Proposal summaries

These are research proposals that have been approved by the ALSPAC exec. The titles include a B number which identifies the proposal and the date on which the proposals received ALSPAC exec approval.

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B4768 - Lung Function COPD Epigenetics and Accelerated Ageing Across the Lifespan - 11/12/2024

B number: 
B4768
Principal applicant name: 
Rosa Faner | Universitat de Barcelona / FRCB-IDIBAPS (SPAIN)
Co-applicants: 
Julieta Viglino, Sandra Casas, Jack Grenvillle, James Dodd
Title of project: 
Lung Function, COPD, Epigenetics and Accelerated Ageing Across the Lifespan
Proposal summary: 

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

Impact of research: 
Epigenetic signatures associated with lung function decline or COPD found in children, teens, or young adults may offer valuable predictive targets for respiratory diseases, enabling earlier intervention and prevention strategies.
Date proposal received: 
Thursday, 5 December, 2024
Date proposal approved: 
Monday, 9 December, 2024
Keywords: 
Genetics, Respiratory - Chronic Obstructive Pulmonary disease, Statistical methods, Epigenetics

B4772 - Epigenetic Biomarkers of Immune Activation in Mental Health Trajectories - 09/12/2024

B number: 
B4772
Principal applicant name: 
Sinan Guloksuz | Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University (The Netherlands)
Co-applicants: 
Winni Schalkwijk, MSc
Title of project: 
Epigenetic Biomarkers of Immune Activation in Mental Health Trajectories
Proposal summary: 

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).

Impact of research: 
This project will have impact on the research field by: - increasing understanding about the value of DNAm biomarkers of immune activation in epidemiological research, extensively characterising these markers with respect to their developmental stability, environmental influences and involved immune pathways. - providing some novel epigenetic scores which capture shared variation across inflammatory proteins, which can be used in further research. - validating the use of epigenetic biomarkers of inflammation developed in children and adolescents of ALSPAC in an external dataset (Generation R). - providing key insights into the value of epigenetic biomarkers of immune activation in predicting mental health outcomes.
Date proposal received: 
Thursday, 5 December, 2024
Date proposal approved: 
Monday, 9 December, 2024
Keywords: 
Epigenetic epidemiology; immune system biomarkers; gene-environment interactions in mental health trajectories of youth, Mental health, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc.

B4774 - Impact of Early Childhood Free Sugar Consumption on Childhood and Adolescent Obesity and Cardiometabolic Risk - 09/12/2024

B number: 
B4774
Principal applicant name: 
Jean Welsh | Emory University (USA)
Co-applicants: 
Katelyn Chiang
Title of project: 
Impact of Early Childhood Free Sugar Consumption on Childhood and Adolescent Obesity and Cardiometabolic Risk
Proposal summary: 

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

Impact of research: 
Findings from this research will increase the supporting pediatric nutrition evidence base and may be used to strengthen or modify existing infant and toddler nutrition guidance. Results may help elucidate appropriate levels of free sugar and sugar-containing beverage intake and what patterns of sugar-containing beverage intake in early life are most detrimental. Results may also help public health practitioners develop more effective nutrition education messages and better target children most at risk of sustaining poor health outcomes from early life free sugar and sugar-containing beverage consumption.
Date proposal received: 
Friday, 6 December, 2024
Date proposal approved: 
Monday, 9 December, 2024
Keywords: 
Epidemiology, Obesity, Statistical methods, Nutrition - breast feeding, diet

B4742 - Can the negative effects of low socioeconomic status on child cognitive development be negated by home environment factors - 09/12/2024

B number: 
B4742
Principal applicant name: 
Natasha Kirkham | Birkbeck, University of London
Co-applicants: 
Miss Helen Yuki Grimshaw
Title of project: 
Can the negative effects of low socioeconomic status on child cognitive development be negated by home environment factors?
Proposal summary: 

An abundance of previous research has demonstrated the damaging effects of low socioeconomic status (SES) on a child's emerging cognitive skills, and this leads to an achievement gap which exists by the time children enter school; a gap which continues to widen throughout the school years. Building on previous findings that have suggested that some factors, such as neighbourhood chaos, may have a protective effect against the detrimental effects of low SES, this study aims to investigate whether certain parenting styles and home environment factors may negate the effects of SES on child cognitive development and subsequent school achievement. These will include control parenting, warmth parenting, distracting parenting, background noise parenting, parental verbal and non-verbal engagement with children, physical proximity parenting, child mental health, and parental cognitive ability. By investigating these potentially mediating factors, we hope to shed light on ways of supporting the cognitive development of disadvantaged children.

