Proposal summaries
B2500 - Understanding asthma phenotypes
Asthma is a complex disease that takes many different forms. There is some debate about whether asthma is really one disease or a set of different diseases that share some characteristics. By understanding the variation in how asthma presents, we hope to gain greater insight into how asthma might be caused. THis project will be part of a network of similar studies in both high and low income countries to see whether the factors that are associated with different asthma types vary by the sort of environment in which people live.
B2502 - The role of the chemical exposome in determining the aetiology of urogenital malformations in the male neonate
Urogenital malformations in male neonates is thought to be associated with exposure of the foetus to mixtures of endocrine disrupting chemicals during pregnancy. However, the causative chemical agents and their mixtures have not yet been identified. This project will use new discovery-based chemical methods to analyse samples of maternal urine from an ALSPAC cohort containing cases with urogenital malformations. The goal of the work is to identify key mixtures of chemical contaminants that have endocrine disrupting activity and cause malformations in the developing foetus.
B2496 - Adult Eating Behaviour Questionnaire in ALSPAC
Eating behaviours like how full you feel after eating a meal or how quickly you eat have been related to the development of obesity in infants, children and adolescents. A new questionnaire to measure these behaviours is currently being developed for use with adults and could reveal new options for identifying people at risk of gaining weight and thus most in need of help to prevent weight gain. We would like to use this questionnaire in ALSPAC to measure these types of behaviours and work out if they are useful for predicting weight gain. We will also look at factors throughout life (previously measured in ALSPAC Young Adults) that are associated with adult eating behaviours. Ultimately this will enable us to design ways to help people to avoid eating in ways that makes gaining too much weight more likely.
B2501 - Alcohol Misuse Electronic Longitudinal Alcohol Study in Communities - 31/07/2015
The number of children who are affected by parental alcohol misuse is largely unknown although estimates suggest a third of all UK children live with at least one parent who uses alcohol hazardously. How this impacts on their health, mental health and education is unclear.
B2498 - Exploring mechanisms linking Vitamin D levels and cancer-related phenotypes in healthy people A Recall by Genotype study - 31/07/2015
The role for Vitamin D and its active metabolite, 1,25-dihydroxy-vitamin D in slowing cancer progression has been demonstrated in numerous preclinical studies; however, results from human studies has been inconclusive [1]. Current evidence from in vitro [2-4] and in vivo [5] studies suggest that a possible mechanism by which Vitamin D decreases proliferation and stimulates apoptosis of breast tumours is by antagonizing the effects of IGF-I and by stimulating the expression of IGFBP-3. It was also shown that IGFBP-3 mediates Vitamin D induced growth inhibition of prostate cancer cells via p21/WAF1 [6]. Given the interest in the potential role of Vitamin D in inhibiting cancer progression, further research is needed to investigate the mechanisms underlying these associations.
This proposal is for a Recall by Genotype study to recall individuals stratified by genetic risk scores for Vitamin D (based on genetic variants that affect Vitamin D synthesis, metabolism and transport) to enable detailed and precise phenotyping
References:
1.Feldman, D., A.V. Krishnan, S. Swami, E. Giovannucci and B.J. Feldman, The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer, 2014. 14(5): p. 342-57.
2. Xie, S.P., S.Y. James and K.W. Colston, Vitamin D derivatives inhibit the mitogenic effects of IGF-I on MCF-7 human breast cancer cells. J Endocrinol, 1997. 154(3): p. 495-504.
3. Colston, K.W., C.M. Perks, S.P. Xie and J.M. Holly, Growth inhibition of both MCF-7 and Hs578T human breast cancer cell lines by vitamin D analogues is associated with increased expression of insulin-like growth factor binding protein-3. J Mol Endocrinol, 1998. 20(1): p. 157-62.
4. Xie, S.P., G. Pirianov and K.W. Colston, Vitamin D analogues suppress IGF-I signalling and promote apoptosis in breast cancer cells. Eur J Cancer, 1999. 35(12): p. 1717-23.
5. Lee, H.J., S. Paul, N. Atalla, P.E. Thomas, X. Lin, I. Yang, B. Buckley, G. Lu, X. Zheng, Y.R. Lou, A.H. Conney, H. Maehr, L. Adorini, M. Uskokovic and N. Suh, Gemini vitamin D analogues inhibit estrogen receptor-positive and estrogen receptor-negative mammary tumorigenesis without hypercalcemic toxicity. Cancer Prev Res (Phila), 2008. 1(6): p. 476-84.
