Lung development and lung aging are often considered two independent phenomena, but they are tightly interrelated.

Here we propose that alterations during lung development influence age-related physiological deterioration and cause premature lung aging. We expect that the lung (lung tissue and bronchial biopsies), as affected organ in COPD, accumulates the highest burden of methylation changes, but that some of them, are reflected in the circulating blood. Subsequently we will explore if these changes are identifiable early in life. We sought to explore this hypothesis by comparing the epigenetic profile associated with FEV1

Previous research has shown that epigenetic markers, like DNA methylation, reflect environmental exposures and can predict disease outcomes. The immune system is known to be involved the development of mental health problems and is one of the main body systems that regulates the response to various environmental risk factors. Therefore, the epigenome of immune cells could carry valuable information about the role of the immune system in mental health. Recent studies show that epigenetic markers of inflammation outperform circulating inflammatory protein levels in predicting inflammation-related diseases, due to their higher temporal stability, which may better capture chronic inflammation. Also, epigenetic processes are involved in developmental programming of both the immune system and nervous system, making epigenetic markers attractive for studying developmental origins of immune-related mental health risk. When applying such epigenetic markers in research on the immune-mental health link, developmental stages need to be considered, to elucidate epigenetic timing effects. With this project, we aim to explore the potential of epigenetic biomarkers to study how immune activation throughout development contributes to the risk of mental health problems, as a potential resilience mechanism in response to environmental risk factors.

This project is embedded in the Youth-GEMs project, an european consortium on gene-environment interactions in mental health trajectories of youth (ALSPAC proposal B3879).

Our team has previously utilized ALSPAC data and published findings suggesting that a) maternal nutritional status during pregnancy and b) free sugar intake at age 3 years are both positively associated with hepatic steatosis in young adulthood.1,2 We would like to extend our research to examine associations between early life free sugar and sugar-containing beverage consumption at 18 months and obesity and cardiometabolic risk throughout childhood and adolescence. Building off our earlier findings related to maternal nutritional status, we will also examine effect modification of the free sugar and later obesity association by maternal metabolic dysfunction and diet during pregnancy.

Increasingly, research has implicated early childhood as a critical window for the establishment and maintenance of obesity, necessitating a focus on preventing obesity early in life. Consequently, it is critically important to develop a better understanding of early life dietary factors that increase obesity risk. Current infant and toddler dietary recommendations include a focus on minimizing free sugar consumption as excessive intake may predispose children to obesity, but the evidence underpinning these guidelines is limited. It is unclear what amount of free sugar intake during early life conveys increased risk of obesity and compromised cardiometabolic health, and what factors modify this risk. Further, maternal metabolic dysfunction during pregnancy is associated with increased risk of offspring chronic disease via in-utero metabolic programming, and recent research has suggested that an interplay may exist between the prenatal environment, early nutrition, and later cardiometabolic health. However, to date, no researchers have examined how the early free sugar-childhood obesity relationship may be modified by maternal conditions such as pre-pregnancy obesity, excessive gestational weight gain, and gestational diabetes. A better understanding of the potential effect modification by maternal health during pregnancy could help provide insights into which, if any, groups may benefit from increased, targeted early life nutrition guidance. We will utilize longitudinal data from a British birth cohort study (Avon Longitudinal Study of Parents and Children) to assess the association between free sugar and sugar-containing beverage consumption at 18 months and obesity at ages 5, 7, 13, 15 and 17 years and cardiometabolic risk at ages 15 and 17 and examine effect modification of the associations by maternal metabolic dysfunction and diet during pregnancy. Our findings will inform existing infant and toddler nutrition guidelines and help guide the development and targeting of early childhood obesity prevention interventions.

Publications from original proposal:
1. Sekkarie A, Welsh JA, Northstone K, Stein AD, Ramakrishnan U, Vos MB. Associations between Free Sugar and Sugary Beverage Intake in Early Childhood and Adult NAFLD in a Population-Based UK Cohort. Children. 2021; 8(4):290. doi: 10.3390/children8040290
2. Sekkarie A, Welsh JA, Northstone K, Stein AD, Ramakrishnan U, Vos MB. Associations of maternal diet and nutritional status with offspring hepatic steatosis in the Avon longitudinal study of parents and children. BMC Nutr. 2021;7(1):28. Published 2021 Jul 8. doi:10.1186/s40795-021-00433-3

This project aims to improve our understanding of how mental health conditions emerge and develop during childhood, adolescence and early adulthood. By studying the interplay between biological and environmental factors, we aim to uncover how these influences can either contribute to drive or prevent the onset of mental ill-health. This research is part of the Youth-GEMs project, a European consortium dedicated to investigating gene-environment interactions in the mental health trajectories of young people (ALSPAC proposal B3879).

The number of young people (aged under 40) being diagnosed with high blood pressure is increasing. Patients with high blood pressure are often overweight or obese and together this substantially increases their risk of cardiovascular and metabolic diseases. At the moment, mechanisms linking obesity and hypertension in young people are not very well understood but abnormalities in a hormone called aldosterone have been associated with both pathologies. There is increasing evidence that the contribution of aldosterone to blood pressure and cardiovascular disease is substantially under recognised. This project proposes to recruit participants in the ALSPAC cohort to perform a short but high-dimensional observational study. I will use a non-invasive biological sampling technique called microdialysis to measure the dynamics of aldosterone in relation to sleep, activity, posture, and internal body rhythms in obese people with and without hypertension, and in a non-obese control comparison group. Access associated phenotype and longitudinal data related to blood pressure and other parameters from ALSPAC will provide enormous extra value.

