Proposal summaries
B2413 - Impact of environmental exposures on sperm parameters and male fertility - 09/04/2015
Infertility is a significant health problem worldwide, estimated to affect approximately 1:6 couples of reproductive age. Whilst reports of global declines in semen quality are controversial, the increasing prevalence of male subfertility stands as uncontested fact: male factor is now the leading cause of fertility problems, and accounts for almost half of all cases. Exposure to environmental toxicants, such as heavy metals, organic solvents and pesticides, as well as lifestyle choices, including obesity and poor diet, drugs (prescribed medication and otherwise) and smoking are all suggested to be contributory causes to male subfertility, but effects are poorly defined. Unexplained poor sperm motility (asthenozoospermia) is the commonest clinical abnormality in subfertile males, yet our limited knowledge of the exact workings of spermatozoa mean that this problem is incompletely understood, neither do we know how to correct it. Incredibly, there is no drug that a subfertile man can take, nor that can be added to his sperm in vitro, to improve sperm motility. Couples instead rely on Artificial Reproduction Technology (ART), such as IVF, which is expensive, invasive and not without risk. Nonetheless, year-on-year, ART is increasingly utilised worldwide. In order to tackle a global health problem, there is clearly a need to better understand the pathological processes affecting male reproductive health.
Sperm motility, calcium and CatSper
Sperm motility is arguably the most important characteristic to impact on male fertility. Increase and fluxes in intracellular calcium [Ca2+]i are fundamental to the regulation of sperm motility and function, including changes in direction, hyperactivation and chemotaxis. [Ca2+]i is regulated by at least two processes: mobilisation of Ca2+ stored in the sperm neck region and/or movement into the cell via Ca2+ permeable ion channels and transporters, mainly CatSper channels. CatSper channels are essential for male fertility and are present in the flagellum of human sperm. Landmark studies have demonstrated Ca2+ entry into human sperm in response to progesterone (a product of cumulus cells) is via CatSper channels. CatSper channels are also activated by organic molecules that apparently evoke chemotaxis, and it has therefore been proposed that this ion channel acts as a polymodal chemosensor integrating multiple chemical cues from the female reproductive tract to elicit functional responses to direct sperm towards the egg.
Environmental exposures
Xenobiotics are any alien molecules that are foreign to mammalian biological systems. Such substances include pesticides, herbicides, cosmetics, preservatives, cleaning materials and pharmaceutical products, and have worked their way into our lives in a variety of forms. Even though awareness of the biological risks of chemical toxicity has increased considerably in recent years, the majority of these chemicals have long half-lives and can still be detected in the environment decades after their release. Xenobiotics may have direct or indirect effects on sperm motility and function, including interference with physiological CatSper responses, which subsequently manifests as male subfertility. For example, dichlorodiphenyldichloroethylene (DDE) is an organochlorine pesticide, an endocrine disruptor and known reproductive toxicant to certain species of birds due to thinning of their eggshells. DDE is fat soluble, and tends to build up in the fat of animals. Due to its stability in fat, DDE is rarely excreted from the body, and body levels tend to increase throughout life. In vitro exposure to DDE affects functional sperm parameters and we have demonstrated that it activates CatSper at environmentally relevant concentrations.
Trans-generational reproductive impact
For many disease states it is now recognised that the risk of disease in adult life is determined by a combination of genetics, the intra-uterine environment, childhood exposures and adult lifestyle, but the impact of each of these components on sperm parameters and male fertility is largely unknown. The impact of environmental factors on the epigenome and male fertility, and significance of epigenetic changes/aberrations (often hypermethylation) in assisted reproduction are beginning to be understood. However, identification of the respective contribution of genetic and timecourse environmental exposures to male reproductive capacity in adulthood is not only very limited, but also very challenging, particularly due to the difficulty of obtaining data on multiple factors throughout life.
