Sex and gender must be taken into account in health research and the provision of care. While sex refers to biological differences and gender refers to sociocultural effects, these terms are often used interchangeably, and most studies only consider their combined effects in a binary framework comparing two sexes/genders. We aim to develop a tool to distinguish gender from sex using epigenetic markers (chemical alterations to DNA that can be readily measured in biological samples such as blood). This will enable researchers and health care providers to go beyond simply dividing into two groups by sex (male vs female), and will recognize a continuum of masculinity and femininity, relevant to both cis and trans individuals. This tool will improve research into the social determinants of health, and help to tailor health care decisions and interventions to individuals.

The prevalence of self-harm in young people is increasing whilst the age of self-harm onset is decreasing. Prevention and early identification of self-harm is critical to prevent additional adverse outcomes. The majority of research to date has focused on self-harm during adolescence and adulthood. Little is known about the prevalence of childhood self-harm in the general population, its risk factors, and likely outcomes. The CHARM project is uniquely positioned to answer these questions, with data on self-harm behaviours in children as young as three and longitudinally up to age 16 years. This is combined with a wealth of longitudinal data including questionnaires, linkage to national health registries, genetic data, parent data and detailed environmental exposure data. The CHARM project will leverage this amazing resource to build the most detailed picture to date of emergence, persistence and aetiology of childhood self-harm in the general population. Furthermore, we will apply genetic epidemiology techniques to strengthen causal inference, which increases the likelihood of interventions being effective. Together, these analyses will paint a rich picture of an understudied phenotype and help inform intervention design to prevent childhood self-harm and consequently prevent later adverse outcomes.

High blood pressure (BP) is a major risk factor for cardiovascular as well as non-cardiovascular diseases. Underlying molecular pathways related to BP regulation are not fully understood. The aim of the project is to identify ethnic-specific metabolites associated with cross-sectional measures of blood pressure levels and hypertension status. The project leaders have already found associations between specific metabolites and blood pressure levels or hypertension status in their discovery cohorts. Replication analyses will be conducted in several cohorts that are members of the CHARGE Metabolomics consortium, including ALSPAC.

This project will investigate the association between noise exposure during pregnancy and DNA methylation in children

In the past 25 years, studies like the Welsh Adverse Childhood Experiences and Resiliency Survey (Public Health Whales 2018) and a representative British household survey (Bellis et al. 2014) have revealed that adverse childhood experiences (ACEs), such as abuse and neglect, are very common. They have highlighted an unfortunate truth that around 50% of children in England and Wales have experienced at least one form of adversity in childhood (Public Health Whales 2018, Bellis et al., 2014).

Traditionally, researchers have measured ACEs by summing up the total number of adversities experienced (cumulative risk models) across childhood and adolescence. Additionally, researchers have stressed the importance of investigating the individual impact of specific adversities, called specificity models. Both methods, however, have their weaknesses. Cumulative risk models do not account for the child’s experiences, and the duration and the timing of the experience. Conversely, examining individual adversities ignores the co-occurrence of these experiences and allows the relationship to potentially be confounded by other adversities.

In recent years, researchers such as Ellis and colleagues (2022) have introduced a new, comprehensive method to assess environmental adversity, known as dimensional models. A dimensional approach to measuring and classifying ACEs is a powerful tool as it recognises and evaluates a wide spectrum of negative experiences that differ in severity and timing. This enables researchers to delve into the ways and reasons by which negative environmental experiences affect developmental processes.

ACEs have been linked to many adverse cardiovascular health outcomes in every stage of the life span. In childhood 4 or more ACEs have been linked to increased resting heart rate (HR) in late childhood (12-14 years) (Petty et al., 2013) and enlarged arterial stiffness from childhood to young adulthood over time (Rafiq et al., 2020). Adults who experience a larger number and a greater impact to adverse life events in childhood demonstrated higher HR reactivity in response to an acute psychological stressor, indicating that life events are associated with elevated HR and reduced HR complexity in response to acute stress (Schneider et al., 2021). Moreover, these results indicate that poor cardiovascular outcomes appear earlier than expected in late childhood and early adolescence, stressing the importance of early intervention.

