Proposal summaries
B3313 - Biosocial Birth Cohort Research A cross-disciplinary network - 30/05/2019
This project will establish a network in which social scientists, geneticists and epidemiologists work together to better understand, and benefit from, longitudinal birth cohort studies, which follow participants throughout their lives, often including multiple generations. These studies are becoming more important in disease research, to understand how environmental factors affect our health. So far, social scientists have not played a prominent role in the design or implementation of this type of study. The input of social scientists is important to better understand the relationship between biology and society emerging from birth cohort studies. This project will fill this gap by creating a network of scientists from all disciplines, including the social sciences. The project will include longitudinal birth cohort studies in the Global North and also in the Global South, where little research has been carried out on how these studies work, how they are maintained and used.
B3319 - Clinical and cognitive profiles of adults with psychotic experiences with and without preceding PTSD - 28/05/2019
There is substantial evidence demonstrating that in addition to the well-established link between exposure to childhood trauma and Posttraumatic Stress Disorder, PTSD has been associated with an increased risk for other severe psychiatric disorders such as psychosis. Individuals with psychosis have been found to have higher comorbid rates of PSTD compared to the general population (30%-50% vs 7%-9%). Importantly, the link between psychosis and PTSD is complex and multifactorial. There is very little knowledge on what could explain the high comorbidity between PTSD and psychosis, and more specifically the mechanisms/pathways that may explain why trauma may lead to psychotic symptoms, PTSD or to a combination of both. To date, the literature has focused on two main hypotheses: a) PTSD stands as a mediator of the relationship between childhood trauma and psychotic symptom severity. A model of continuity has also been suggested, implying that psychotic symptoms would be an exacerbation of the PTSD symptoms and b) PTSD and psychosis are both part of a broader spectrum of reactions to trauma with similar explanatory mechanisms at the level of cognitive schemas (e.g. beliefs about self and others), attributional styles and dissociative processes. There is a paucity of empirical evidence evaluating either of these hypotheses. Examining clinical and cognitive profiles of adults with psychotic experiences, with and without preceding PTSD (after childhood trauma) would be the first step towards disentangling complex relationship between the two disorders.
B3318 - Genetics of Child Growth Trajectories - 23/05/2019
Our team is interested in variables that influence the weight gain patterns of young children. In this study we aim at identifying genetic variants (differences in the DNA between individuals) that could be used to predict which children are most at risk at developing childhood obesity. With this information we could identify children who would benefit most from early life obesity interventions.
B3316 - Genetics susceptibility to high BMI and its relationship to food intake in children - 23/05/2019
B3311 - Prediction of cardio-metabolic risk from circulating metabolites A longitudinal study from childhood to early adulthood - 28/05/2019
B3315 - Intergeneration transmission of sexual abuse and violence - 20/05/2019
Children, particularly daughters, of mothers who have been victims of sexual violence and abuse have a higher risk of becoming victims of sexual violence and abuse, compared to children of mothers who have no such victimisation histories. The majority of studies examining this intergeneration 'transmission' of sexual abuse and violence have been conducted using samples from populations in which there are a high number of victims and outside the UK. Furthermore, studies have tended to focus on the sexual abuse histories of the mother and not the father. This study, using a general population sample (i.e., of people not specifically identified on the basis of being victims of sexual abuse) will enable us to identify the extent to which mothers' sexual abuse experiences increase the risk of similar victimisation in their children. We will also examine the impact of the sexual histories of fathers and what other factors (e.g., other types of abuse experienced by the mother and/or father, parents' mental health, children's early development and conduct disorders) exacerbate or reduce the risk of intergeneration transmission.
B3314 - The metabolomic profiling of cigarette smoking - 20/05/2019
It is hypothesized that exposure to cigarette smoking could influence the risk of cardiovascular diseases through direct modification of the lipoprotein profile, lipotoxicity and change in chronic oxidative stress. However, the metabolic profiling of cigarette smoking have not been precisely investigated.
Using the ALSPAC data, this study aims to provide insights into the molecular effect of smoking both in terms of the composition and the concentration of the molecular species affected.
B3310 - Puberty timing and cardiovascular structure and function at age 25 years - 13/05/2019
Puberty timing has been decreasing for several decades. Earlier puberty is thought to be associated with greater cardiovascular disease risk. The aim of this project is to examine the association between puberty timing and cardiac measures at age 25 years.