6. Boyle, B.J., X.Y. Zhao, P. Cohen and D. Feldman, Insulin-like growth factor binding protein-3 mediates 1 alpha,25-dihydroxyvitamin d(3) growth inhibition in the LNCaP prostate cancer cell line through p21/WAF1. J Urol, 2001. 165(4): p. 1319-24.
B2499 - Exploring mechanisms linking glucose levels and cancer-related phenotypes in healthy people A Recall by Genotype study - 31/07/2015
Lifestyle factors that worsen glycaemic control have been hypothesized to contribute to cancer progression and compromise the effectiveness of treatment [1-5]. Based on previous in vitro studies, it was found that in high glucose conditions, breast and prostate cancer cells were more resistant to chemotherapy and this was via the increased expression of IGFBP-2 and down-regulation of PTEN levels ([6, 7] and unpublished data). Further research is needed to understand the mechanisms underlying the association between hyperglycaemia, cancer progression and the development of chemoresistance.
This proposal is for a Recall by Genotype study using genome-wide genotypic risk score for circulating glucose. With Dr Robert Scott (collaborator), we have developed a genome-wide genotypic risk score for circulating glucose that explains ~5% of observed variance in glucose levels (p =6.4x10-32). Recall of individuals based on the upper and lower tails of the genotypic risk score for glucose will enable the assessment of the biological implications of genetically randomised hyperglycaemia in humans and to enable further detailed and precise phenotyping.
References:
1. Hammarsten, J. and B. Hogstedt, Hyperinsulinaemia: a prospective risk factor for lethal clinical prostate cancer. Eur J Cancer, 2005. 41(18): p. 2887-95.
2. Hammarsten, J. and B. Hogstedt, Clinical, haemodynamic, anthropometric, metabolic and insulin profile of men with high-stage and high-grade clinical prostate cancer. Blood Press, 2004. 13(1): p. 47-55.
3. Chen, Z., W. Lu, C. Garcia-Prieto and P. Huang, The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr, 2007. 39(3): p. 267-74.
4. Yu, O.H., W.D. Foulkes, Z. Dastani, R.M. Martin, R. Eeles, P. Consortium, C.G. Investigators and J.B. Richards, An assessment of the shared allelic architecture between type II diabetes and prostate cancer. Cancer Epidemiol Biomarkers Prev, 2013. 22(8): p. 1473-5.
5. Pierce, B.L. and H. Ahsan, Genetic susceptibility to type 2 diabetes is associated with reduced prostate cancer risk. Hum Hered, 2010. 69(3): p. 193-201.
6. Biernacka, K.M., C.C. Uzoh, L. Zeng, R.A. Persad, A. Bahl, D. Gillatt, C.M. Perks and J.M. Holly, Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2. Endocr Relat Cancer, 2013. 20(5): p. 741-51.
7. Uzoh, C.C., J.M. Holly, K.M. Biernacka, R.A. Persad, A. Bahl, D. Gillatt and C.M. Perks, Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via IGF-dependent or -independent mechanisms and reduces the efficacy of docetaxel. Br J Cancer, 2011. 104(10): p. 1587-93.
B2491 - Prenatal tobacco exposure in lymphoblastoid cell lines and B cells IEU - 31/07/2015
Prenatal exposure to tobacco through maternal smoking during pregnancy increases the risk of many negative health and behavioural outcomes. Across human populations, smoking during pregnancy remains above 10%. To better discover and apply effective interventions, it is important to determine the exposure of each child. Unfortunately, simply asking mothers about their smoking behaviour is not sufficient due to lapses in memory, reluctance to admit smoking or failure to accurately define smoking behaviour. Measurement of cotinine in maternal blood, urine or saliva can improve detection but may miss cases of intermittent smoking because cotinine is cleared quickly during pregnancy. Fortunately, children retain evidence of prenatal tobacco exposure in the DNA methylation of their blood even beyond the age of 17. However, since blood collections are a precious and finite resource many cohort studies have derived lymphoblastoid cell lines (LCLs) from blood samples. LCLs are B cells that have been transformed to spontaneously replicate, thereby providing a constant supply of new biological material. Although the transformation process is known to disrupt DNA methylation marks, a recent study has reported associations between LCL DNA methylation and present tobacco smoking. We would like to test associations of prenatal tobacco exposure in LCL DNA methylation and determine the extent to which the transformation process has modified these associations by comparing them to associations in B cells isolated from matching blood samples. B cell isolation is necessary because each of the many cell types found in blood has a unique DNA methylation profile.