Impact of research: 
By identifying factors within the home environment that may reduce the damaging effects of low SES on early child cognitive development, we hope to be one step closer to developing effective interventions for supporting disadvantaged children and their cognitive skills.
Date proposal received: 
Friday, 6 December, 2024
Date proposal approved: 
Monday, 9 December, 2024
Keywords: 
Developmental psychology, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Parenting

B4775 - Intergenerational Trajectories of Depression Maternal Mental Health Genetic Susceptibility and Family Dynamics - 09/12/2024

B number: 
B4775
Principal applicant name: 
Yanmiao Cao | Shandong Normal University (China)
Co-applicants: 
Xiaqing Qin, M.D.
Title of project: 
Intergenerational Trajectories of Depression: Maternal Mental Health, Genetic Susceptibility, and Family Dynamics
Proposal summary: 

There is a growing body of evidence suggesting that maternal depression during pregnancy and the postnatal period can have profound and lasting effects on the mental health of offspring, particularly in terms of depression. This study aims to explore the intergenerational trajectories of depression, focusing on the role of maternal mental health, genetic susceptibility, and family dynamics as potential mediators and moderators in the transmission of depression from mother to child.

Building on previous research that has established a link between maternal depression and offspring mental health outcomes (Goodman et al., 2018), this project will employ a longitudinal approach to examine the trajectory of maternal depression and its influence on the development of offspring depression. We will explore the genetic underpinnings of depression by incorporating genetic risk scores (GRS) to assess the genetic liability within families. This approach allows us to understand not just the environmental transmission but also the genetic contribution to the intergenerational pattern of depression.

The study will also investigate the mediating role of family dynamics, such as parenting practices and the parent-child relationship, in the association between maternal depression and offspring depression. The impact of paternal involvement and the couple relationship quality on maternal postpartum depression and child development will be considered.

Impact of research: 
The findings from this project will contribute to a more nuanced understanding of the complex interplay between maternal mental health, genetic predispositions, and family dynamics in the development of offspring depression. By identifying key periods of vulnerability and potential intervention points, our research can inform the development of targeted strategies to mitigate the long-term adverse effects of maternal depression on offspring. The insights gained are expected to be instrumental in shaping public policies and intervention programmes aimed at reducing the intergenerational cycle of depression and associated adverse outcomes.
Date proposal received: 
Sunday, 8 December, 2024
Date proposal approved: 
Monday, 9 December, 2024
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Computer simulations/modelling/algorithms, GWAS, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Cognition - cognitive function, Genomics, Mothers - maternal age, menopause, obstetrics, Offspring, Parenting, Sex differences

B4761 - Investigation of the utility of transcriptomic and epigenetic data for diagnosing the onset of puberty - 06/12/2024

B number: 
B4761
Principal applicant name: 
Adam Stevens | University of Manchester (UK)
Co-applicants: 
Beverly Hird, Dr Philip Murray, Prof Peter Clayton
Title of project: 
Investigation of the utility of transcriptomic and epigenetic data for diagnosing the onset of puberty
Proposal summary: 

Growth and Puberty are fundamental aspects of childhood development. Puberty is the period of transition between childhood and adulthood, resulting in the capacity to reproduce and is associated with a significant increase in rate of growth. The mechanisms underlying the control of human growth as well as initiation of human puberty are poorly understood. Knowledge of the mechanisms, as well as being of great interest, could contribute to the care and treatment of children with early and late puberty. The proposed study aims to further understanding of the control of childhood growth and triggers of pubertal onset using measures of gene activity in normal children from the ALSPAC cohort. By examining the pattern of growth and puberty in normal children and comparing this with patterns of gene activity, we hope to identify markers of pubertal onset and identify which genes influence growth rate. We aim to use this information to develop a blood test for use in children with possible disorders of puberty.

Impact of research: 
Identifying an omics signature of puberty, allowing prediction of pubertal status.
Date proposal received: 
Friday, 29 November, 2024
Date proposal approved: 
Friday, 6 December, 2024
Keywords: 
Endocrinology, Abnormal puberty timing, Unable to select more than one: Computer simulations/modelling/algorithms DNA sequencing RNA Statistical methods, Unable to select more than one: Development Epigenetics Expression Growth Puberty

B4771 - MODELLING THE ECONOMIC CONSEQUENCES OF CHILDHOOD ANXIETY PROBLEMS - 09/12/2024

B number: 
B4771
Principal applicant name: 
Mara Violato | University of Oxford (United Kingdom)
Co-applicants: 
Dr Shuye Yu
Title of project: 
MODELLING THE ECONOMIC CONSEQUENCES OF CHILDHOOD ANXIETY PROBLEMS
Proposal summary: 

This research will adopt a life course approach to the assessment of child mental health outcomes and associated costs. Primary analyses of the Avon Longitudinal Study of Parents and Children (ALSPAC) will be conducted to identify the natural history of child anxiety problems into early adulthood, and quantify their lasting effects - over the life cycle - in terms of educational attainments, adult health, employment and, if possible, associated health and social care use, and productivity costs.

