Proposal summaries
B2335 - 10000 hours Children Childcare and Developmental Opportunity - 20/11/2014
Analysis of the ALSPAC data forms part of a larger grant application examining the genetic markers of phenotypic measures of emotional reactivity in early childcare settings. More specifically, the ALSPAC data will be used for the validation of a GWAS study examining associations with individual temprements and will form a cross-test of methodological reliability.
AIMS. The aims of the broader research program are to:
1.Characterise individual difference in child emotional reactivity through assessment of the the statistical association of genotype with physiological, observational, physiological, and report measures.
2.Examine the interaction of child emotional reactivity with qualities of the childcare environment to and assess impact on social-emotional regulation and behavioural development.
3.Identify the meaning of individual difference in children's reactivity for policy and practice in childcare settings.
The specific aims relevent to the use of the ALSPAC data will be to valiate genotypic markers identified within our target cohort, by examining the same geneotypes and their association with phenotypic variables of temprement, sleep, behaviour and behavioural diagnoses within the ALSPAC data set.
VARIABLES
Genotypes of interest will be ientified via an indepenent cohort study to be conducte as part of the grant application and are not known at this time. Phenotypic variables of interest will be temperament, behaviour, behavioural diagnoses and sleep characterisitcs. Socio-economic status and childcare charatersitics of the children are also requested.
B2334 - Effect of Socioeconomic Depreciation on Child Development A Longitudinal Study - 20/11/2014
Socioeconomic stability plays an important role in the normal development of a child. So, it is not surprising that adverse socioeconomic conditions arising from difficult financial circumstances have been associated with a number of mental health and cognitive problems. The motivation for the current line of thinking is a recent study published in JAMA: Psychiatry wherein we noted that macroeconomic shocks such as recessions can have long-term effects on the mental and emotional health of children between the ages of 0-18 months. Over the last two years, we have been expanding our work on the concept of socioeconomic depreciation (SED) or drop in family income. In this proposal, we will examine the mechanism behind the influence of SED on future behavior problems. Specifically, we are proposing that SED will affect attachment, which in turn will affect social development. Since attachment variables are not available in the ALSPAC data, ALSPAC will not be used to develop this particular hypothesis. However, ALSPAC will be used to explore the role of social development in future behavior problems. (Figure 1 available on request).
Secondly, we propose to explore the effects of prenatal exposure to SED. Borrowing from literature on fetal programming, we propose that prenatal exposure may lead to changes in temperament and increase vulnerability to behavior problems. Temperament has been described as a stable system of traits that moderates susceptibility to behavioral and emotional problems. In line with this argument, this study will examine if temperament moderates the link between SED and behavioral and emotional problems (Figure 2 available on request).
This proposal also extends our work into SED by testing for gene by environment interactions using the large public data sets from the Psychiatric Genomics Consortium (PGC). Because Dr. Faraone is on the PGC's Coordinating Committee, this aspect of the work will be straightforward. For each disorder, the PGC computed a SNP heritability, which indexes the amount of heritability due to common SNP variants. These SNP heritabilities were all much greater than zero and were statistically significant. These analyses also showed substantial and significant correlations between the heritabilities of some of these disorders. For example the correlation between schizophrenia and each of the mood disorders was greater than 0.4. This cross disorder polygenic overlap, along with prior evidence of overlap for single SNP variants and for CNVs, has confirmed prior work from genetic epidemiology indicating shared genetic risk factors among multiple psychiatric disorders. This work is relevant to genetic studies of SED because it allows us to create molecular polygenic scores for use in testing gene by environment interaction. These scores may explain, for example, whey two children raised in identical SED circumstances have different outcomes. When added to knowledge about SED, these genetic data could help allocate scarce resources where they are most urgently needed.
For this project, we propose to use ALSPAC. Details about our proposed work with ALSPAC are discussed below. ALSPAC data will be used to test the following hypotheses. The scientific outline (Section 8) provides a list of specific variables requested, and how those variables will be used in hypothesis testing. In that table, DV refers to Dependent (or Outcome) Variable, IV to Independent (or Exposure) Variable, MV to Moderating Variable, and CV to Confounding Variable.