Aims
By utilising the Avon Longitudinal Study of Pregnancy and Children (ALSPAC) cohort, we aim to address the contribution of genetic and timecourse environmental exposures to male reproductive capacity in adulthood. This cohort is a huge resource and has the fantastic potential to provide prospective longitudinal data, allowing not only quantification of relative contributions of various elements, but the potential to identify critical timepoints and how these associations change with progression from fetal life, childhood, adolescence and into adult life.
B2412 - Maternal Smoking During Pregnancy andChildhood Obesity linear association or threshold effect An IPD Meta-Analysis - 09/04/2015
Aims:
A positive association between maternal smoking in pregnancy and childhood obesity has been confirmed in a number of meta-analyses of observational studies (Oken, Levitan et al. 2008, Ino 2010, Weng, Redsell et al. 2012). This empirical evidence for a causal association between intrauterine exposure to nicotine and childhood overweight later in life, however, has been questioned because of potential residual confounding (Raum, Kupper-Nybelen et al. 2011, Yang, Decker et al. 2013). Major concerns regarding possible residual confounding were based on the observation that children who were exposed to paternal or secondhand smoking while in utero as well as after pregnancy also had an increased risk of being overweight, and that this risk was similar to that observed in children with maternal intrauterine exposure to much higher levels of nicotine or other smoked products (Leary, Smith et al. 2006, Kleiser, Schaffrath Rosario et al. 2009, Plachta-Danielzik, Kehden et al. 2012, Harris, Willett et al. 2013). These results were surprising given that second-hand environmental tobacco smoke (ETS) exposure is not necessarily considered an intrauterine exposure, and the associated exposure dose of nicotine is much lower compared to that seen with direct maternal smoking (Florescu, Ferrence et al. 2007). Although mutual adjustment did not eliminate the effect of maternal smoking (Leary, Smith et al. 2006, Apfelbacher, Loerbroks et al. 2008, von Kries, Bolte et al. 2008, Kleiser, Schaffrath Rosario et al. 2009), the persistence of a similar effect size from paternal smoking either during or after pregnancy on childhood overweight raises concern about the potential of both ETS and maternal smoking in pregnancy to affect childhood overweight, and might be a reflection of a common unidentified family characteristic accounting for residual confounding, such as genetic or environmental factors, which could explain the effects of both paternal and maternal smoking during pregnancy.
An alternative explanation might be that there exists a very low threshold of smoke exposure from either father or mother leading to a priming effect that increases a child's risk to become overweight later on in life: in this case, the low exposure from ETS or paternal smoking would be sufficient for the priming effect and a linear dose effect of maternal smoking in pregnancy would not be observed. Indeed, it is still unclear whether or not a linear dose effect of maternal smoking on childhood overweight exists. Some studies suggest that a linear dose effect does exist (Power and Jefferis 2002, Hill, Shen et al. 2005), however, most confidence limits of the dose-related effect estimates overlap widely. The associations observed in other studies suggest instead a threshold effect, with a steep increase in effect at low exposure levels that flattens out at higher exposure levels (Reilly, Armstrong et al. 2005, Chen, Pennell et al. 2006).
Assuming a threshold effect, exposure to paternal smoking and ETS levels above the threshold could yield similar effects on childhood obesity as maternal smoking exposure in pregnancy, which would be compatible with the concept that low dose smoking exposure leads to an intrauterine priming effect which increases the offspring's risk to become overweight later on in life. This individual patient data (IPD) meta-analysis aims to identify whether a linear dose-effect relationship exists for maternal smoking during pregnancy on childhood obesity.
B2411 - Environmental risk factors of health-risk behaviours Using DNA to strenghten causal inference - 26/03/2015
Health-risk behaviours - here including alcohol, tobacco, drug use, risk taking and antisocial behaviour - are prevalent in early adulthood and highly comorbid. They constitute a major public health challenge impacting individuals, families and society. Identifying environmental risk factors causally associated with health-risk behaviours is crucial to design effective interventions.