Impact of research: 
Producing evidence-base on the consequences of early mental health problems so to encourage prevention/early intervention.
Date proposal received: 
Thursday, 5 December, 2024
Date proposal approved: 
Friday, 6 December, 2024
Keywords: 
Health Economics, Mental health, Statistical methods, Child anxiety problems Child mental health problems Applied econometrics and statistics

B4770 - Exploring Transdiagnostic Trajectories in Youth Mental Health The Role of the Genome and Exposome - 06/12/2024

B number: 
B4770
Principal applicant name: 
Sinan Guloksuz | Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University (The Netherlands)
Co-applicants: 
Angelo Arias Magnasco, MSc, Dr. Lotta-Katrin Pries, Dr. Bochao Danae Lin
Title of project: 
Exploring Transdiagnostic Trajectories in Youth Mental Health: The Role of the Genome and Exposome
Proposal summary: 

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).

Impact of research: 
This project is expected to have a significant impact across multiple domains: scientific research, clinical practice, and policy-making. By creating an accessible knowledge platform, it will enhance our understanding of mental health and illness trajectories during critical developmental stages. The project will also contribute to the development of robust prediction tools for early intervention, enabling improved healthcare for young people. Ultimately, this work aims to reduce suffering, disability, and the socioeconomic consequences of mental health disorders, fostering a healthier and more resilient society.
Date proposal received: 
Thursday, 5 December, 2024
Date proposal approved: 
Friday, 6 December, 2024
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Environment - enviromental exposure, pollution, Genetic epidemiology

B4764 - Exploring the Impact of Poverty on Child Well-being A Longitudinal Analysis of Mental Health and Criminal Behaviours - 05/12/2024

B number: 
B4764
Principal applicant name: 
Gemma Hammerton | University of Bristol (United Kingdom)
Co-applicants: 
Boyang Yu, Professor Kate Tilling, Professor George Leckie, Dr Richard Parker, Dr Alex Kwong
Title of project: 
Exploring the Impact of Poverty on Child Well-being: A Longitudinal Analysis of Mental Health and Criminal Behaviours
Proposal summary: 

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.

Impact of research: 
This project will advance our understanding of the interplay between family financial hardship during childhood and the long-term effects on mental health and criminal behaviour across early adulthood. By integrating findings from a diverse set of analytical methods and leveraging longitudinal data, our research aims to provide insights into the critical periods and potential intervention points to mitigate long-term adverse effects specifically because of financial disadvantages. We also expect our findings to generate actionable insights to inform public policies and intervention strategies aimed at reducing the adverse impacts of financial disadvantages on mental health and criminal behaviour. These insights will focus on promoting mental health resilience and reducing criminal behaviour through early and sustained interventions. This PhD project will result in at least three publications using ALSPAC data. Findings will also be disseminated at through presentations at various international conferences and internally at the University of Bristol.
Date proposal received: 
Monday, 2 December, 2024
Date proposal approved: 
Thursday, 5 December, 2024
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Statistical methods, Childhood - childcare, childhood adversity, Statistical methods

B4767 - Enhancing Genetic Insights Through Longitudinal Analysis and Novel Statistical Tools - 06/12/2024

B number: 
B4767
Principal applicant name: 
Ole A. Andreassen | Centre for Precision Psychiatry, Division of Mental Health and Addiction, University of Oslo, Oslo, Norway (Norway)
Co-applicants: 
Jakub Kopal
Title of project: 
Enhancing Genetic Insights Through Longitudinal Analysis and Novel Statistical Tools
Proposal summary: 

Complex human genetic disorders are major contributors to global morbidity and mortality. Understanding their underlying pathophysiology is essential for advancing treatment and prevention. These disorders have heritability estimates between 40-80% and are considered polygenic, involving the interplay of multiple genes alongside environmental influences. This complexity complicates efforts to understand causal factors and disease mechanisms, predict individual susceptibility and uncover the molecular mechanisms involved, both of which are critical to improving treatment options. Genome-wide association studies (GWAS) have uncovered numerous trait-associated single nucleotide polymorphisms (SNPs) in diverse complex phenotypes. However, existing methods largely overlook the dynamic interactions between genetic and environmental factors over time, limiting our ability to fully understand and predict the progression of complex human disorders. This proposal aims to utilize ALSPAC data to investigate the genetic architecture of human traits, with a focus on the complex interplay among genetic factors and environmental influences, in mental disorders and co-morbid conditions. Leveraging ALSPAC’s rich longitudinal data, we will analyze SNPs linked to both baseline and longitudinal phenotypes and their changes over time, advancing our understanding of the dynamic genetic and environmental contributions to the development and progression of these traits.