2490 - Maternal Epigenetic Predictors of Height BMI and Heritability Variance
Complex genetic traits are traits (e.g height and BMI) are multifactorial and can’t explained by variation in single genes.. To understand the genetic basis of such traits, investigators have queried across the genome to find multiple variants associated with the traits, such as the genome-wide association study (GWAS). Another possibility is to look at modifications to DNA itself that may change how genes behave - these changes are epigenetic (epi, meaning on or upon). We propose to explore how maternal epigenetic modifications are associated to their children’s height and BMI. In addition, we will try to understand how epigenetic modifications can play a role in determining how similar the heights and BMIs of a mother and her child will be.
2497 - Epigenetic Mechanisms of Breast Cancer Risk Exposures
There are many factors that influence whether someone will get breast cancer. These include things that cannot be changed such as family history, breast density or hormonal factors like age at menopause. They also include lifestyle factors that can be changed such as alcohol intake, smoking, physical activity, BMI and oral contraceptive use. For many of these lifestyle factors there are currently no methods to accurately measure the accumulation of these exposures over an individual’s lifetime. We believe that we have identified a method to accurately measure accumulated exposures in a blood sample, to quantify breast cancer risk associated with these exposures over their lifetime. We will start by developing a molecular measure of hormonal oestrogen exposures based on DNA methylation data from 2500 women from several international cohorts and including nested breast cancer case control studies. We hope to validate this measure of cumulative oestrogen exposure associated with DNA methylation in additional cohort studies such as ALSPAC. We will validate these measurements associated with cumulative oestrogen exposure in blood samples from 1200 women using an alternative methodology. We will also investigate how other lifestyle factors, which are known breast cancer risk factors, might influence this oestrogen exposure measurement. This study may provide a new way in which to measure exposures that will help in understanding a women’s risk of developing breast cancer. Future work will then test this measurement as method of measuring breast cancer risk.
B2503 - Mapping Parental Anxiety Trajectories Impact on Child
There has a great deal of research that has shown that maternal depression has a long-term effect on the child. Longitudinal studies have also shown that maternal anxiety can affect the child, including recent studies from ALSPAC that have shown that maternal anxiety during pregnancy can have a long term effect on the child.
There is considerable interest in the idea that pregnancy and the postnatal period represent a "critical period" of development for the mother-infant relationship and for the infant. If the "critical period" idea is correct, then maternal mental health problems that occur during this period should be particularly harmful to the infant compared to maternal mental health problems that occur at other periods of the child's life. Other studies, however, have shown that chronic and recurring forms of maternal mental health problems have a stronger and more lasting effect than "critical periods" of maternal poor mental health.
In this proposal, we aim to investigate longitudinal PATTERNS of maternal anxiety. A patterns approach to mental health may be helpful in understanding what kinds of individuals struggle most, and if there are particular patterns or timepoints that are particularly important for child outcomes.
We expect that within mothers who experience anxiety, the pattern of anxiety across time will differ. We will use newer statistical procedures to model these different groups, or classes, of patterns. For example, some mothers may have chronic anxiety, some may have recurring patterns, and some may have episodic patterns. Other studies of patterns or trajectories of mental health problems (primarily depression) have detected low, high, decreasing and increasing patterns across time. Once we have established a well-performing model of maternal anxiety, we want to assess whether there are individual factors that predict the type of pattern of anxiety mothers have. For example, are mothers who live in poverty more likely to experience recurring or chronic patterns of anxiety? We also want to see if the pattern of anxiety varies based on other factors that might be happening for mothers. For example, we expect that stressful life events and depression may vary across time with anxiety, although one may precede the other in time. We will use lagged analyses to examine these effects. We also think that some baseline factors might change how closely life events, anxiety and depression co-vary. Women who have a history of abuse, for instance, may have a stronger link between life events and anxiety over time than those who don't have that history. Lastly, and importantly, we want to see if different patterns of anxiety predict child outcomes. We will use cross-lagged analyses to examine if there are reciprocal effects of child behaviours on maternal anxiety, and vice versa.