The main objective of the proposed research project is to identify environmental risk factors causally associated with health-risk behaviours in emerging adulthood. To achieve this aim, the project will build on advances in genetics, using DNA information to strengthen causal inference.
The project will largely build on already collected data and, pending on funding may include additional data collection regarding health risk behaviours and environmental risk in early adulthood.
The project will investigate three major questions:
1. Comorbidity between health-risk behaviours: We will test whether the observed comorbidity within health-risk behaviours is due to underlying causal relationships or arises from genetic and environmental confounding (for instance alcohol use and antisocial behaviour).
2. Magnitude and consequences of gene-environment correlations: We will examine gene-environment correlations by looking at genetic influences on environmental risk factors (e.g. neighbourhood safety). We will then test to what extent the relationship between risk factors and health-risk behaviours may arise from shared genetic influences.
3. Early and concurrent environmental predictors: We will build on the longitudinal feature of the datasets to examine how early and concurrent risk-factors predict health-risk behaviours. We will contrast conventional analyses and classical techniques to examine causality with analyses using DNA information to strengthen causal inference.
B2410 - Investigating causal associations between caffeine consumption and ADHD - 26/03/2015
Aims:
An association between caffeine consumption and ADHD is well-established, but whether this is causal is harder to ascertain. In particular the direction of any causal association is unclear. We will use Mendelian randomisation to assess the association between a risk score predicting caffeine consumption and ADHD, and between a risk score predicting ADHD and caffeine consumption.
B2409 - Exploring the heritability of facial features in fathers and offspring using spatially-dense geometric morphometrics - 19/03/2015
Background
The face is a biological display of our identity and controlled in the most part by genes.1-3 There is consistent facial concordance between identical twins,4 identifiable facial features within families,5 geographic populations,6 and the sexes,7 and finally distinctive facial features associated with particular genetic conditions.8,9 This suggests that inter-individual variation in craniofacial morphology is primarily determined by genetic variation.
Studies of craniofacial heritability are performed on twin and parent-offspring databases and provide insight in the relative contribution of genetic and environmental effects on craniofacial parameters.4,5,10,11 Heritability studies allow the focus on those facial parameters displaying a strong genetic component as well as acknowledging possible environmental influences. Most if not all studies on craniofacial heritability start from sparse descriptions of facial shape using a limited set of manually indicated landmarks. Variation in these landmarks is then comprised using principal component analysis or by measuring geometric features such as distances, curvature, ratios and/or angles. Subsequently, for each principal component or geometric feature separately a heritability score is computed using correlations between parent and offspring or between twins. However, sparse representations typically overlook salient features of facial shape. Furthermore, heritability studies today do not investigate co-inheritance between different geometric features. Doing so would allow subdivision of facial shape into modules (multiple landmarks and measurements grouped together) of co-inheritance, that when analyzed as groups could reveal higher levels of inheritance.
Research Aim
The aim of this proposal is to perform a spatially-dense analysis of facial heritability and co-heritability starting with Fathers and offspring data available within ALSPAC. The study outcome is two-fold. In a first instance a spatially dense view on facial heritability per landmark will be provided. In a second instance, a subdivision of facial shape into modules of co-inheritance will be provided. Subsequently, the benefit of such a modularization will be tested in a limited association study between facial shape and known craniofacial genes based on BRIM.12
B2408 - An investigation into the determinants of fatigue in a population-based cohort of young adults - 19/03/2015
Hypotheses
1. Musculoskeletal phenotypes during adolescence (particularly pain, joint hypermobility, muscle morphology) are associated with chronic fatigue as an adult. This association will be influenced by anxiety/depression, obesity and gender.
2. There are subdivisions of the musculoskeletal fatigue phenotype with different risk factors and potentially different responses to interventions.