Impact of research: 
The likely impact of this research will be significant in advancing our understanding of causal factors and disease mechanisms, as well as genetic risk prediction and understanding the progression of complex human disorders. This will provide valuable insights into the dynamic nature of genetic and environmental contributions to mental health and other complex traits, leading to earlier and more tailored interventions. Clinically, this work could pave the way for implementing age-specific risk assessments, allowing healthcare providers to make more informed, personalized decisions in managing mental health and related co-morbid conditions.
Date proposal received: 
Thursday, 5 December, 2024
Date proposal approved: 
Thursday, 5 December, 2024
Keywords: 
Genetics, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Cognitive impairment, Hypertension, Mental health, Computer simulations/modelling/algorithms, Gene mapping, GWAS, Medical imaging, Metabolomics, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Cohort studies - attrition, bias, participant engagement, ethics, Environment - enviromental exposure, pollution, Genetics, Genome wide association study, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B4762 - Preparation of new and updated NMR data for general release - 02/12/2024

B number: 
B4762
Principal applicant name: 
Laura Corbin | University of Bristol (United Kingdom)
Co-applicants: 
Ms. Maryam Makanvand, Amy Dawes, Professor Nicholas Timpson
Title of project: 
Preparation of new and updated NMR data for general release
Proposal summary: 

Nuclear Magnetic Radiation (NMR) Data assesses systematic metabolites in blood samples at 4 exiting time points in the ALSPAC cohort (G1); age 7, age 15, age 18, and at age 24. 229 metabolites were quantified (149 concentrations plus 80 ratios derived from these) including cholesterol, triglyceride, and other lipid content in lipoprotein subclass particles (very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL)), apolipoprotein-B and apolipoprotein-A-1, fatty acids and amino acids, and inflammatory glycoprotein acetyls (Bell et al 2021). There are two new updates to this data:

1- Update to data: The latest version of Nightingale Health's NMR data (Quantification library version 2020), has been improved to provide more accurate measurements. These updates ensure that the concentration levels of various biomarkers better align with those measured by clinical tests and other laboratory methods. Additionally, the data used to calibrate lipoprotein subclasses (key indicators of cholesterol and cardiovascular health) has been extended. This updated version is identical to the dataset used for analysing UK Biobank's 500,000 plasma samples between 2021 and 2024.
2- New time point at age 30: Along with the already existing timepoint in the ALSPAC NMR dataset, a new timepoint is now available at age 30

The aim of this project is to prepare the new and updated data for general release.

Impact of research: 
Great impact, allowing availability and use of new ALSPAC NMR data to engage in wider research
Date proposal received: 
Friday, 29 November, 2024
Date proposal approved: 
Monday, 2 December, 2024
Keywords: 
Bioinformatics, NMR, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B4757 - Investigating the contributions of fetal and maternal genetic variation in GDF15 in nausea vomiting and hyperemesis gravid aru - 02/12/2024

B number: 
B4757
Principal applicant name: 
Rachel Freathy | University of Exeter (UK)
Co-applicants: 
Ms Rhian Swarbrick, Dr Rob Beamont, Miss Annika Jaitner
Title of project: 
Investigating the contributions of fetal and maternal genetic variation in GDF15, in nausea, vomiting and hyperemesis gravid aru
Proposal summary: 

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.

Impact of research: 
What do you think the likely impact of your research will be? Advancing understanding on the relationship between maternal and fetal genotypes in their contributions to nausea and vomiting during pregnancy. Contribute to the evidence-base around hyperemesis gravidarum and nausea and vomiting during pregnancy, which could be utilised to identify new predictive biomarkers for early screening or new targets for treatment. We expect this work to result in at least one high impact publication.
Date proposal received: 
Thursday, 28 November, 2024
Date proposal approved: 
Monday, 2 December, 2024
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), hyperemesis gravidarum, nausea and vomiting in pregnancy, Statistical methods, nausea, vomiting, hyperemesis, pregnancy, genetics

B4758 - The impact of intergenerational transmission of mental health problems on childrens development in early life - 02/12/2024