B2333 - Association between asthma/allergies and depression/anxiety/self harm - 20/11/2014
Several reports indicate that asthma and depression co-occur(1). The association has been reported in countries with different social and cultural histories (2) suggesting a true association between these two conditions. In addition, some studies report a higher rate of suicide or suicide-related behaviours among asthma patients(3). Several pathways that include both directions of association (asthma leading to depression or depression leading to asthma) or common aetiological process that would increase the risk of both conditions have been proposed.
AIM. To determine whether there is an association between asthma/allergy and depression/anxiety/self-harm.
Specific objectives are:
1.Establish whether there is a cross-sectional association between asthma/atopy and depression/anxiety self-harm in children and adolescents.
2.Establish whether children with asthma/atopy have higher risk of developing depression/anxiety self-harm (prospective).
3.Establish whether cross-sectional and prospective associations between asthma and depression vary by gender.
4.Determine the pathways underpinning an association between asthma (and/or atopy) and depression (anxiety/self-harm).
B2332 - Autism sleep mental health parent distress and chronic pain in childhood - 20/11/2014
Aims:
To describe the prevalence of pain within those with diagnosed autistic spectrum disorder.
To describe the prevalence of pain within those with autistic like symptoms including social and communication difficulties, prematurity and delays reaching developmental milestones.
To explore if depression and anxiety are higher amongst those with autism and pain.
To explore if people with autism and pain suffer from sleep deprivation.
To explore how prevalent sleep deprivation is in people who present with persistant pain compared to those who present with autism and persistent pain.
To explore if sleep is dependant on anxiety scores in those with pain more than those without pain.
To explorwe if children with a diagnosed autistic spectrum disorder have other chronic sleep, pain or anxiety conditions.
B2331 - Translational Psychiatry - genetic variation and dysfunction of human ARC gene - 20/11/2014
The immediate early gene, ARC, is a key regulator of protein synthesis-dependent synaptic plasticity. Synaptic plasticity functions in memory as well as in adaptive changes related to fear, anxiety, and reward. Dysfunction of synaptic plasticity is increasingly implicated in neuropsychiatric conditions including depression, schizophrenia and autism spectrum disorders. Our recent work links several SNPs in Arc to cognitive function. We tested whether ARC variants are associated with six measures of cognitive functioning in two healthy samples-the Norwegian Cognitive NeuroGenetics (NCNG) sample and the Swedish Betula sample. Of a total 71 ARC variants, 21 were nominally associated with human cognitive functions involving semantic knowledge, visuospatial abilities, delayed episodic memory, and general cognitive abilities (IQ).
Preliminary meta-analysis of large-scale genome-wide association studies' (GWAS) results across two neuropsychiatric conditions showing the most genetic overlap - SCZ and BP (http://www.med.unc.edu/pgc) - reveals a synergetic effect of two SNPs located in the regulatory downstream 3' region of the ARC gene (rs7465272 and rs7835613, p = 2.31e-06 and 9.01e-06 respectively). Adding MDD to the joint meta-analysis further reinforces the involvement of one of those SNPs in the susceptibility to neuropsychiatric conditions (rs7835613, p = 7.90e-06). Taking these findings together with known neuronal functions of the ARC gene, we hypothesize that its genetic variants may accentuate such common genetic architecture of cognitive abilities in neuropsychiatric conditions.
Our planned analyses:
1. Genetic association of ARC gene complex with cognitive function (cross-sectional and longitudinal examination)
1.1 ARC gene and cognitive functioning
AIM AND HYPOTHESIS
Here we plan to perform regression analyses to investigate whether common ARC variants are associated with cognition or other aspects of brain plasticity. Since previous studies are suggestive to this association, we hypothesize that various aspects of cognition , plasticity, and/or neuropsychiatric disorders will be associated with ARC variants.
