Proposal summaries
B2893 - Is BP variability related to pregnancy outcome - 01/06/2017
Outside pregnancy, how much blood pressure varies is associated with the risk of heart attack, stroke and similar health problems.
In the CHIPS Trial (Control of Hypertension In Pregnancy Study) of 987 women with high blood pressure that was there before pregnancy or that developed in pregnancy, we found that the more blood pressure varied, the greater the risks for the mother, with possibly reduced risks for the baby. We are seeking to confirm whether these findings can be replicated in another dataset.
B2894 - The impact of maternal folic acid supplementation during pregnancy and childrens psychosocial development - 09/07/2017
Folate is essential to the body to synthesize, repair and methylate DNA. During pregnancy there is an increased demand for folate to aid rapid cell division and growth which is vital for foetal, placental and maternal development (1), therefore folic acid (400ug/d) is recommended to all women from preconception to the end of the first trimester of pregnancy (2). The physical benefits of folic acid supplementation are well documented in the literature; the most notable is protection against first occurrence and reoccurrence of neural tube defects (3), which affects over 900 pregnancies per year in the UK (4). Supplementation has also been shown to reduce the risk of congenital heart defects (5), cleft palette (6). Premature delivery (7) and low infant birth weight (7).
In terms of neurocognitive development, deficiency in maternal folate levels has been shown to negatively impact on the child’s cognitive performance (8), whereas optimal levels positively impact on language and motor development at age four (9) and lower the risk of children Internalising and externalising problems (10;11).
At present UK policy recommendations clearly focus on the protective role of folate during the early stages of pregnancy however, the role of maternal folic acid supplementation during the later stages of pregnancy is less clear and it is unknown whether it confers any other long-term effects in the children.
B2892 - Impact of economic conditions in year of birth on DNA methylation age acceleration - 31/05/2017
Macroeconomic conditions or business cycle status during year of birth have been found to have diverse impacts on later life health (e.g. cognitive function in later life, Doblhammer & van den Berg 2013). Epigenetic modifications are important biological regulatory mechanisms that undergo widespread remodeling during development, are susceptible to modification, and may mediate the impact of early-life environmental factors on later life health. We aim to examine to examine whether macroeconomic status at birth is associated with altered DNA methylation, particularly epigenetic age acceleration, in adults.
B2889 - Paternal characteristics and lifestyle and offspring DNA methylation - 24/05/2017
Although lots of studies have looked at the effect of maternal behaviours on offspring DNA methylation, there is a severe lack of studies looking at paternal characteristics. Increasingly, findings from animal models suggest that paternal exposures can affect offspring health via epigenetic changes to sperm. If this is true in humans, we might expect to see changes in cord blood DNA associated with paternal factors.
We plan to use epigenome-wide association studies in a consortium setting to investigate paternal-specific effects. This will require using strategies to overcome confounding by maternal effects and shared genetics.
B2890 - Childrens Psychosocial Development Meta-analytical Findings Meet Dynamic Panel Models - 24/05/2017
It is widely assumed that witnessing physical aggression between parents is detrimental to children’s well-being, that parent involvement in school increases academic success in offspring, that playing violent Internet games fosters aggression, and that victimization from bullying may result in emotional problems. Many environmental factors known to predict—and presumed to influence--children’s psychosocial development cannot be subject to causal—meaning experimental--analysis for ethical reasons (e.g., a research design where children are randomly assigned to exposure to bullying, harsh parenting, single parenthood/poverty) and/or practical ones (e.g., lack of peer intimacy, insecure attachment, poor self-esteem). Data presumptively illuminating the causes of individual variation in children’s emotions, cognition and behavior, then, mostly derive from observational/correlational studies, studies whose results are being combined ever more frequently for purposes of meta-analysis on the supposition that such efforts can improve causal inference. Because results of both individual studies and of meta-analyses can and are used to inform practice and policy, there is a need to evaluate how solid the empirical foundation is. By applying an econometric method, novel to psychology and medicine, we seek to determine whether prevailing understanding about diverse causes of variation in children’s functioning and mental health is sound.