The connection between ACEs and cardiovascular health is not consistent because of the heterogeneity in ACEs definitions and study populations (Wesarg et al., 2022). To gain better insights into how a child’s unique vulnerability to adversity is mediated by individual characteristics, such as family factors, extrafamilial conditions, personality, or temperament (Belsky et al., 2013), a life course approach using birth cohort data is needed.

Sidonie Kilpatrick’s PhD dissertation investigates how ACEs impact heart-related automatic functions (i.e., autonomic functioning) throughout an individual’s life and identifies factors that can mitigate this impact. She will use data from two studies, the 1946 National Survey of Health and Development (NSHD) and the Avon Longitudinal Study of Parents and Children (ALSPAC), that collect information from the prenatal period to death. She plans to evaluate how ACEs influence resting blood pressure and heart rate across the life span and midlife heart rate variability. Additionally, she plans to evaluate how specific characteristics or interventions can influence resting HR and BP across the life course to better inform early intervention and policy.

References:
Bellis M A, Hughes K, Lechenby N, et al., . National household survey of adverse childhood experiences and their relationship with resilience to health-harming behaviors in England. BMC Med. 2014; 72(12): https://doi.org/10.1186/1741-7015-12-72

Belsky J, Pluess M. Beyond risk, resilience, and dysregulation: phenotypic plasticity and human development. Dev Psychopathol. 2013 Nov;25(4 Pt 2):1243–61.

Ellis BJ, Sheridan MA, Belsky J, McLaughlin KA. Why and how does early adversity influence development? Toward an integrated model of dimensions of environmental experience. Dev Psychopathol. 2022 May;34(2):447–71.

Pretty C, O’Leary DD, Cairney J, Wade TJ. Adverse childhood experiences and the cardiovascular health of children: a cross-sectional study. BMC Pediatr. 2013 Dec 17;13:208.

Public Health Whales, Sources of resilience and their moderating relationships with harms from adverse childhood experiences. Public Health Whales. 2018; https
://www.wales.nhs.uk/sitesplus/documents/888/ACE%20&%20Resilience%20Report %20(Eng_final2).pdf

Rafiq T, O’Leary DD, Dempster KS, Cairney J, Wade TJ. Adverse Childhood Experiences (ACEs) Predict Increased Arterial Stiffness from Childhood to Early Adulthood: Pilot Analysis of the Niagara Longitudinal Heart Study. J Child Adolesc Trauma. 2020 May 30;13(4):505–14.

Schneider M, Kraemmer MM, Weber B, Schwerdtfeger AR. Life events are associated with elevated heart rate and reduced heart complexity to acute psychological stress. Biol Psychol. 2021 Jul 1;163:108116.

Wesarg C, Van den Akker AL, Oei NYL, Wiers RW, Staaks J, Thayer JF, et al. Childhood adversity and vagal regulation: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2022 Dec 1;143:104920.

High blood pressure is a risk factor for heart disease. Most research is carried out using systolic diastolic pressure - the pressure in the heart when the heart muscle contracts. Less is known about diastolic blood pressure - the pressure in the heart when the heart muscle relaxes. This project seeks to better understand diastolic blood pressure - what influences is, and what are its consequences for heart health.

Much research has indicated that obesity is associated with poorer health outcomes. Whilst these studies have tended to investigate average body weight (relative to height), more recently there has been interest in variation in body weight. This work has indicated that people whose body weight goes up and down a lot are more likely to experience future weight gain. This project will investigate variability in weight, using body mass index (BMI, a measure of weight which accounts for height), across the key developmental phase of childhood through to early adulthood. It aims to form a better understanding of the factors associated with variability in BMI across this time.