B2330 - An investigation of maternal risk factors for the development of paediatric obsessive-compulsive disorder - 13/11/2014
BACKGROUND:
Obsessive-compulsive disorder (OCD) commonly has its onset in childhood, affecting 1-4% of young people under the age of 18 (Douglass et al, 1995; Flament et al., 1988; Heyman et al, 2001) . The disorder is highly disabling across domains (Piacentini et al, 2003) and is predictive of a range of negative outcomes (Wewetzer et al., 2001; Micali et al, 2010). Furthermore, if left untreated the disorder typically follows a chronic course (Skoog & Skoog, 1999) and is major source of economic burden, ranking among the top 10 most disabling illnesses recognized by the World Health Organization (Murray & Lopez, 1996). There is a pressing need to further understand the mechanisms underlying the development and maintenance of pediatric OCD, in order to facilitate effective prevention and intervention.
OCD results from a complex interplay between genetic and environmental factors. Twin studies have shown that genetic factors explain 45-65% of the variance in OCD symptoms in children, with the remainder being accounted for by shared and non-shared environment (Pauls, 2008). The specific environmental risk factors remain unknown, but it has been proposed that aspects of family environment contribute to OCD (Van Noppen et al, 2009). Consistent with this, previous studies have demonstrated that parents of young people with OCD show elevated rates of critical and over-intrusive parenting styles (Barrett et al, 2002; Hibbs et al, 1991) and psychiatric disorders (Lenane et al, 1990). However, a major limitation of the research in this field to date is the reliance on cross-sectional designs, meaning that the direction of effects between childhood OCD and parenting style/parental psychopathology remain unclear. To date, no prospective studies have been conducted to test whether such family factors predict the onset of OCD in children.
AIMS:
This primary aim of this study is to test whether maternal parenting style and maternal psychopathology in early childhood predict the subsequent development of OCD symptoms in youth. A secondary aim is to test whether the persistence of OCD symptoms in young people is mediated by maternal parenting style and maternal pscyhopathology.
B2329 - Genic and intergenic heritability analysisof general cognitive ability - 13/11/2014
Aims
Genome Wide Complex Trait Analysis (GCTA) has been applied to Genome Wide Association Study (GWAS) data sets of cognitive ability to show that around half of the phenotypic variation is tagged by common variants (Davies et al., 2011). However, GCTA cannot provide information regarding which variants are more important. This study aims to find regions in the genome that make a significant contribution to the GCTA heritability estimate. Three groups of single nucleotide polymorphisms (SNPs) will be formed; the first group will consist of all SNPs available for use, the second set will consist of SNPs found in genes, whereas the third will be formed from SNPs that are found between genes. GCTA will be perfomed on each group allowing for both the genic and intergenic SNP-sets to be tested against 0 in order to determine if they each make a significant contribution toward intelligence differences. In addition the two groups will be compared against each other to show which regions matter most to human intelligence differences. Using GCTA in this way will help to show that variants within genes account for a significant proportion of the heritability of human intelligence. This will justify the use of gene and gene-set based analyses well as indicate which areas of the genome are of particular importance to cognitive ability.
Hypothesis
It is expected that for general cognitive ability both the geneic and the intergenic SNPs will make significant contributions to the total heritiability estimate. It is also expected that SNPs found within genes will also make a greater contribution toward the heritability estimates than SNPs found between genes as has been demonstrated for height (Yang et al., 2011) and indicated for schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014).
Exposure variables
GCTA has been performed previously on general cognitive ability in The Avon Longitudinal Study of Parents and Children (ALSPAC) group (Benyamin et al., 2013) as it has a suitably large sample size (5517 at age 9) and an execellent test to derive an Intelligence Quotent (IQ) estimate, namely the Wecshler Intelligence Scale for Children-III (WISC-III). For the proposed analyses to take place, the genotype data along with Verbal (Information, similarities, arithmetic, vocabulary, and comprehenssion) and Performance (picture completion, coding, picture arrangement. Block design, and object assembly) subscales of the WISC-III will be used to form an IQ score. GCTA analysis will be performed on this IQ score using all SNPs available for analysis. Next, the total set of SNPs will be divided into genic and intergenic SNP-sets before GCTA is performed on both SNP-sets.