B2888 - Young people and gambling-related harm - 05/07/2017
It is not surprising that those exposed to gambling in adolescence through parental example are more likely to be active gamblers in young adulthood or that young people who had parents with gambling problems are more likely themselves to be problem gamblers. However, the source of these correlations is not understood. A typical pathway to gambling/ problem gambling in young adulthood may be direct: for example, having parents who gamble ânormalisesâ gambling for the young person or the parents actually introduce their children to gambling, facilitating their participation while still under-age. On the other hand, the correlations may not depend on the direct influence of parental behaviour with respect to gambling itself, which may indeed not be decisive. Rather parental gambling and especially problem gambling may serve as proxies for more general household characteristics such as attitude to risk, engagement in stigmatised activities and domestic instability.
The ALSPAC data set includes information on the young adultâs own gambling. Clearly these variables are required as central to the analysis; and we will also plan to include in modelling information on the respondentâs contemporaneous participation in other risky activities as well as standard controls such as educational qualifications.
Equally crucial to the hypotheses to be examined will be information on parental self-reported gambling at child ages 6 and 18. We are also requesting variables which reflect other aspects of parental lifestyle (primarily from mother and partner questionnaires at child age 12).
B2883 - Early Menarche and Risky Behaviours A Mendelian Randomisation Study - 24/05/2017
Timing of puberty has both short- and long-term impacts on physical and mental health for adolescent girls; understanding links between early puberty and health outcomes has important implications for healthcare and policy. This research concerns existing evidence for associations between early puberty in girls and risky behaviors. Such behaviors include risky sexual behaviors (including earlier sexual experiences, unprotected sex and teenage pregnancy) and risky health behaviors (such as alcohol and substance misuse). Although there have been numerous observational reports of links between early puberty and risky behaviors, there have also been inconsistencies. For example, some studies report associations to be persistent into adulthood, whereas others suggest that effects are only present in early, but not late, adolescence. Furthermore, observational studies have numerous limitations, including confounding, reverse causality and bias, which make findings difficult to interpret. Thus, it is currently unclear whether associations between early puberty and risky behaviors in girls may be causal. Although randomized controlled trials (RCTs) are considered the gold standard of epidemiological research methods, testing causal associations between early puberty and risky behaviors is not possible within an RCT design. Alternatively, Mendelian randomization allows the testing of causal relationships between exposure and outcome within a genetically informed design. We propose to test the causal relationship between early puberty in girls and risky behavior using a Mendelian randomization design.
B2886 - Genetics of total and regional body composition - 17/05/2017
This study aims to investigate genetic underpinnings of body composition among adults. By combining measures of total and regional body fat, lean, and bone mass with measures of common genetic markers among participating post-adolescents and mothers in ALSPAC, we aim to search for and describe specific genetic variants that may influence differences in body mass, and ultimately future disease, in a young and middle-aged adult population. Ultimately, this work will be combined with work done in other cohorts of similar-aged adults to increase the scope and reliability of results.
B2884 - ADHD neuro-cogntive functioning and genes - 25/05/2017
Attention deficit Hyperactivity disorder (ADHD) is a neuro-developmental disorder whose origins remain not well understood. Popular theories of ADHD assume that ADHD symptoms are caused by the dysfunction of specific neuro-cognitive mechanisms like the ability to represent and learn from positive and negative feedback (also called prediction errors) or the ability to hold information for further manipulation in the working memory. These neuro-cognitive functions depend on the availability of neurotransmitters (signalling molecules), in particular dopamine, in the brain. Yet, even though there is ample evidence for genetic influence on neurotransmitter availability, and twin studies indicate the heritability of ADHD, the specific genetic contributions to ADHD remain poorly understood.
This project shall use a “computational psychiatry” approach to improve the understanding the specific genetic contributions to ADHD. Computational psychiatry uses mathematical models of cognition and learning that are consistent with behavioural and neurobiological data to identify which neuro-cognitive sub-processes cause impaired learning or cognition. For example, impaired reward-based learning could be explained by the inability to learn from positive feedback or feedback, or to the inability to make choices consistent with learned reward-values. Low performance in cognitive tests could be caused by a low ability (resulting e.g. from noisy working memory representations), or by a preference for fast as opposed to accurate responding.
Because the mathematical models employed in this project have been shown to be good models of the cognitive and neuro-biological processes underlying learning and decision making, they can build a bridge between ADHD symptoms and genes by showing how neuro-cognitive deficits underlying ADHD are in turn associated with genes. We expect stronger associations between neuro-cognitive processes and genes than between ADHD-Symptoms and genes, because the former are likely more directly influence by genes.
Hence, our goals are to describe ADHD phenotypes in terms of neuro-cognitive sub processes obtained through mathematical modelling and to identify genes associated with these phenotypes.