B2494 - Cumulative adversity positive childhood home environment and risk for cardiovascular disease and depression in young adulthood
Evidence is accumulating that psychosocial adversity in early life may have life-long consequences for health, particularly for cardiovascular disease and depression. However, most of the work in this area has significant methodological limitations in measuring adversity, including reliance on unweighted counts of early life adverse events, retrospective reporting of adversity in childhood, and failure to account for trajectories of adversity from birth through adolescence. Moreover, very few studies have examined positive factors from early life that may promote cardiovascular health and mitigate depression risk over the life course. The identification of such early life protective factors, coupled with an enhanced measure of cumulative adversity, will enhance our understanding of how early life experiences can “get into the body” to affect health risk and resilience over the life course. In this study, we will examine trajectories of psychosocial adversity from birth through adolescence, and examine patterning in early adulthood cardiovascular and depression risk according to membership in each trajectory group. We will also develop and validate a measure of childhood positive home environment, and examine whether experiencing a positive home environment is associated with enhanced cardiovascular health and less depressive risk in early adulthood. This study is the first to consider how both the accumulation of psychosocial risk, as well as the accumulation of protective psychosocial factors early in life, affect health over the life course. All study hypotheses will be tested using existing ALSPAC data measured from birth through early adulthood.
B2493 - Development of an E-health package to reduce self-harm facilitate help-seeking and improve mental wellbeing in young people - 31/07/2015
Self-harm is common in adolescence with community studies reporting lifetime rates of 13-18%. Self-harm is distressing for the individual, their friends and family and leads to considerable healthcare costs for the NHS. It is associated with a range of poor outcomes in early adulthood including mental health problems, substance use, and educational and occupational difficulties, and is the strongest risk factor for suicide. Self-harm is therefore a major public health concern.
Early intervention and treatment strategies for those who self-harm are important, however, only one in eight individuals who self-harm seek medical help. This means the majority of self-harm episodes remain hidden from health services. There is an urgent need to develop interventions for young people who self-harm that are effective, accessible and engaging, and for their wider dissemination beyond those seeking medical treatment.
There is increasing interest in using technology (such as the Internet and mobile phones) to educate, monitor, and treat a variety of mental and physical health problems. Several recent government and NHS strategies have highlighted the potential for technologies to transform the delivery of mental health care and improve patient outcomes. E-health interventions have been shown to be effective for a number of different mental health problems, including depression and suicidal thoughts, but few have been developed specifically for individuals who self-harm.
The aim of the research is to is to develop an innovative and user-friendly E-health package for self-harm that is specifically targeted at young people (aged 15-25). Development of the package will be informed by:
• A thorough review of the literature on i) theories for the persistance of self-harm and for help-
seeking and ii) existing E-health interventions for self-harm and suicidal behaviour.
• Analyses of new data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth
cohort examining i) the functions of self-harm, ii) the reasons for stopping self-harm, iii)
preferred sources of help and iv) exploring how young people use technologies.
• Interviews and focus groups with potential users, parents/carers and peers, and professionals
working with young people who self-harm.
B2480 - Meta-analysis on the association between vitamin D and myopia
We are proposing to synthesize the current available evidence in the literature regarding the association between vitamin D and myopia.
B2481 - Estimating stature from long bone length derived from whole body DXA developing methods for forensic anthropology
Forensic anthropology serves the investigative and judicial communities by analysing human remains for medico-legal purposes such as the investigation of homicide, human trafficking, mass disasters and war crimes.
Within this field, the accurate estimation of stature in life can meaningfully contribute to the positive identification of skeletal remains of unknown individuals. Regression equations are most commonly used to estimate stature and have been derived for numerous bones including the femur, tibia, humerus and pelvic girdle, but almost all of the methods are based on data from next-of-kin or observer-identified adult ‘white European’ populations from the first half of the 20thC. There is a pressing need for more inclusive, recent, datasets, and in particular from populations of African and Asian ancestry. This project will extract long bone lengths (femur, tibia, humerus) from a sample of the ALSPAC archive of whole body DXA scans, selected to represent mother-assessed ethnicity cohorts. These data will then be used to derive new stature regression equations for a) age 9 juveniles and b) age 17 young adults across the ethnicity cohorts; these equations will then be applied to an African forensic case which is ongoing (PI: Kate Robson Brown). This research is designed to be achievable in 12 months full time, starting in September 2015, in order to facilitate it running as an MPhil project for Ms Khadija Ali under supervision of Kate Robson Brown, and contributing to this case.