3. There is intergenerational transmission of fatigue vulnerability.
Aims and purpose
Aim 1: To stratify adults at aged 24 with fatigue into various fatigue phenotypes based on associated features including musculoskeletal variables, sleep disturbance, mood disturbance. We will investigate the overlap, basic descriptives and epidemiology of these fatigue phenotypes.
Aim 2: To further our understanding of the association between musculoskeletal variables (specifically musculoskeletal pain, joint hypermobility and muscle morphology) and fatigue in adults, by assessing whether musculoskeletal phenotypes at aged 13.5 are associated with fatigue in adulthood.
Aim 3: To explore causal pathways between anxiety/depression, musculoskeletal phenotypes and fatigue in adults.
Aim 4: To investigate whether the various fatigue phenotypes identified in Aim 1 (e.g. fatigue alone, fatigue+pain, fatigue+hypermobility, fatigue+obesity, fatigue+reduced muscle mass/density, fatigue+mood disturbance) have different risk factor profiles and causal pathways.
Aim 5: To produce the first population-based data on the change in prevalence (natural history) of fatigue between aged 17.8 and aged 24. We will describe the trajectories of fatigue over 6 years to define whether fatigue regresses, progresses or remains stable.
Aim 6: To carry out the first investigation of the intergenerational effects of fatigue by identifying whether parental fatigue phenotypes are transmitted to offspring, whether particular parental characteristics increase the likelihood of transmission of fatigue, and whether particular offspring characteristics increase vulnerability to transmission of fatigue.
B2407 - Effects of smoking during pregnancy on offsprings autistic traits mediation by DNA methylation - 12/03/2015
Background: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterised by deficits in social interaction and repetitive and stereotyped interests and behaviours. The aetiology ot ASD comprises known genetic factors [1,2] and increasing evidence suggests a role for intrauterine environmental factors, such as exposure to maternal smoking during pregnancy [3]. Maternal smoking during pregnancy has been associated with other adverse perinatal outcome such as lower birth weight and higher risk of other neurodevelopmental disorders such as attention deficit hyperactivity disorder [5], therefore smoking during pregnancy is a biologically plausible hypothesis in the aetiology of autism but the evidence is still inconsistent. Epigenetics is one potential mechanism linking intrauterine exposures and postnatal outcomes. DNA methylation changes induced by the prenatal exposure could affect genes that are implicated in the aetiology of ASD and therefore DNA methylation could be a causal mediator for the increase risk of ASD. A recent study in the ALSPAC has shown that maternal smoking is associated to DNA methylation changes across the genome, including the replication of genes that were found in other cohorts and new targets [6]. Although an association between maternal smoking in pregnancy and autism might be plausible, there is much inconsistencies in studies to date. In particular, when investigating causal effects in observational studies there is the possibility of unobserved and residual confounding and a way to overcome this issue is by using genetic variants as proxies for the exposure as in a Mendelian Randomization framework [7]. GWAS studies have observed robust associations between smoking and a locus on chromosome 15 involving the CHRNA3 gene, as well as associations in other genes such as BDNF [8].
Aim: We aim to investigate the causal relationship between maternal smoking during pregnancy and childhood's autistic traits and whether this is mediated via DNA methylation changes at birth.
B2406 - A Mendelian Randomisation study of Skin tone and Vitamin D - 12/03/2015
In this project I will examine the association between Skin tone, Vitamin D levels and a range of health outcomes. It has been shown in previous studies using ALSPAC data (Bonilla et al 2014) that children who had genetic variants associated with fairer skin have higher vitamin D levels. I wish to test the hypothesis that children with fairer skin will have lower BMI and blood pressure once the vitamin D levels have been controlled for. In this study I will use Instrumental Variables analysis to examine the effect of Skin tone and Vitamin D levels on a range of health outcomes such as BMI and blood pressure using the genetic variants associated with skin tone and Vitamin D levels to control for potential confounding in this estimation. Due to potential confounding in this study I will also control for time spent in the sun and whether or not a child has ever been sunburnt using questionnaire results, the gender of the child and the ethnicity of the child.