Outcome variables
The proportion of phenotypic varainace attributable to the genetic variation in each of the three groups will form the outcome variable.
Confounding variables
One potential source of confounding would be that the two SNP-sets could tag the same variants due to the existence of linkage disequilibrium.
B2327 - Vitamin D in Pregnancy and Perinatal Depression - 12/11/2014
Background:
Results from a recent meta-analysis suggest that low Vitamin D levels are associated with depression1. As pregnancy is a time for increased nutritional demands, precipitation of depression would be more likely during pregnancy if this hypothetical association were causal. Low vitamin D levels are common during pregnancy, particularly in high-risk groups.2,3,4 Some studies have reported an association between low vitamin D levels and depressive symptoms during pregnancy5,6 and in the postnatal period.7,8,9 However, other studies have not supported this hypothesis.10 Previous studies have been limited by sample size7,9, identification of depression10, or follow up time to development of symptoms.5,6,8
Aims:
*To determine the relationship between vitamin D (serum 25-hydroxyvitamin D3 and D2) and perinatal depression.
*To personally develop research skills in preparation for applying for research fellowships
B2318 - Prenatal and early childhood environmental risk factors for psychiatric outcomes using a novel exposure biomarker - 06/11/2014
There is substantial evidence that early environmental insults increase risk for psychiatric disorders,
especially those with strong neurodevelopmental origins. Thus, there is a need to reliably identify these
environmental factors, as well as whether higher exposure level during critical periods for
neurodevelopment are related to greater risk for psychiatric disorders. Moreover, while environmental
toxins have been reliably associated with early neurodevelopment, similar investigations into longer term
and psychiatric outcomes are scarce.
Current approaches use indirect measures of fetal exposure, such as chemical concentrations in maternal
blood and urine, which may not accurately reflect fetal uptake for many toxins due to variable partitioning
across the placenta (Smith et al., 2007). Thus, a direct marker of early exposure is needed to aid our
understanding of the etiology of psychiatric disorders, as well as to aid prevention.
The current study proposes to use a unique and well-characterized birth cohort: the Avon Longitudinal
Study of Parents and Children (ALSPAC) and applying an extensively developed and piloted method to
determine multi-toxin early exposure (Arora et al., 2006, 2011; 2012; 2013; Hare et al., 2011; Austin et
al., 2013). Human deciduous teeth undergo systematic mineralization commencing prenatally and are
composed of a collagen-based, lipid-containing, calcium-rich apatite matrix, which accumulates bone
seeking elements and organic compounds. The methodology combines detailed histological analysis and
associated analytical tools to establish a comprehensive record of weekly to monthly exposure history of
multiple chemicals and metals and history of infections from the second trimester through early
childhood.
Aims
The overall goal of this project is to determine the association of early life environmental metal and
chemical toxin and infection exposures with multiple psychiatric and neurological outcomes: psychotic
like experiences, depression, mild cognitive impairment and autstic-like traits. A detailed history of
exposure during prenatal and early childhood development will be established to distinguish between two
important aspects of the exposure profile:
1) Exposure timing: We will construct weekly to monthly exposure history over the prenatal and early
childhood periods in order to identify the developmental period(s) most strongly associated with risk for
poor psychiatric and neurological outcomes.
2) Exposure intensity: Cumulative exposure may be more important than exposure during any single
developmental window and our biomarker allows measurement of cumulative exposure from the prenatal
period to the time of tooth shedding, which occurs between ages 6 to 12 years.
B2316 - Examining the long-term outcome of early onset depression in 10-13 year olds - 31/10/2014
Aims
1. To investigate the long-term outcomes of early onset depression in children affected at the ages of 10 and 13 years.
2. To examine the potential moderating effect of factors that might predict long-term outcome, including comorbid psychiatric disorder and family history of depression.
3. To examine the course and correlates of depressive symptoms and disorder across adolescence in boys.
Background
Depression in pre-adolescence is a serious, neglected disorder. It is common, has poor outcomes, and has been the subject of very little research. This project will investigate the course of early onset depression in a large population cohort study
B2315 - Bayesian individual knot point models for modelling growth - 31/10/2014
This project is IEU research, linked with Laura Howe's MRC fellowship and the IEU stats theme. Analysis will be carried out by Sam Brilleman with supervision from Laura Howe and Kate Tilling.