B number: 
B4758
Principal applicant name: 
Isabel Morales-Munoz | University of Birmingham (United Kingdom)
Co-applicants: 
Prof Steven Marwaha, Prof Joht Singh Chandan, Prof Georgios Gkoutos, Dr Nicola Adderley
Title of project: 
The impact of intergenerational transmission of mental health problems on children’s development in early life
Proposal summary: 

Mental health problems can run in families, and children with parents or grandparents who struggle with mental health are at a higher risk of facing challenges in their development. For example, when parents or grandparents have mental health problems, it can sometimes lead to poorer outcomes for children. However, it’s not yet clear whether this is due to a general pattern of mental health issues or due to specific mental health conditions only. We also don’t fully understand whether some aspects of a child’s development, like their behaviour, health, or learning, are more affected than others. Importantly, not all children with a family history of mental health problems will have developmental issues. Therefore, it’s crucial to figure out what helps protect children and build resilience against these risks. To explore this, we are using data from the ALSPAC, which includes information on three generations: grandparents (G0), parents (G1), and children (G2). We aim to find out if children with a family history of mental health problems are more likely to face challenges in early childhood, such as having a difficult temperament, poor health, behavioural issues (like trouble sleeping), or delays in language development.

Impact of research: 
Our research can lead to improvements in understanding, prevention, and intervention for developmental challenges linked to the intergenerational transmission of mental health problems. For example, our research can help identify vulnerable children early, enabling timely support and monitoring. Further, understanding protective factors can empower families and communities to build resilience in children, offering practical tools and strategies to buffer against the negative effects of mental health problems in the family. Finally, this research could inform healthcare and education policies, ensuring resources are directed to programs that support children and families affected by mental health challenges across generations.
Date proposal received: 
Friday, 29 November, 2024
Date proposal approved: 
Monday, 2 December, 2024
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Development, Offspring, Psychology - personality, Sleep

B4755 - Predictive Power of BMI-PRS Across Different Life Stages A Central Step in Understanding the Genetic Basis of Obesity - 29/11/2024

B number: 
B4755
Principal applicant name: 
Dr. Jeroen van Rooij | Department of Internal medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands (The Netherlands)
Co-applicants: 
Bahar Sedaghatihayat, MSc, Dr. Janine Felix, j.felix@erasmusmc.nl
Title of project: 
Predictive Power of BMI-PRS Across Different Life Stages: A Central Step in Understanding the Genetic Basis of Obesity
Proposal summary: 

Our genetic makeup, which is stable across life, influences our health and can serve as an early risk indicator for various diseases. Precise genetic tests exist for single-gene diseases, but common and complex conditions like obesity result from the subtle effects of many genes. We use Polygenic Risk Scores (PRSs) to assess comprehensive genetic risk for diseases or traits, encompassing many (hundreds to millions of) genetic variants. For BMI, for which high values can present a significant health concern, a PRS containing 941 common genetic variants influencing adult BMI has been established using UK Biobank data. However, these genetic variants are identified in mostly adult populations (> 50 years), and their performance in other age groups has been less well established. The transition from normal to high BMI and its onset at various life stages, particularly from childhood to adulthood, remains complex and warrants deeper exploration.

Impact of research: 
By analyzing the predictive power of BMI-PRS on BMI trajectories from childhood through adulthood, this research seeks to provide a more nuanced understanding of the genetic basis of body mass index.
Date proposal received: 
Wednesday, 27 November, 2024
Date proposal approved: 
Friday, 29 November, 2024
Keywords: 
Genetics, Obesity, Polygenic risk scores, Genetics

B4756 - Pilot analyses for Fellowship application related to cognitive change in ALSPAC G0 mothers and partners - 29/11/2024

B number: 
B4756
Principal applicant name: 
Neil Goulding | Centre for Academic Child Health, Population Health Sciences, Bristol Medical School, University of Bristol (United Kingdom)
Co-applicants: 
Dr Matthew Suderman, Professor Jean Golding, Mrs Yasmin Iles-Caven
Title of project: 
Pilot analyses for Fellowship application related to cognitive change in ALSPAC G0 mothers and partners
Proposal summary: 

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.