People who experience early life family financial hardship are more likely to encounter mental health challenges and engage in criminal behaviours during adolescence. However, fewer studies have explored how these outcomes in adulthood are influenced by early family financial hardship, especially criminal behaviour. Interestingly, while most people’s criminal behaviours peak during mid- to late-adolescence and diminish during early adulthood, a small proportion of individuals continue involvement in criminal behaviour during adulthood. Understanding the extent of this criminal behaviour continuation and how it is influenced by early life family financial hardship is important but under researched.

Previous studies tend to measure family socioeconomic status (usually with family income, parental education and occupation) and its association with later outcomes. This broad concept could potentially lead to oversimplification, whereas examining financial hardship alone allows for a more targeted analysis, shedding light on the specific challenges posed by economic constraints and their direct impact on offspring mental health and criminal behaviours. Moreover, it is important to distinguish between people’s feeling about their financial situation and the actual financial figures, as these perspectives can influence outcomes differently. Having a precise measurement for exposures can provide reliable conclusions for our findings and can promote more effective interventions and utilisation for public policy.

Previous studies have shown parental mental health and parenting styles influence the effects of family financial hardship on offspring (Devenish et al., 2017). However, fewer studies have explored how adolescents’ self-esteem, which indicates how people feel about themselves, can influence associations between family financial hardship with depression and criminal behaviour in adulthood, despite strong evidence for associations between self-esteem and mental health (Keane & Loades, 2017).

Comparing with early life financial hardship, more recent economic stresses can also impact young people’s wellbeing (Dunn et al., 2018). Given that many people live away from their parents and have their own work/study, their own financial situation can also associate with their mental health outcomes and potential engagement of criminal behaviours. Therefore, how adulthood financial situation relates to young adults’ mental health and criminal behaviour, is also an important avenue for research.

References to previously published work in the summary below are given as
PubMed IDs.
Nausea and vomiting during pregnancy (NVP) is estimated to occur in around 70%
of women globally, with 1.1% of women estimated to experience severe cases,
diagnosed as Hyperemesis Gravidarum (HG) (PMID: 23863575). HG is associated
with dehydration and weight loss, which can result in hospitalisation and have
significant detrimental effects for both mother and fetus. These include increased
risk of morbidity, placental complications, small for gestational age birth, maternal
psychological distress and increased risk of developmental delay for offspring
(PMID: 35367190, PMID: 25898368, PMID: 23360164, PMID: 33713683, PMID:
21413857) .
A recent study (PMID: 38092039) made great progress in understanding a major
cause of NVP and HG. Using a variety of analyses, especially of human genetic
data, the authors showed that maternal sensitivity to a protein released from the
placenta called growth differentiation factor 15 (GDF15), is key causal risk factor.
This finding was exciting as it suggested avenues for future research into
prevention or treatment. Evidence for the role of GDF15 included associations of
variants (single letter changes in the DNA code) in the GDF15 gene region with
both risk of NVP or HG, and with GDF15 levels in the blood (PMID: 35218128,
PMID:29563502, PMID: 38092039). The finding that women who have naturally
low levels of GDF15 are more sensitive to the GDF15 released from the placenta
and more susceptible to NVP and HG, raised the possibility that a fetal genetic
variants which increase GDF15 production may also influence HG or NVP risk.
There was some evidence in a small sample that the genotype of the fetus, relative
to the mother, may be associated with the proportion of fetal-placental derived
GDF15 contributing to circulating GDF15, potentially mediating experiences of
nausea and vomiting (PMID: 38092039). However, analyses of maternal and fetal
genotype data in well powered samples are needed to confirm this, which is the
focus of our proposed project. We aim to explore the maternal and fetal genetic
contributions of genetic variants to nausea and vomiting during pregnancy.

Avoidant Restrictive Food Intake Disorder (ARFID) is a severe eating disorder that causes people to avoid certain foods or limit their intake. Unlike other eating disorders, ARFID isn’t about body image—it can stem from low appetite, sensory sensitivity to textures and smells, or a fear of choking or vomiting. Affecting around 1–2% of the population, ARFID can lead to malnutrition, health complications, and significant distress.
Our research focuses on understanding ARFID’s causes and how it varies between individuals. We aim to answer big questions: Is ARFID primarily a neurodevelopmental condition, an anxiety disorder, or influenced by physical health issues? Are there distinct subtypes of ARFID requiring different treatments? What are the genetic, environmental, and developmental risk factors for ARFID, and do these differ by subtype?
To explore these questions, we will analyse ALSPAC data, alongside data from the Norwegian MoBa cohort and the Born in Bradford cohort, and work closely with people living with ARFID, healthcare providers, and the eating disorder charity Beat. By involving those with lived experience at every stage, we will ensure our findings are relevant and impactful.
This project will help identify new approaches to diagnosing and treating ARFID, creating evidence-based tools for clinicians and improving support for those affected. With ARFID research in its early stages, this work is crucial to advancing our understanding and shaping better services.
Our goal is to bring real-world benefits to individuals and families struggling with ARFID, ensuring they receive the care and support they need.

This project is for conducting pilot analyses for Fellowship applications (e.g. Wellcome/MRC Career Development Awards) that I will be submitting in the area of cognitive change in ALSPAC G0 mothers and partners. Primarily, I will be calculating numbers of participants who have data on potential exposures (e.g. genetics, DNA methylation, proteomics and metabolomics) and potential outcomes (e.g. cognitive data), to see if planned analyses are feasible.