Aim: to evaluate the use of Bayesian individual knot point models for modelling growth across childhood and adolescence and estimating age of puberty onset, and to compare these models with alternative approaches such as SITAR
Exposure: age
Outcome: height and weight
Confounding variables: gender
Project justification: Self-reported measures of pubertal status can be inaccurate and there is often lots of missing data due to participant embarrassment. Height-based indices of pubertal development offer an attractive alternative that may be both more accurate and result in less missing data. In this project, we will use all available height and weight data to estimate trajectories of growth across childhood and adolescence, using models that allow person-specific ages at which the rate of growth changes. The idea is that the timing of these knowpoints may be informative about pubertal growth spurts. The models will be compared with other approaches to identifying pubertal growth spurts from growth trajectories, e.g. superimposition by translation and rotation (SITAR), a method developed by Tim Cole.
B2314 - Handling multivariate missingness in health and behaviour data via multiple imputation under MNAR Issues in Practice - 31/10/2014
BACKGROUND:
Data collected by ALSPAC to explore potential predictors of adolscent alcohol, tobacco and cannabis consumption exhibit substantial levels of missingness in both outcomes and covariates and are plausibly missing not at random (MNAR). This is also the case for data collected by ALSPAC to explore potential correlates of adolescent mental health. Standard maximum likelihood and Bayesian full probability modelling procedures can quickly become computationally infeasible in the presence of multivariate MNAR missingness. We propose to tackle this difficulty by extending a popular procedure for performing multiple imputation under MAR, Fully Conditional Specification, to handle MNAR missingness mechanisms. Our method will be broadly applicable to future analyses of the ALSPAC data and to both cross-sectional and longitudinal data.
AIMS:
1. To develop a new statistical method for handling datasets with multivariate MNAR missingness.
2. To use this new method to further explore the missing data mechanism for
a. key variables on alcohol, tobacco and cannabis use in teenagers.
b. key variables on mental health outcomes in teenagers.
B2326 - Recognising the hidden face of autismdefining the characteristics and needs of females with autistic difficulties - 23/10/2014
AIMS
We aim to discover:
1. The rates of ASD and of the broader autism phenotype in AT+ females, compared to AT+ males, AT- females and AT- males.
2. The rates of undiagnosed ASD in AT+ females, compared to AT+ males, and the characteristics across the lifespan that are associated with undiagnosed ASD.
3. The characteristics of the female autistic phenotype. To this end we will compare AT+ males and females on current and previous measures of social communication and inflexibility. We will also investigate whether the female autistic phenotpye reflects typical gender differences, by comparing gender differences for AT+ participants with gender differences for AT- participants.
4. The needs females with childhood autistic difficulties, by assessing mental health, well being and adaptive functioning of AT+ females across their childhood, adolescence and early adulthood.
5. Risk and protective factors in childhood that influence adult outcomes for women who have AT+ in childhood, by looking for associations between individual (e.g. childhood anxiety, IQ) and environmental (parenting, socio-economic status, educational provision) factors measured prospectively in ALSPAC.
B2313 - Participant views on research ethics in Children of the 90s supporting participant-aligned policy development - 23/10/2014
Introduction
The social context in which biomedical research occurs is constantly changing, eg. social media is reshaping views and expectations about individual privacy; understandings of health are constantly evolving. At the same time, new research technologies are becoming available with increasing rapidity, eg. new 'omics tools for analysis. Any change in society or technology may raise new ethical questions for studies such as ALSPAC and may have implications for the policies used to govern these studies.
New policy issues emerge relatively frequently but not necessarily in predictable patterns. Recently emerging issues of concern to cohort studies and biobanks internationally have included: return of incidental findings, recall by genotype, commercial funding in research and data sharing. Legislation proscribes some actions related to these emerging issues, (eg. EU Directive 95/46/EC: 'Protection of personal data', 2012), funder policy provides broad guidelines for policy (eg. MRC/Wellcome Trust 'Framework on the feedback of health-related findings in research', 2014), and individual studies produce in house policy (ALSPAC 'Disclosure of biomedical information to participants', 2011).