Impact of research: 
The potential impact of this research project would be a successful Fellowship application, which would then allow me the opportunity in the future to build multi-omic predictors of cognitive decline. If I succeed in acquiring a Fellowship, it could fund potential ongoing cognitive tests for ALSPAC G0 mothers and partners (see project number B4728 - Collection of new and ongoing G0 cognition data).
Date proposal received: 
Wednesday, 27 November, 2024
Date proposal approved: 
Friday, 29 November, 2024
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Cognitive impairment, Simple exploratory analyses to calculate numbers of participants who have data on potential exposures and outcomes., Ageing

B4752 - Genetic and environmental factors in child adjustment and mental health - 02/12/2024

B number: 
B4752
Principal applicant name: 
Gabriela Ksinanova | Masaryk University, Faculty of Science, RECETOX (Czechia)
Co-applicants: 
Rebecca Lacey, Ph.D., Albert Ksinan, Ph.D.
Title of project: 
Genetic and environmental factors in child adjustment and mental health
Proposal summary: 

Understanding the factors associated with adolescent psychosocial adjustment and mental health is crucially important as mental health challenges that arise during these years often have enduring consequences throughout adulthood. Research indicates that mental health disorders in adolescence can hinder social, educational, and occupational outcomes, resulting in significant long-term impairments (Kessler et al., 2005). Mental health problems and health-compromising behaviors can often be traced back to adolescence, with 50% of mental health difficulties being established by the age of 15 (Kessler et al., 2005; Sawyer et al., 2012). The economic burden of mental health problems in young populations is profound, with estimates indicating both direct healthcare expenses and substantial indirect costs associated with increased social service needs, and the economic impact on families (Gustavsson et al., 2011; Knapp et al., 2011).

Factors leading to maladjustment and mental health problems in children and adolescents are often multifaceted, typically arising from a combination of individual vulnerabilities and environmental stressors. The individual factors include increased genetic risk for externalizing behaviors and depression, difficult temperament (e.g., high neuroticism), or developmental delays. One of the most salient environmental stressors is childhood adversity (i.e., adverse childhood experiences), typically operationalized as various forms of abuse, neglect, and household disfunction experienced before age 18 (Felitti et al., 1998; Hughes et al., 2017). Adverse childhood experiences are strongly associated with a socioeconomic disadvantage (Lacey, et al., 2022) and are structured by socioeconomic factors at both the family (Walsh et al., 2019) and macro level (Lewer et al., 2019). Thus, poverty and socioeconomic inequality can be considered as drivers of adverse childhood experiences (ACE; Institute of Health Equity, 2020; Walsh et al., 2019).

Environmental effects not only complement genetic influences but also interact with them, embodying the gene-environment (GxE) concept—the idea that environments modify genetic effects. For example, the effects of genetic risk on problem behaviors was amplified in environments characterized by poverty or maladaptive parenting (Chubar et al., 2020; Jensen et al., 2017). The existing studies on GxE usually follow the diathesis-stress model, which suggests that individuals with pre-existing vulnerability (such as genetic risk) are more susceptible to negative outcomes when exposed to adverse environments (Colodro-Conde et al., 2018; Zuckerman, 1999).

Lastly, large-scale societal conditions, including economic downturns, socioeconomic transformations, and geopolitical conflicts have a profound influence on well-being and mental health (Deindl, 2013). As countries considerably differ in their socioeconomic conditions, the scale in which they are affected by crises and by their response to them (Cascini et al., 2022), country characteristics are an important factor contributing to variation in young people’s mental health.

The aim of this project is twofold: a) to test the environmental risk (defined as childhood adversity and socioeconomic disadvantage) and genetic risks for maladjustment and mental health difficulties in ALSPAC cohort, and b) to examine the association between socioeconomic inequality, childhood adversity and adolescent mental health across two sister cohorts (ALSPAC and ELSPAC-CZ) that represent different socioeconomic environments. Data collection of both cohorts took place during the 1990s; however, while this was a time of relative stability in the United Kingdom, Czechoslovakia (later Czech Republic) was undergoing a turbulent post-communist transformation. This project will be the first to harmonize and directly compare data from both cohorts.