B2489 - ALSPAC iPSC bank -
ALSPAC has generated many cell lines from white blood cells. We would like to exploit this resource by treating some of the cell lines in a specific way to produce induced pluripotent stem cells (also known as iPS cells or iPSCs). iPS cells can be programmed to take up characteristics of different cell types, for example cardiac or skin cells. Producing such cells from the ALSPAC participants will enable researchers to look the effects of different genetic variants or environmental exposures on different types of cells helping to determine the mechanisms of disease. The aim of this project is to establish procedures and processes for creation and use of iPS cells from the ALSPAC cohort to enhance future research.
B2479 - Early life determinants of breast density implications for breast cancer prevention
Breast cancer is the most common female cancer globally. Greater breast density, i.e. the amount of fibro-glandular tissue seen on a mammogram or MRI of the breast, is a strong and highly common risk factor for breast cancer in the general population. The magnitude and consistency of the relationship between breast density and breast cancer risk make this the most significant target for breast cancer prevention. Epidemiologic data consistently report that higher birth weight (suggesting more rapid prenatal growth) and rapid height growth at puberty strongly predict later life breast cancer risk. Pubertal development also predicts breast cancer risk, with earlier age at menarche a strong risk factor for breast cancer. Sex steroids and growth factors regulate height growth and pubertal development as well as breast fibro-glandular tissue proliferation, suggesting that common mechanisms underlie growth, puberty, breast density and cancer risk. We will utilize data from two of the most comprehensively characterised pregnancy cohorts internationally. Together, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Western Australian Pregnancy Cohort (Raine) Study provide one of the few opportunities internationally to quantify how pre and postnatal growth, diet and endogenous and exogenous breast carcinogens impact on young adult breast density. Cohort strengths include: 1) large sample size (500 MRI-breast density measurements in ALSPAC; 600 to be collected in Raine); 2) existing repeat measures of pre and postnatal growth, adiposity, sex hormones and growth factors through to young adulthood; and 3) existing repeat measures of diet from infancy through to adulthood.
B2482 - Association between dietary measures and later development of psychotic symptoms in the ALSPAC cohort - 17/07/2015
Essential fatty acids and risk of psychotic symptoms in the ALSPAC cohort outline
Aim:
To investigate whether essential fatty acids intake both perinatally and in childhood and is associated with the later development of psychotic symptoms or disorder in adolescence.
B2488 - Dairy intake in pregnancy anthropometry in infancy and childhood - 16/07/2015
AIMS: To investigate associations between intake of dairy foods in pregnancy with anthropometric measures at birth, infancy, early and late childhood
B2487 - Using genetic data to understand the relationship between growth and cardiometabolic health - 16/07/2015
Genome-wide association studies (GWAS) have uncovered multiple single nucleotide polymorphisms (SNPs) that are associated with height[1], adiposity[2, 3], cardiometabolic diseases[4] and intermediate cardiometabolic phenotypes.[5, 6] However, most GWAS have been carried out in caucasian adults, and the association between the SNPs and phenotypes in different ethnic groups and at different stages of the life course remains uncertain.
Within epidemiology, observational data are often used to assess the association between an exposure and a health outcome of interest in situations where a randomized controlled trial (which provides stronger evidence of causality) is not possible or not ethical. These studies are, however, plagued with difficulties due to bias and confounding.[7, 8] Mendelian Randomization[9] (MR) is a technique that uses genetic variants related to an exposure of interest to obtain an estimate of the exposure-outcome association that is not affected by confounding or reverse causality.
This PhD proposal will 1) further understanding of the genetic architecture of anthropometry and cardiometabolic traits, and 2) use MR to advance understanding of the causal relationships between anthropometry and cardiometabolic health.
B2486 - Using a healthy population to explore the biological pathways underlying inflammatory bowel disease - 16/07/2015
AIMS:
To investigate the downstream effects of genetic variants associated with inflammatory bowel disease (IBD) in healthy indiviuduals, focusing particularly on metabolites and metabolic pathways.