For this aim we will model data from neuropsychological and experimental tests collected in the ALSPAC Teen focus data collections to first identify in which neuro-cognitive processes ADHD patients have the most important deficits. In a second step, we will investigate genetic associations for the neuro-cognitive processes with the largest deficits.
In sum, this project will use mathematical modelling of task performance to identify neuro-cognitive processes that mediate the influence of genes on ADHD symptoms. Modelling neuro-cognitive functioning will improve the understanding of ADHD and contribute to the definition of phenotypes that facilitate the detection of genetic contributions to ADHD.
B2887 - Comparing outcomes in adults who were looked after or adopted as children - 17/05/2017
Looked after children are amongst the most vulnerable in society. They have experienced adversity in their family life at a level which necessitated the involvement of social services, resulting in the local authority taking on parental responsibility, and usually their removal from the family home. These children are known to do worse than their peers across many domains, including education, mental health, and social support. Fewer studies have considered later adulthood, and how the adversities faced by people who experience being in care as children persist or change over time. A minority of children are adopted from care, with the aim of giving them a permanent new family. Few studies have compared outcomes in adults who were adopted to those who remained looked after.
B2885 - Research to support an inquiry into young peoples future health prospects - 02/06/2017
This project will add to the evidence base on the relationship between health, socioeconomic factors, and service usage in young people. We will employ a holistic definition of health encompassing factors related to emotional well-being, housing, employment and employment prospects, health behaviours and general health. The outputs will be designed to be easily understood and be usable for a wide range of stakeholders. A key aim of this study is identify how socioeconomic inequalities may impact on health outcomes to identify vulnerable groups which may need additional support to reach their full potential. Work package 1 will be divided into two phases. The first stage will be a scoping review. The scoping review will provide an overview of the factors that impact on young people’s health. The second stage will explore how survey and administrative data can be used for statistical analysis to determine:
A1) The relationship between economic and social factors on young people’s health
A2) Provide preliminary analysis of how access to key services may impact on the young people’s social determinants of health
A3) Map young people’s service use in their adolescence and young adulthood in relation to their health and economic and social factors.
B2882 - Haptoglobin and cardiovascular disease - 10/05/2017
Haptoglobin is one of the most abundant proteins in blood, and plays a role in protecting the body from harmful effects of another blood protein, haemoglobin. Haptoglobin may play an important role in altering the severity of outcomes after brain haemorrhage. We will use the ALSPAC cohort to measure the effects of genetic variants on the levels of haptoglobin. These genetic variants will then be used in a separate study to determine whether haptoglobin levels affect the severity or consequences of brain haemorrhage.
B2881 - Understanding the Antecedents and Outcomes of Adolescent Cannabis Use Trajectories - 23/05/2017
Globally, cannabis is the most commonly used illicit drug. As cannabis policy is liberalising, there is an expected increase in adolescent use. This introduces an urgent need to understand what underlies harmful use, and to understand if cannabis plays a role in mental health disorder development. A key consideration in understanding the health impacts of cannabis is frequency of use. Cannabis dependence, characterised by loss of control over use and poor health and social functioning is more likely with frequent use. Yet, we know little about what factors determine frequency of use (and thus likelihood of related harm) among adolescents; a group in which use is high (40-70% prevalence), and for whom frequent use may lead to particularly poor mental health outcomes, including depression and anxiety
This fellowship will investigate trajectories of cannabis use among adolescents in the general population, exploring the role of Early Life Stress (ELS; a consistent correlate of use and dependence) in frequent cannabis use.
B2877 - Understanding the role of community and structural disadvantages in the perpetration of intimate partner violence against women - 22/05/2017
The most common form of violence perpetrated against women is intimate partner violence (IPV), which is the act or threat of physical, psychological, or sexual harm by a current or former partner. This project proposes to investigate how community and structural disadvantages increase the risk of IPV and inform effective prevention strategies. In particular, we define community disadvantages as negative conditions in the community environment, such as community-level crime and unemployment, and structural disadvantages as markers of low social status at the individual level that are determined by social, political, and economic structures, such as having a low income or low education. Exposure to community and structural violence and deprivation may cause or exacerbate violence in relationships by normalising psychological and physical aggression, decreasing the capacity or will for intervention into ‘domestic affairs’, or increasing life stress and trauma. Yet to our knowledge there are few studies that have tested whether structural disadvantages precede and are associated with IPV against women over time and no longitudinal study that has tested how the community environment may affect IPV among women outside the United States.