References:
Colodro-Conde, L., Couvy-Duchesne, B., Zhu, G., Coventry, W. L., Byrne, E. M., Gordon, S., ... & Martin, N. G. (2018). A direct test of the diathesis–stress model for depression. Molecular psychiatry, 23(7), 1590-1596.
Deindl, C. (2013). The influence of living conditions in early life on life satisfaction in old age. Advances in Life Course Research, 18, 107-114.
Felitti, V. J., Anda, R. F., Nordenberg, D., Williamson, D. F., Spitz, A. M., Edwards, V., Koss, M. P., & Marks, J. S. (1998). Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: The adverse childhood experiences (ACE) Study. American Journal of Preventive Medicine, 14(4), 245–258. https://doi.org/10.1016/S0749-3797(98)00017-8
Gustavsson, A., et al. (2011). Cost of disorders of the brain in Europe 2010. European Neuropsychopharmacology, 21(10), 718-779.
Hughes, K., Bellis, M. A., Hardcastle, K. A., Sethi, D., Butchart, A., Mikton, C., Jones, L., & Dunne, M. P. (2017). The effect of multiple adverse childhood experiences on health: A systematic review and meta-analysis. The Lancet Public Health, 2(8), e356–e366. https://doi.org/10.1016/S2468-2667(17)30118-4
Institute of Health Equity. (2020). Health equity in England: The Marmot review 10 years on. https://www.health.org.uk/publications/reports/the-marmot-review-10-year...
Jensen, S. K., Berens, A. E., & Nelson, C. A. (2017). Effects of poverty on interacting biological systems underlying child development. The Lancet Child & Adolescent Health, 1(3), 225-239.
Kessler, R.C., Berglund, P., Demler, O., Jin, R., Merikangas, K.R., & Walters, E.E. (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication Archives of General Psychiatry, 62, 593-602.
Knapp, M., McDaid, D., & Parsonage, M. (Eds.). (2011). Mental health promotion and mental illness prevention: The economic case. London: Department of Health.
Lacey, R. E., Howe, L. D., Kelly-Irving, M., Bartley, M., & Kelly, Y. (2022). The Clustering of Adverse Childhood Experiences in the Avon Longitudinal Study of Parents and Children: Are Gender and Poverty Important? Journal of Interpersonal Violence, 37(5–6), 2218–2241. https://doi.org/10.1177/0886260520935096
Lewer D., King E., Bramley G., Fitzpatrick S., Treanor M. C., Maguire N., … Story A. (2019). The ACE Index: Mapping childhood adversity in England. Journal of Public Health. Advance online publication. 10.1093/pubmed/fdz158
Sawyer, S.M., Afifi, R.A., Bearinger, L.H., Blakemore, S.-J., Dick, B., Ezeh, A.C., et al. (2012). Adolescence: A foundation for future health. Lancet, 379, 1630-1640.
Walsh D., McCartney G., Smith M., Armour G. (2019). Relationship between childhood socioeconomic position and adverse childhood experiences (ACEs): A systematic review. Journal of Epidemiology & Community Health, 73(12), 1087–1093. [DOI] [PMC free article] [PubMed] [Google Scholar]
Zuckerman M. Diathesis-stress models. In: Vulnerability to Psychopathology: A Biosocial Model. American Psychological Association; 1999:3-23. doi:10.1037/10316-001

Impact of research: 
The results of the study can inform personality-focused interventions by identifying individuals particularly vulnerable to the effects of adverse environment. Additionally, the study will contribute to understanding the role of socioeconomic disadvantage in an increased risk for both childhood adversity and mental health problems by comparing two cohorts representing different socioeconomic environments.
Date proposal received: 
Tuesday, 26 November, 2024
Date proposal approved: 
Tuesday, 26 November, 2024
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Statistical methods, Childhood - childcare, childhood adversity, Genetic epidemiology, Statistical methods

B4745 - Exploring the link between autism spectrum disorder and an increased risk of postpartum depression - 25/11/2024

B number: 
B4745
Principal applicant name: 
Alexandria Andrayas | School of Psychological Science
Co-applicants: 
Ellie Roberts, Professor Marcus Munafo
Title of project: 
Exploring the link between autism spectrum disorder and an increased risk of postpartum depression
Proposal summary: 

The aim of this project is to explore if having Autism Spectrum Disorder (ASD) increases the risk of Post-Partum Depression (PPD). PPD is the most common mental disorder experienced by women after pregnancy, affecting 10% to 20% of new mothers. Research suggests that individuals with ASD may face a higher risk of PPD due to challenges specific to autism, such as difficulties adjusting to change, lower self-esteem, and social stigma.

Also, there is evidence that mental health outcomes differ based on when individuals with ASD are diagnosed. Those diagnosed later in life often experience more loneliness, lower self-esteem, and use less effective coping strategies, which are known risk factors for PPD. This project will investigate whether the risk of PPD is amplified in late-diagnosed autistic individuals, who may face added emotional challenges during the postpartum period. To date, no existing longitudinal studies have explored these potential mechanisms.

Currently, significant gaps remain in understanding how autism impacts the transition to motherhood, as research in this area often reflects a neurotypical perspective. This study seeks to address this gap by examining the long-term outcomes for individuals with ASD as they become mothers, using a longitudinal approach to provide new insights into the link between ASD and PPD.