B3309 - Understanding the mechanisms linking the urban environment to psychotic experiences across the lifespan - 21/05/2019
Individuals who are raised in urban (versus rural) settings are around twice as likely to develop a psychotic disorder in adulthood. This association has now been replicated for subclinical psychotic experiences during childhood and adulthood (e.g., hearing voices, extreme paranoia). These symptoms lie on a continuum with clinical psychosis and therefore provide a useful marker to explore the urbanicity-psychosis association in the general population. Given that 70% of the worldâs population will live in urban areas by 2050, it is essential that we uncover the pathways linking cities and psychosis so that we can inform intervention efforts.
Research supports a role of neighbourhood social factors correlated with urbanicity in the aetiology of psychotic experiences, such as neighbourhood disorder and social fragmentation (i.e., weak connections between individuals in a community). In addition, emerging research suggests that urban residents have a higher genetic risk for schizophrenia, meaning that the urbanicity-psychosis association could be partly confounded by genes.
However, very little is currently known about the potential role of air pollution in the link between cities and psychosis. Air pollution is the world's biggest environmental health problem, and is particularly problematic in cities. Recent cross-sectional research has provided the first evidence linking air pollution to psychotic experiences among teenagers.
However, longitudinal research into the link between air pollution and psychotic experiences is needed to establish the temporal nature of associations. In addition, neighbourhood social exposures are highly correlated with air pollution (i.e., the most deprived neighbourhoods also tend to be the most polluted). The interplay between neighbourhood social conditions and air pollution (i.e., confounding versus interaction) in relation to psychotic experiences is not known. Furthermore, though influences on inflammatory and cognitive processes are the most commonly suggested mechanisms linking urban exposures to psychosis, very few studies have directly tested these mechanisms.
This project will examine 1) the longitudinal associations of air pollution exposure from birth to age 15 with psychotic experiences in childhood and adolescence, 2) the interplay between neighbourhood social characteristics (neighbourhood disorder and social fragmentation) and air pollution in the emergence of psychotic experiences, and 3) potential biopsychological mechanisms linking urban neighbourhood exposures with psychotic experiences, including inflammation and cognition.
B3306 - Modelling techniques for accelerated longitudinal studies - 07/05/2019
I met with Dr Fanny Kilpi following her presentation on some of the maternal data with cognitive outcomes from ALSPAC. Dr Jon Heron noticed the similarity in terms of structure of her dataset and wondered whether we could use these data to trial a new method of handling data produced from another study that we are involved with called cVEDA.
The purpose of this exercise is to trial a method/s of dealing with data including missing data that is completely new to me and the cVEDA (Indian cohort) team. It is purely for learning purposes and to consider any assumptions and adjustments we may make to our models when our final dataset is officially released at the end of 2020 i.e. a practice dataset.
Despite a publishable manuscript not being our primary goal it would be useful to have some input into how best to use these data, and which exclusions to make (e.g. HRT etc). Also, we may discover the analytical approach to be useful to you and then a publication may result if all collaborators consider this a worthwhile exercise and outcome.
B3308 - The development of genetically-based pathways underlying problematic alcohol use - 07/05/2019
Problematic alcohol use is a serious public health threat. Research suggests that there exist unique, biologically-based "types" of adolescents who are at high risk for problematic alcohol use. Discovering these types will help us identify personalized prevention targets for this condition. This proposal will examine patterns by which adolescent risk factors for problematic alcohol use (conduct problems, depressive symptoms, and personality traits) are inherited to identify new highly heritable traits. This proposal will also test sex differences in these new genetically-based traits and their relation to problematic alcohol use to shed light on whether differing treatments are needed for males and females.
B3307 - A multi-cohort GWAS of income using ALSPAC - 07/05/2019
B3299 - Clinical and Genetic Predictors of Polycystic Ovary Syndrome - 30/04/2019
Polycystic ovary syndrome (PCOS) is a common disorder affecting women associated with major adverse health outcomes including subfertility and increased risk for type 2 diabetes. PCOS is a complex genetic trait which arises from a combination of genetic risk and environmental such as obesity. Currently, a conclusive diagnosis of PCOS cannot be made until sexual maturation is complete and the patient develops the characteristic diagnostic features of hyperandrogenism, oligomenorrhea, and/or polycystic ovarian morphology. However, studies in girls with increased risk for PCOS, including daughters of affected women and girls with obesity, have identified early reproductive and metabolic features of the syndrome even prior to the onset of puberty. Investigations into the early origins of PCOS have been limited by small sample size and lack of longitudinal data. The ALSPAC cohort includes critical data needed to investigate PCOS, including maternal reproductive histories, hormone levels, and offspring pubertal development, reproductive hormone levels, and menstrual histories. These proposal seeks to identify early clinical and genetic predictors of PCOS. Data collected in this project will be used for preliminary data in planned future innovative investigations of the early origins of PCOS. This study will propose using a translational approach integrating whole genome sequencing, epigenetic, and metabolomics data available in this cohort with clinical predictors of PCOS. This proposed research will have a sustained and lasting impact on the field as it will inform future efforts toward development of targeted prevention and early treatment approaches in at-risk girls.