In this project I would also like to use the genotype data for the mothers to test the association between the fairer skin/higher vitamin D levels and the outcomes BMI and Blood pressure in female adults using Instrumental Variable Analysis and two sample Mendelian Randomisation. This analysis will test the same hypothesis as the analysis of the child data however rather than using Instrumental Variable analysis to assess the effect of skin tone on the outcomes considered I will use two sample Mendelian Randomisation to test the hypothesis that the SNPs shown to be associated in other studies with skin tone have an effect on BMI and Blood pressure. To control for additional confounding in this analysis I will also control for the age and ethnicity of the mother.
Levels of Vitamin D in individuals vary over the year and so in each of the analyses above I intend to control for the time of year at which the Vitamin D levels where sampled in order to control for any variation caused by differences in the season of sampling. Another source of potential confounding in this data is from population stratification due to systematic differences in the frequency of alleles for skin tone across different sections of the population. Therefore, I will control for additional potential population stratification in the data using Principal Components analysis of the genotype data.
I would like to use ALSPAC for this analysis due to the availability of the phenotypes and genotypes needed for this analysis in both children and mothers enabling analysis of the relationship between skin tone, Vitamin D and BMI/blood pressure in both children and adults.
B2402 - An examination of the association between school engagement at 10-11 yrs and sexual health and behaviours at 21 yrs - 05/03/2015
Background
Identifying factors in childhood that are associated with later poor sexual health (e.g. early sexual behaviour, sexually transmitted infections, and teenage pregnancy) may be valuable in recognising and targeting populations at risk (Parkes et al., 2014). Lower school grades and school adjustment problems in childhood have been proposed as potentially important determinants of early sexual initiation (Zimmer-Gembeck et al., 2008), and recent studies using ALSPAC data found persistent school dislike in primary school to be associated with early sexual behaviour and sexual risk taking, reported at age 15 years (Parkes et al., 2014) and low educational attainment at 11 years to be associated with Chlamydia infection at 18 years (Crichton et al., 2014). We wish to extend this work, to examine the association between school academic achievement and school engagement in childhood with sexual health outcomes reported at age 21 years.
Aim
To determine if academic achievement or school engagement in Year 6 (age 10-11 years, final year of primary school) predict self-reported sexual health/behaviours at age 21 years.
B2401 - Maternal substance use in pregnancy and childs educational attainment at age 16 years - 05/03/2015
Background
Two previous studies using ALSPAC data have examined the association between prenatal alcohol exposure and educational perfomance at Key Stage 2 (the last year of primary school, aged 11 years approximately). One study contrasted maternal and paternal alcohol intake in pregnancy, and found that maternal binge drinking was associated with lower KS2 scores but paternal binge drinking was not, thus suggesting an intrauterine mechanism (Alati, 2013). In support of this, a second study found children of mothers whose genotype predisposed them to lower alcohol consumption during pregnancy had a better performance at KS2 than the children of mothers whose genotype predisposed to heavier drinking; a finding which suggests positive associations in observational studies between self-reported moderate alcohol intake in pregnancy and child's educational attainment are explained by residual confounding by factors associated with socio-economic position (Zuccolo, 2013).
Prenatal cannabis exposure has also been shown to have a negative effect on intellectual development at age 6 (Goldschmidt, 2008), resulting in lower educational attainment at age 14 years (Goldschmidt, 2012). This association has not previously been explored using ALSPAC data. Intrauterine exposure to tobacco smoke and child's IQ at 8 has been studies using ALSPAC; associations between maternal and paternal smoking and child's IQ were similar, suggesting any relationship between smoking in pregnancy and child's IQ may not explained by intrauterine exposure (Alati, 2008).