Our project will have four stages. First, we will examine whether greater exposure to negative community conditions, such as community crime and unemployment, over time leads to the experience of intimate partner violence in young adulthood. Second, we will test whether the effects of negative community exposures on IPV are amplified when individuals have experienced structural disadvantages over time, such as low socioeconomic status. Third, we will investigate whether community and structural contexts affect IPV by influencing broader individual- and family-level conditions such as substance misuse, mental health, and family environments in childhood. Finally, we will analyse whether these effects vary based on whether a person is male or female or the victim or perpetrator of violence.
B2879 - Questionnaire for dietary preference - 05/05/2017
This project seeks to undertake collection of data from a questionnaire of dietary preference at the next ALSPAC (young adult) questionnaire sweep.
B2878 - Variation in Age at Menarche A Test of Evolutionary Hypotheses - 27/04/2017
The onset of female reproductive potential (menarche) is an important stage in women’s development, resulting in both profound biological and socio-cultural change. Several studies have indicated that age at menarche is associated with father absence, in that females who do not live with their father in childhood reach reproductive age faster (Moffitt et al., 1992). These findings present an evolutionary puzzle as decreased parental investment, such as resulting from an absent father, ought to negatively impact offspring fitness, resulting in delayed reproduction. One set of adaptive explanations (Belsky et al., 1991) suggests that individuals alter their reproductive decision-making based on early-life adversity, such as father absence, as this is a cue for a high-mortality environment, in which case earlier reproduction may increase reproductive success. However, a recent alternative adaptive theory based on inclusive fitness considerations suggests that these father absence effects reflect the conflict between investing in one’s own reproduction (for direct fitness benefits) and investing in their mother’s reproduction (i.e., investing in siblings for indirect fitness benefits). Children are more likely to forego reproduction and invest in siblings if these are full siblings, due to higher relatedness coefficients, while with half- or step-siblings, which would be associated with father absence, children are more likely to invest in their own reproduction (Moya & Sear, 2014). To date, no tests of these competing hypotheses have been conducted. I therefore aim to explore the relative merits of each of these adaptive theories for the observed accelerated reproductive timing associated with father absence.
B2880 - Assessing causality in metabolic systems - 27/04/2017
B2876 - Contribution of eQTL analysis to international collaboration - 24/04/2017
Understanding how genetic variation influences gene expression is important for understanding disease. A large international consortium is performing a meta analysis of genetic influences on gene expression (eQTLs), and the ALSPAC study can contribute. It will involve performing the analysis and sharing the summary results only. No individual level data will be shared.
B2867 - SERPINA1 gene polymorphisms and preschool wheezing phenotypes - 30/06/2017
Wheezing in preschool children is a common problem worldwide, affecting up to 50% of children under the age of 6 years [1]. Preschool wheezing is a heterogeneous group of diseases and various cohort studies (including ALSPAC) have proposed a number of phenotypes that differ in time-course, associated factors such as atopy and risk of asthma in later life [2].
The importance of identifying the phenotype in a wheezing child is apparent because of parental concern, treatment considerations, and long-term prognosis. A complex approach to a wheezy child is often needed and includes clinical course (including frequency and severity of individual episodes), family history of asthma and atopy, various biomarkers such as blood and nasal secretion eosinophils [3,4], total and specific IgE [5], exhaled fraction of nitric oxide [6], ICAM1 [7], and other exhaled breath condensate markers [8]. There are data that chronic obstructive diseases in adulthood, including asthma and COPD, start in childhood [9] and indeed the features of certain preschool wheezing phenotypes are similar to those of COPD [10].
Alpha-1 antitrypsin (AAT) is the major genetic factor of chronic obstructive pulmonary disease (COPD) [11]. More than three million people die each year due to COPD and about 90% of COPD-related deaths happen in low-income countries. It is the third most common condition to cause death in the United States [12]. More than 235 million people have asthma which is the most common chronic disease in childhood (WHO data, 2017; http://www.who.int/respiratory/en/). There is no curative treatment for COPD.
Since alpha-1 antitrypsin also exhibits numerous immunomodulatory functions and suppresses inflammatory response, all these features may play a role in the pathogenesis of preschool wheezing.