B3305 - EFSA systematic review of Sugars 30-04-2019 - 120653 - 30/04/2019
Review of the literature relating dietary intake of sugars to adverse health outcomes is being undertaken by EFSA. Five ALSPAC papers have been selected for the review and need extra details added on precise intakes of sugars in order to improve their usefulness to the review
B3304 - HDR Data Discovery Preparation for ATLAS - 02/05/2019
Medical research in the UK is still hindered by a perceived lack of suitable data and sample resources that can be used by the research community. This perception contrasts starkly with the knowledge that there are hundreds of potential resources that can supply data and samples. The work of the Tissue Directory and Coordination Centre and backed by the Medicines Discovery Catapult has shown that the actual problem experienced by both academic and commercial researchers is the inability to find suitable resources. The consequence is that researchers tend to utilise the resources that are close by proximity (because they can go and talk to the resource directly) rather than close to their research goals. This approach is driven because there is no easy mechanism in which to discover other potential national resources.
The Tissue Directory and Coordination Centre (TDCC) is the UKs national centre that is tasked with coordinating biobanks (samples and data) to ensure that researchers re-use existing resources before seeking to collect new samples or datasets. TDCC is a joint endeavour between the University of Nottingham and University College London. TDCC has created a Tissue Directory to allow a high-level search on aggregated meta data that works well for clinical and disease orientated biobanks. In part the Tissue Directory has begun to solve the issue of findability but the challenge has evolved. Researchers can search on very high-level classification of disease, gender and age and resources matching those criteria are displayed. This Directory acts as a first filter but does not allow researchers to ask detailed feasibility questions. Although candidate resources are listed the confidence that the data or samples required do actually exist remain low once sub-typing is considered. Assuming the identified resources have a search portal (many do not), the researcher would have to create accounts in each in order to perform a more detailed search. This effort can often go unrewarded as the ultimate answer is often that once more detailed criteria are added, the resource does not have the data or samples required.
It is clear that in order to support and utilise existing UK investment in health care resources we must have a more efficient mechanism in which a researcher can ask a relatively detailed question and understand whether resources exist that could support them. It is especially important that researchers find out quickly if something is not feasible (rather than investing time and finding it is not) and equally that referrals to the resources (such as ALSPAC) from the search system does not create irrelevant traffic. By bringing together key academic, technology and research infrastructure stakeholders we are seeking to change this to make the necessary change.
B3297 - Methods to identifying genetically regulated components using transcriptome data - 09/05/2019
Although genome-wide association studies (GWAS) have been very successful in identification of genetic variants associated with complex traits, the mechanistic links between these variants and complex traits are still largely unknown. A scientific hypothesis is that genetic variants influence complex traits via affecting cellular traits, e.g., regulating gene expression and altering protein abundance. Yet, how to systematically examine this hypothesis remains an open problem.
Recently, large genomic consortia are generating a vast volume of genomic data towards comprehensively characterizing the regulatory role of genetic variants. For example, the Genotype-Tissue Expression Project (GTEx) has collected genomic profile of 449 individuals, comprised of measurements of gene expression from multiple tissues and about 12.5 million DNA bases, providing unprecedented opportunities to dissect genetic contributions to complex traits. Statistical methods that effectively harness multilayer data (genetic variants, cellular traits and organismal traits) for mechanistic interpretation are highly demanding. The phenomenon that genetic variants have individually weak effects on complex traits makes statistical modeling very challenging, because it requires that the developed models can efficiently exploit information in low signal-noise-ratio (SNR) regimes.