Aims
This proposed study would extend previous work to determine if any negative impact of intrauterine exposure to alcohol, cannabis or tobacco on educational attainment persists to Key Stage 4 (GCSEs, taken when aged 15-16 years). [The inclusion of cannabis as an exposure will depend on whether numbers are adequate].
B2400 - Lookup of methQTL signals for variants associated with anthropometric traits and identified in the UK10K project - 05/03/2015
The UK10K project represents one of the first large scale applications of next generation sequencing to population based epidemiological samples and the examination of complex phenotypes. The objectives of this work are to record whole genome sequence variation at and below 1% minor allele frequency, to provide an imputation reference and to use this, not only to provide a resource for the scientific community (both genotypes and phenotypes), but also to examine genetic associations across a spectrum of genetic variation.
The study is composed of two samples drawn from European population based epidemiological studies (The Avon Longitudinal Study of Parents and children and Twins UK) and forms a collection of nearly 4000 participants now with whole genome sequence data and phenotypes (along with complementary imputed internal replication data sets). A total of 1,990 individuals from TwinsUK and 2,040 individuals from ALSPAC were consented for sequencing. Variant sites and genotype likelihoods were called using samtools and genotypes were refined and phased using BEAGLE, with similar procedures to the 1000 Genomes Project.
In addition, both ALSPAC and TwinsUK consented to release phenotype data related to cardiovascular disease as a public resource for the association analyses. Twelve anthropometric traits including height, weight, BMI, waist-hip-ratio, waist-hip-ratio (BMIadj), waist circumference, waist circumference (BMIadj), hip circumference and hip circumference (BMI adj) and DXA measures (total fat mass, total lean mass and trunk fat mass) phenotypes were released. The association analyses for the anthropometric traits are currently reaching a critical phase for the singlepoint associations, and also for those more rare variants with analyses being undertaken using variant aggregation techniques such as SKAT. Consequently, we are following up possible avenues for unraveling the underlying molecular mechanism of the identified genetic associations. To this end, we are writing to seek a collaborative arrangement efforts to continue our analysis of both single point and rare variant associations using expression (already part of UK10K agreement) and methylation data.
B2399 - Association between brain anatomy and genetic risk for mental disorders in healthy volunteers - 05/03/2015
This project aims at combining multiple MRI datasets obtained in the same magnet (scanner) through very similar acquisiton procedures in order to investigate the association between anatomical markers and genetic risk factors for major mental disorders (psychosis, bipolar disorder and Alzheimer's disease) and associated polygenic pathway scores (e.g. dopaminergic transmission) in healthy participants. The combination of ALSPAC's and our own samples will constitute a unique resource to investigate neuroimaging and genetic associations, since it will include data from potentially up to 1,000 participants avoiding the counfounds of previous similar efforts from other groups using different magnets and not always equivalent data acquisition methods.
B2398 - Genomics of Neuropsychiatric Traits in Children and Adolescents MRC IEU project - 05/03/2015
Aims & Hypotheses
The overall aim of our research is to identify genetic variants associated with a neuropsychiatric traits in children using community-based samples. We are interested in three specific traits: obsessive-compulsive traits, ADHD traits and response inhibition as measured by the Stop-Signal Task. Given that response inhibition is an endophenotype for ADHD, we expect that identifying genetic variants associated with response inhibition will also help us identify genetic variants associated with ADHD.
B2397 - Metabolomic profile of Familial hypercholesterolaemia - 05/03/2015
Familial hypercholesterolaemia (FH) is an inherited condition affecting at least one in 500, although current studies suggest that the frequency is much higher (1 in 250). Affected individuals are characterised by a significant increase of LDL cholesterol levels from birth. It is ussually caused by mutations in one of three genes (LDLR, APOB or PCSK9), however recently a polygenic cause of high LDL-C has been found to mimic the clinical FH phenotype. Our preliminary results showed that individuals with the polygenic form of FH have significantly higher triglyceride levels in comparison to the monogenic FH patients, which suggest that different metabolic pathways may be involved in the development of hypercholesterolaemia in these two forms of FH. We therefore would like to:
1) Compare the metabolomic profiles of the polygenic vs the monogenic FH to see if there are different pathways involved in the two groups
2) Focus on the known FH associated loci (LDLR and APOB) and compare the FH mutations versus common occuring polymorphisms in the same locus which have previously been associated with lipids in large scale association studies. This will help us test if the FH mutations are associated with metabolic changes different to those attributed to their genes in studies using healthy population samples.