Puberty is defined as the transition from infancy to reproductive maturity characterized by the acceleration of growth velocity and the development of secondary sexual characteristics and genitals. Normal puberty onset ranges between 8-13 years old for girls, and 9-14 years old for boys. It is clinically defined as the onset of Tanner stage 2 in thelarche for girls (development of breast buds) and by Tanner stage 2 in external genitalia development for boys (increase in testicular volume to >4mL). Age at menarche in girls and age at peak height velocity in both sexes are landmarks which can be used to evaluate pubertal timing.

Endocrine disrupting chemicals (EDCs) have become increasingly prevalent in the past century as manmade products and chemicals have been made essential in our daily lives. There are nearly 85 000 human-made chemicals in the world, and 1000 or more of those could be endocrine disruptors. There are two main types of EDCs: the persistent organic compounds with decade-long half-lives such as dichloro-diphenyl-trichloroethane (DDT) in pesticides and polychlorinated biphenyls (PCBs), and those that have a shorter half-life but can cause long-term health consequences such as phthalates and bisphenol A. EDCs disrupt the body’s delicate endocrine homeostasis by acting as an agonist or antagonist when binding to hormone receptors, thereby causing unwanted effects, such as earlier timing of puberty in girls and boys. The four EDCs of interest in our study are dibutyl phthalate, bisphenol A (BPA), dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyl (PCB).

Phthalates are a large group of omnipresent compounds used as liquid plasticizers. They are found in food packaging, cosmetic products, shampoo, children’s toys and medical device tubing. It was found that first and second-trimester exposure to Bis(2-ethylhexyl) phthalate (DEHP) was associated with increased peripubertal serum estradiol levels, whereas third-trimester exposure was associated to a delay of pubarche onset. BPA is used to make polycarbonate plastic and epoxy resin. It can be found in food packaging, toys, and canned beverages’ linings. At low concentrations, BPA and other phenol compete with endogenous estrogens for binding, whereas at higher concentrations they have anti-androgenic properties.
DDT was used in many organochlorine pesticides and insecticides before being banned in 1972 in multiple countries. In 2006 however, it was reintroduced in some areas by the World Health Organization in order to fight malaria and control other vector-borne diseases. DDT exposure begins prenatally and lasts throughout a lifetime, as it is found in abundance in consumed food products, and is found to have anti-androgenic properties. PCBs were found in lubricants, electrical equipment and plasticizers up until they were banned in 1979. Studies show that childhood exposures of PCBs are associated with earlier pubertal milestones in boys, such as earlier Tanner stages.
Although a large body of evidence from observational studies exists linking EDCs to pubertal timing variations, these associations can be confounded by factors such as low socio-economic status and obesity and cannot establish causality. In the absence of evidence from randomized controlled trials- which would be unethical to employ, the causal link between EDCs and pubertal timing remains undetermined. We have generated preliminary results using two-sample Mendelian randomization for 19 EDCs, most of which do not support a causal association of genetically determined levels of these EDCs with age at menarche in girls or age at voice change or facial hair in boys. Using genetic variants associated with levels of these EDCs, which are not influenced by environmental confounders, we aim to investigate if genetic predisposition to higher levels of these chemicals could affect pubertal timing in ALSPAC children.
In the proposed project, we hypothesize that genetic risk scores (GRS) composed of one to multiple single nucleotide polymorphisms (SNPs) associated with levels of 19 endocrine disrupting chemicals (dibutyl phthalate, BPA, DDT and 16 types of PCBs) in the largest available genome-wide association studies for EDC levels, could be associated to an altered age at menarche in girls or age at peak height velocity in both girls and boys (adjusting for sex) with and without adjusting for BMI SDS at age 8 and socio-economic status.

A data note describing the linked data obtained by ALSPAC about the participants in ALSPAC held by AWP (Avon Wiltshire Partnership MH NHS Trust). This will describe the data available for future research.