In the proposed research, we aim at developing statistical methods to advance mechanistic understanding of the role of associated variants in complex traits. The key idea is built upon the emerging scientific evidence that genetic effects at the cellular level are much stronger than those at the organismal level. In our pilot study, we proposed a statistical approach, AUDIS, to accounting for uncertainty in dissecting genetic contributions to complex traits by leveraging regulatory information. We also developed a parameter expanded expectation-maximization (PX-EM) algorithm to ensure that AUDIS can perform stably in low SNR regimes. Interestingly, two popular methods in this field, SKAT and PrediXcan can be connected via a stagewise view of AUDIS, as supported by results from comprehensive simulation studies. Then we applied stagewise AUDIS to analyze 20 complex traits in GERA by incorporating the transcriptome data in the Genetic European Variation in Health and Disease (GEUVADIS) Project. Real data analysis results show that AUDIS can identify more genetically regulated genes that are significantly associated with complex traits, without inflated type I errors. To continue in this promising direction, we propose generalized AUDIS models to allow detection of trait-associated expression quantitative trait loci (eQTLs), as well as integrative analysis of GWAS data with transcriptome data from multiple tissues. We also propose to investigate theoretical properties of our methods, e.g., why AUDIS can be immune to model mis-specification.
The novelty of this research is that a statistically efficient and computationally feasible framework is developed to dissect genetic contributions to complex traits. Specifically, the proposed methods (AUDIS and its generalizations) can effectively borrow regulatory information at the cellular level and then boost statistical power of identifying genetically-regulated and trait-associated genes, even though in low SNR regimes. The stagewise view of AUDIS not only offers a statistical connection between existing approaches, but also highlights the importance of statistically rigorous design. Unlike conventional engineering approaches that often only consider a point estimate or a maximum a posteriori probability estimate, the stagewise view of AUDIS implies that the posterior distribution obtained in former stage should be naturally incorporated as the prior in the later stage. This gives birth to a modularized design of the whole data analytics system, greatly helping biomedical researchers to gain new scientific insights. The statistical and computational skills developed here are also broadly useful to many other applications in the field of data science.
B3302 - Road traffic injuries and risk behaviours in children and young people with special educational needs - 29/04/2019
Road traffic injuries are known to affect the vulnerable in our society. Children travelling to and from school, and young people especially young road drivers, are known to be at risk of being involved in a road traffic crash. We wish to explore whether children and young people with special educational needs (including physical or behavioural disabilities or learning difficulties) are at an increased risk of being injured in a road traffic crash. By better understanding how children with special educational needs are involved in road traffic crash events we can develop and test targeted interventions to prevent these injuries and deaths, and support the parents and carers of children and young people with special educational needs.
B3303 - An integrative analysis of biological and environmental risks for mental ill-health in young adulthood to precision psychiatry - 02/05/2019
Childhood adversity is associated with increased risk of future psychiatric illness (Croft et al., 2018). Raised levels of markers of inflammation are also associated future psychiatric illness. We have shown that certain lipids (O'Gorman et al,2017 ) and complement and coagulation proteins (English et al, 2018; Focking et al, 2019) are also raised and /or dysregulated in association with future psychotic illness, and we have shown that these lipid and proteins changes are functionally related to each other (Madrid et al, 2019). Changes to these biological markers may reflect these environmental exposures, in addition to representing novel targets for therapeutic intervention. We have also shown that the complement and coagulation pathway proteins are elevated by exposure to stress in an animal model of social defeat (Focking et al, 2019). There are however, important gaps in our knowledge regarding the relationship between psychiatric outcomes, early exposure to adversity, and early biological measures such as blood protein, lipid, and inflammatory markers levels. Our proposal will address these gaps.
This current proposal aims to utilise a longitudinal design involving all subjects within the ALSPAC Cohort who gave blood at age 11 (n=2160) and / or age 17 (n=1776) and who participated in interviews at age 24 . Cytokine, proteomic and lipidomic analyses will be undertaken in plasma samples from all of these subjects. Exposure to childhood adversity will be determined using existing data from ALSPAC children and parents for a range of possible experiences such as bullying, physical abuse, sexual abuse and emotional neglect, as previously described (Croft et al., 2018). The primary outcomes of interest would be subjects at age 24 who report 1) psychotic experiences 2) depressive / affective symptoms 3) anxiety symptoms and 4) fulfill criteria for any psychiatric disorder at age 24. A secondary outcome will be that of global functioning, as determined from available ALSPAC data, at age 24.
Data will be compared and integrated between groups, and examined in relation to the detailed environmental exposure data available within ALSPAC.
Our overarching aim is to investigate the longitudinal relationship between environmental exposures, blood markers and different psychiatric outcomes.