AAT’s primary function is inhibition of proteases but it has other functions apart from protease inhibition [13] and is involved in the inflammatory processes [14]. It has been noted that oxidative stress is of greater magnitude in children with variant AAT alleles [15] and the Pi*Z type has proinflammatory properties [16]. Protease inhibitors (including AAT) are thought to be involved in childhood asthma exacerbations [17]. It has also been suggested that COPD patients who are heterozygotes (MZ genotype) had experienced wheezing in early childhood but were symptom-free until late adulthood and developed COPD. All these findings suggest that AAT may play a role in the development of preschool wheezing disorders.
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2. Lasso-Pirot A, Delgado-Villalta S, Spanier AJ. Early childhood wheezers: identifying asthma in later life. J Asthma Allergy. 2015;8: 63–73. doi:10.2147/JAA.S70066
3. Just J, Belfar S, Wanin S, Pribil C, Grimfeld A, Duru G. Impact of innate and environmental factors on wheezing persistence during childhood. J Asthma. 2010;47: 412–416. doi:10.3109/02770900903584035
4. Shinohara M, Wakiguchi H, Saito H, Matsumoto K. Presence of eosinophils in nasal secretion during acute respiratory tract infection in young children predicts subsequent wheezing within two months. Allergol Int. 2008;57: 359–365. doi:10.2332/allergolint.O-08-544
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6. Shim JY. Association of wheezing phenotypes with fractional exhaled nitric oxide in children. Korean J Pediatr. 2014;57: 211–216. doi:10.3345/kjp.2014.57.5.211
7. Klaassen EMM, van de Kant KDG, Jöbsis Q, Penders J, van Schooten FJ, Quaak M, et al. Integrative genomic analysis identifies a role for intercellular adhesion molecule 1 in childhood asthma. Pediatr Allergy Immunol. 2014;25: 166–172. doi:10.1111/pai.12187
8. van de Kant KDG, Jansen MA, Klaassen EMM, van der Grinten CP, Rijkers GT, Muris JWM, et al. Elevated inflammatory markers at preschool age precede persistent wheezing at school age. Pediatr Allergy Immunol. 2012;23: 259–264. doi:10.1111/j.1399-3038.2011.01244.x
9. Martinez FD. Early-Life Origins of Chronic Obstructive Pulmonary Disease. N Engl J Med. 2016;375: 871–878. doi:10.1056/NEJMra1603287
10. Kerkhof M, Boezen HM, Granell R, Wijga AH, Brunekreef B, Smit HA, et al. Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes. J Allergy Clin Immunol. 2014/1;133: 68–76.e4. doi:10.1016/j.jaci.2013.06.004
11. Stoller JK, Aboussouan LS. A Review of α1-Antitrypsin Deficiency. Am J Respir Crit Care Med. 02/2012;185: 246–259. doi:10.1164/rccm.201108-1428CI
12. Kochanek KD, Murphy SL, Xu J, Arias E. Mortality in the United States, 2013. NCHS Data Brief. 2014; 1–8. Available: https://www.ncbi.nlm.nih.gov/pubmed/25549183
13. Jonigk D, Al-Omari M, Maegel L, Müller M, Izykowski N, Hong J, et al. Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase. Proc Natl Acad Sci U S A. 2013;110: 15007–15012. doi:10.1073/pnas.1309648110
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17. Nishioka T, Uchida K, Meno K, Ishii T, Aoki T, Imada Y, et al. Alpha-1-antitrypsin and complement component C7 are involved in asthma exacerbation. Proteomics Clin Appl. 2008;2: 46–54. doi:10.1002/prca.200780065
B2858 - 24-hour ambulatory measures of blood pressure and their association with cardiac structure and function in adolescents - 19/04/2017
Although cardiovascular disease (CVD) generally manifests in adulthood, the development of cardiovascular pathology is known to start in early life. Higher mean blood pressure (BP) is an established risk factor for CVD. The magnitude of association for BP measured in adolescence/early adulthood with CVD incidence and mortality is the same as the association for BP measured in mid-life or older adulthood, with evidence from prospective cohort studies, RCTs and Mendelian Randomization highlighting the importance of cumulative risk with longer duration of high BP, and the importance of early life interventions to prevent age-related increases. Studies in adults have also demonstrated that greater within-individual variability of BP over a 24-hour period is a risk factor for CVD independently of mean level. BP ‘dipping’ is the degree to which BP is lower during the night compared with the daytime; lower dipping is also associated with CVD risk independent of mean BP level. Much less is known about BP variability and BP dipping within children and adolescents, with the available evidence coming from a small number of studies from the USA.