Replication will be available through UCLEB where similar information is available.
B2403 - Unravelling the link between depression and violence in adolescents - 05/03/2015
Background
Depression is one of the most widespread mental health concerns in the world (Kessler & Bromet, 2013). It is often linked to inwardly directed harm such as self-injuries and suicide (Cuijpers et al., 2014; Hawton et al., 2012; Hawton et al., 2003). The association between depression and violence against others remains uncertain. Emerging evidence is showing that depression and violent behaviours are associated. Positive depression-violence associations have been reported in cross-sectional community survey and register-based investigations (Coid et al., 2006; Wallence et al., 1998; Swanson, 1990), and longitudinal cohort studies (Arseneault et al., 2000; Monahan et al., 1983). Recent research on a total population cohort has shown that risk of violent crime was increased in individuals with depression even after adjustment for familial, socio-demographic and individual factors (Fazel et al., 2015). To date, however, evidence regarding this link has been largely limited to adult and selected samples of individuals in secondary or tertiary care. It is not clear whether the magnitude of depression-violence link is different according to the developmental stages of an individual and whether it is related to more sensitive markers of the illness course. Further, it is not known the mechanisms of any association.
Aim: This project sets out to dissect the depression-violence link with a developmental perspective. Subsequently, this project proposes to test the moderating role of situational factors (i.e., stressful life events) and the mediating role of self-regulation abilities (i.e., inhibition, locus of control), self-harm, and peer victimization. The gained knowledge will be used to facilitate the development of tailor-made prevention and intervention strategies to mitigate the link between depression and violence.
B2395 - External validation of two studies on risk factors and prediction of childhood asthma - 26/02/2015
Background: We recently published two studies in which we developed a novel and robust tool for predicting asthma at school age in preschool children with wheeze or cough (REF1), and determined the association between breastfeeding and school-age lung function (REF2). The two studies made use of population-based cohorts from children of Leicestershire, United Kingdom.
Aim: We want to externally validate the findings of those two studies using the ALSPAC data set.
B2394 - Socioeconomic gradient of smoking comparing families where one or two parents smoke - 26/02/2015
We seek approval to repeat this analysis among the four English STELAR cohorts. Data requested are (at a given timepoint) socioeconomic status, number of smoking adults in the child's house, number of adults in the house (this addresses the issue of single parent families). In some of the cohorts, these outcomes may be available at more than one time point and this would allow us to see whether these observations are static or change over time.
B2393 - Using a genetic risk score for Coronary Artery Disease to investigate casusal influences on the metabolome - 19/02/2015
Multi-locus genetic risk profiles, or genetic risk scores (GRS) aggregate data from multiple SNPs to provide a robust genetic instrument for traits of interest. They are more powerful than single SNP GWAS scores as the use of multiple sites reduces the effects of pleitropy and minor allele frequencies. GRS have been developed for many conditions including CAD and obesity. They provide a useful genetic tool for probing the causal pathways of multifactorial diseases.
In this study we intend to use multiple GRSs developed from CARDioGRAMplusC4D SNPs as a genetic instrument of CAD to investigate associations between predictors of CAD and differences in metabolite profile in ALSPAC mothers and children. GRSs are the exposure variable in this case, and altered metabolite profile is the exposure. We will use a range of GRSs developed using varied SNP significance threshlds to demnstrate the robustness of GRSs a genetic instrument, while investigating the genetic influence on the metabolism at a pathway specific and global level.