Impact of research: 
There is currently a dearth of research demonstrating the link between autism and postpartum depression. With further empirical validation, this research could influence clinical practices and inform parenting strategies for neurodiverse mothers.
Date proposal received: 
Thursday, 21 November, 2024
Date proposal approved: 
Monday, 25 November, 2024
Keywords: 
Epidemiology, Mental health, Statistical methods, Parenting

B4749 - Smart Watch Face - Predicting Offspring Reproductive Development Using Maternal Placenta DNA Methylation Clock - 26/11/2024

B number: 
B4749
Principal applicant name: 
Ping Zeng | Department of Biostatistics, School of Public Health, Xuzhou Medical University (中国)
Co-applicants: 
Chu Zheng, Xinghao Yu
Title of project: 
Smart Watch Face - Predicting Offspring Reproductive Development Using Maternal Placenta DNA Methylation Clock.
Proposal summary: 

This study focuses on the physiological behaviors of pregnant women and the health of their offspring. It leverages population information and biological samples from ALSPAC (Avon Longitudinal Study of Parents and Children), the Shanghai Minhang Birth Cohort, and the Millennium Cohort Study. By employing novel statistical modeling strategies and machine learning techniques, the research predicts the epigenetic age of pregnant women, a unique population, through DNA methylation data of maternal and child samples. Building upon this, the study further investigates the impact of actual age, epigenetic age, and accelerated epigenetic aging on the reproductive development outcomes of the offspring. This approach aims to provide new insights into the role of epigenetic mechanisms in the mother-child interaction and offspring development, offering potential epigenetic targets for interventions to improve maternal and child health.

Impact of research: 
This study constructs an epigenetic clock for pregnant women based on placental DNA methylation information, addressing the applicability gap of traditional methods for estimating epigenetic age in the pregnant population and improving the accuracy and specificity of such estimates. By incorporating the actual age of the mother, her epigenetic age, and the accelerated epigenetic age (the residual difference between epigenetic age and actual age) into a unified analytical framework, this research explores how these factors jointly influence the reproductive and developmental processes of the offspring, providing new insights and methods for predicting and optimizing the healthy development of the offspring. Through in-depth investigation of the intrinsic relationship between maternal epigenetic age and offspring reproductive development, the study uncovers the epigenetic mechanisms underlying the mother-fetus interaction, offering scientific evidence and potential intervention targets for optimizing maternal and infant health management, preventing birth defects, and promoting the healthy growth of the offspring. This work is expected to guide clinical practice in the field of maternal and infant health in the future.
Date proposal received: 
Friday, 22 November, 2024
Date proposal approved: 
Monday, 25 November, 2024
Keywords: 
Genetics, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., DNA sequencing, Epigenetics

B4743 - Genome-Wide Association Study of lipids and the influence of education - 25/11/2024

B number: 
B4743
Principal applicant name: 
Marisa Canadas Garre | University of Bristol (United Kingdom)
Co-applicants: 
Professor Nicholas Timpson, Dr Laura Corbin
Title of project: 
Genome-Wide Association Study of lipids and the influence of education
Proposal summary: 

The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium is an international organization founded to facilitate large-scale genetic studies among multiple large and well-characterised groups of participants.
The goal of the CHARGE studies is to identify susceptibility genes involved in diseases of the heart, lung, and blood and their risk factors.
In our study, we will analyse the association of gene variants with serum lipids, considering the effect of the educational level in ALSPAC participants. The results will be combined with results from other groups of participants around the world to be able to identify new gene variants that help understand the biology of serum lipids.

Impact of research: 
Greater understanding of the aetiology of hyperlipidaemias. This study will help identify novel genetic variants involved in serum lipids pathways and how genetic variants affect these traits considering potential interactions with educational attainment.
Date proposal received: 
Thursday, 21 November, 2024
Date proposal approved: 
Monday, 25 November, 2024
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Hypertension, Obesity, Hyperlipidaemias, Computer simulations/modelling/algorithms, DNA sequencing, Gene mapping, GWAS, Metabolomics, Microarrays, Proteomics, RNA, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., BMI, Cardiovascular, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Metabolic - metabolism, Whole genome sequencing

B4750 - Does physical activity moderate the relationship between genetic liability to depression and severity of depressive symptoms - 25/11/2024

B number: 
B4750
Principal applicant name: 
Robyn Wootton | School of Psychological Science, University of Bristol
Co-applicants: 
Farzana Ali
Title of project: 
Does physical activity moderate the relationship between genetic liability to depression and severity of depressive symptoms?
Proposal summary: 

Individuals with a higher genetic propensity for depression are more likely to experience later depression symptoms. Evidence suggests moderate effects of exercise on improving symptoms of depression and anxiety. In this project, we explore whether the effects of exercise on depression symptoms differ depending on the genetic liability of the individual.

Impact of research: 
Better understand how exercise can differentially affect mental health outcomes and better tailor exercise interventions towards who they will be most effective for.
Date proposal received: 
Friday, 22 November, 2024
Date proposal approved: 
Monday, 25 November, 2024
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Genetic epidemiology

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