We have the following specific objectives;
1. To investigate the longitudinal pattern of biomarker change in the different disorders.
2. To investigate the relationship between environmental exposures and biomarker expression.
3. To integrate this data with other, already available, genomic, neuroimaging and neuropsychology data in order to build a predictive model of psychiatric disorders generally based on early biological and environmental data.
This proposal represents a unique opportunity to understand the relationship between environmental experiences, longitudinal measures of biological markers and psychiatric outcomes at age 24.
References:
Croft, J., Heron, J., Teufel, C., Cannon, M., Wolke, D., Thompson, A., . . . Zammit, S. (2018). Association of Trauma Type, Age of Exposure, and Frequency in Childhood and Adolescence With Psychotic Experiences in Early Adulthood. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2018.3155. Davison J, O'Gorman A, Brennan L, Cotter DR. A systematic review of metabolite biomarkers of schizophrenia. Schizophr Res. 2018 May;195:32-50. doi: 10.1016/j.schres.2017.09.021. Epub 2017 Sep 22. Review. PMID: 28947341.
Davison J, O'Gorman A, Brennan L, Cotter DR. A systematic review of metabolite biomarkers of schizophrenia. Schizophr Res. 2018 May;195:32-50. doi: 10.1016/j.schres.2017.09.021. Epub 2017 Sep 22. Review. PMID: 28947341.
English JA, Lopez LM, O'Gorman A, Föcking M, Hryniewiecka M, Scaife C, Sabherwal S, Wynne K, Dicker P, Rutten BPF, Lewis G, Zammit S, Cannon M, Cagney G, Cotter DR. Blood-Based Protein Changes in Childhood Are Associated With Increased Risk for Later Psychotic Disorder: Evidence From a Nested Case-Control Study of the ALSPAC Longitudinal Birth Cohort. Schizophr Bull. 2018 Feb 15;44(2):297-306. PMID: 29036721.
Föcking M, Sabherwal S, Cates HM, Scaife C, Dicker P, Hryniewiecka M, Wynne K, Rutten BPF, Lewis G, Cannon M, Nestler EJ, Heurich M, Cagney G, Zammit S, Cotter DR. Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress. Mol Psychiatry. 2019 Jan 11. PMID: 30635638.
Madrid-Gambin F, Föcking M, Sabherwal S, Heurich M, English JA, O'Gorman A, Suvitaival T, Ahonen L, Cannon M, Lewis G, Mattila I, Scaife C, Madden S, Hyötyläinen T, OreÅ¡iÄ M, Zammit S, Cagney G, Cotter DR, Brennan L. Integrated Lipidomics and Proteomics Point to Early Blood-Based Changes in Childhood Preceding Later Development of Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children. Biol Psychiatry. 2019 Jan 30. PMID: 30878195.
O'Gorman A, Suvitaival T, Ahonen L, Cannon M, Zammit S, Lewis G, Roche HM, Mattila I, Hyotylainen T, Oresic M, Brennan L, Cotter DR. Identification of a plasma signature of psychotic disorder in children and adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Transl Psychiatry. 2017 Sep 26;7(9):e1240. doi: 10.1038/tp.2017.211. PMID: 28949339
B3295 - Internalising problems in children An epigenome-wide association study - 18/04/2019
Rationale: Internalising problems (depression & anxiety) in children have been found to be predictive of negative outcomes later in life (Sallis et al., 2018) but the biological mechanisms underlying the development of these disorders are not well understood. There is some evidence that epigenetics might play a role, but results are mixed (Barker, Walton, & Cecil, 2018). In this study, we will examine internalizing traits in childhood and methylation, both cross-sectionally and at birth.
B3300 - Assessing epigenetic changes in relation to night shift work - 18/04/2019
Shift work is a widespread feature of our society, with a third of men and a fifth of women in the UK engaged in it. However, shift work has been linked with a number of poor health outcomes, including obesity, diabetes, heart disease, depression and some types of cancer. The pathways mechanisms by which shift work might lead to these diseases are poorly understood. A major area of interest is the effect shift work, and night shift work in particular, has on altering a personâs body clock. There is information available on shift work patterns at multiple time points in Understanding Society. The availability of blood samples for some study participants provides an opportunity to look at biological changes associated with shift work, including the impact shift work might have on epigenetic modifications, which influence how our genes are expressed turned on or off (via epigenetic changes). This work will help us better understand how the occupational exposure of working shifts might become embodied in human biology, with the potential for long term health consequences.