Three GRSs for CAD will be produced based on highly strict, moderate, and lenient SNP significance thresholds using CARDioGRAMplusC4D data. A selection of the most significant SNPs will also be analysed seperately. The individual SNPs and strict GRS should reveal how specific SNPs or groups of SNPs influence isolated metabolic pathways related to CAD, while the more lenient GRSs demostrate the wider influence of genetic variants on global metabolism. These GRSs will be regressed against the top ten principle components of NMR metabolite data from mothers and children. Principle components that are significantly associated can then be deconstructed to reveal specific changes in metabolite levels. By using principle components instead of individual metabolite concentrations, the number of analyses is significantly reduced, and the components themselves may represent biologically meaningful metabolic pathways.
B2392 - Long-term outcomes of children with borderline personality disorder traits at 11-12 years - 19/02/2015
BACKGROUND: Recently there has been a growing body of research examining Borderline Personality Disorder in youth, i.e., childhood and adolescence (Hawes, 2014). Nevertheless, diagnosis in this age group remains controversial, partly due to concerns regarding the validity of the construct (Griffiths, 2011). Predictive validity reflects the degree to which BPD in youth is prognostic of future impairment, and is considered a crucial aspect of the validity of a construct (Van Os et al., 2009). While, a small body of literature has considered the stability of BPD symptoms over time, there are few studies that have examined the long-term clinical and psychosocial impacts of the disorder. The few studies that have reported negative outcomes in youth with BPD symptoms in community populations (e.g., Cohen et al., 2007; Winograd et al., 2008) utilised ad hoc, self-created assessments of BPD rather than established, validated tools. Furthermore, these studies did not consider the mechanistic pathways from early BPD symptoms to outcomes in late adolescence/early adulthood (e.g., do BPD symptoms increase risk of bullying exposure, subsequently heightening risk of depression symptoms?).
AIMS: To explore to what extent BPD symptoms at 11-12 years of age are predictive of future psychopathology and negative psychosocial outcomes, and to examine mechanisms via which increased risk manifests.
B2391 - Investigating putative risk factors for Alzheimers disease using Mendelian Randomization - 19/02/2015
The aim of this study to investigate the role of potential risk factors for Alzheimer's (AD) using Mendelian Randomization. Smoking, hypertension, increased body weight, dyslipidemia and type 2 diabetes have all been suggested as risk factors for AD but the results of epidemiological studies on them have been inconclusive.
In this project we are planning to use genetic variants that are robustly associated with the above exposures to test if they have a causal effect on AD through Mendelian randomization (MR). For blood pressure, BMI, lipids and type 2 diabetes the method of analysis will be a 2-sample MR in which the "reduced-form" estimate (the coefficient for the association between the IV and the outcome) and the "first-stage" estimate (the coefficient for the association between the IV and the exposure) are obtained from non-overlapping samples (Pierce and Burgess 2013). The instrumental variables for the MR analysis will consist of an allelic score calculated based on the results of independent genome-wide association studies of the above traits.
Polygenic risk scores will be calculated based on the results of published GWAS studies. These identified risk alleles will be used to calculate a polygenic score for each individual in an independent (target) sample (ALSPAC), corresponding to the mean number of score alleles (weighted by the logarithm of the odds ratio) across the set of SNPs, using PLINK. Standard linear regression models will be used to calculate coefficients for the association of the polygenic scores with the trait of interest in the ALSPAC target sample (first-stage coefficients). The reduced-form coefficients of the genetic variants/polygenic scores will be calculated in the International Genetics of Alzheimer's Project (IGAP) sample, which is independent of the target sample where the first-stage coefficients would be calculated. The IGAP sample is a collaboration of 4 groups in Europe and USA with approximately 60,000 individuals (either with AD or controls). Genetic data are available on all of them. We have obtained permission to perform this analysis in the IGAP sample.