Transparency of study policies and practice, especially as new issues emerge, is axiomatic to building and maintaining trust. For longitudinal studies maintaining trust with their participants is crucial to the establishment and maintenance of the long term relationships that characterise these studies; relationships that are realised in participant retention. But extant trust is not enough. Policies must also continue to be sensitive to and aligned with participant (social) values and norms. One way to achieve this is to ensure meaningful engagement of participants in the issues that impact them. Children of the 90s has always been keen to involve participants in the research and ethical decisions made about the study. As part of that commitment the Data to Knowledge Research Group, University of Bristol, will undertake a series of qualitative studies to explore, in depth, the views and perspectives of participants on key emerging research/ethical issues. Drawing from the findings of these qualitative studies ALSPAC will then invite the wider cohort to become involved in engagement activities to assess the views of the broader constituency.
This programme of work will address key issues as they arise over the duration of the current strategic award funding (2014-2019). In the first instance these will include return of incidental findings, recall by genotype, commercial funding in research. In each case the aims and objectives of the research will take the form:
Aim
To gain a better understanding of Children of the 90s participants' perspectives on the issue under study.
Objectives
1. To assess the attitudes of participants to the issue and to understand whether these attitudes may change over time.
2. To understand the potential impact of the issue on Children of the 90s participants.
3. To help inform the policy on the issue in Children of the 90s.
Proposed methods
B2312 - Whole genome sequence based analysis of liver function within the UK10K project - 23/10/2014
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. For TwinsUK, liver phenotypes including bilirubin, alkaline phosphatase, GGT and albumin were released. The association analyses for the liver phenotypes 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 increasing our sample sizes, in particular data sets with existing whole genome sequence data such as ALSPAC. To this end, we are writing to seek a collaborative arrangement efforts to continue our analysis of both single point and rare variant associations. These phenotypes would not be part of the UK10K public release.
B2310 - Formulating Identifying and Estimating the Genomic Architecture of Non-cognitive Skill Formation - 23/10/2014
Background:
Economists and psychologists have established that non-cognitive traits, such as persistence and motivation, are more strongly associated with educational, labour market and risky behaviour outcomes than cognitive measures such as IQ (1-3). This observation has been used to motivate substantial government investments in early years interventions, such as Head Start in the US and Sure Start in the UK. These programs are partly designed to develop children's non-cognitive skills and ultimately improve their outcomes as adults (4). Yet, despite the increasing enthusiasm for these initiatives amongst policy makers, there are still major unresolved questions about whether the associations of non-cognitive skills and later outcomes are due to underlying causal relationships.
The evidence about the importance of non-cognitive skills is largely based on observational studies, both cross sectional and longitudinal. It is very difficult to infer causation in these studies, because of the challenge in sufficiently accounting for all the potential differences between individuals. This may be one reason why, in practice, experimental and quasi-experimental studies have found that the success of early interventions has been mixed (5). Additionally, we do not know the extent to which the associations between non-cognitive skills and educational and labour market outcomes are driven by common genetic and environment factors. The progress in genome-wide data and statistical tools such as GCTA mean it is now possible to estimate both the contribution of common genetic variation to these traits and the proportions of the associations of non-cognitive skills and outcomes which are due to a shared genetic aetiology. Finally, we can use these methods to show how common genetic variation influences these traits across the life course (6).
Aims:
We will use Genome-wide Complex Trait Analysis to investigate the genetic architecture underlying cognitive and non-cognitive skills.
B2309 - Genomewide association study for BMI in infants and children the Early Growth Genetics consortium - 23/10/2014
The analyses to be undertaken for this project at simple and require only a number of basic procedures. These will all be run by local ALSPAC analysts (Timpson or Stergiakouli) and only results provided for the work of the consortium. Analyses follow:
(i) GWAS for BMI (see attached protocol (based on the 1000g analysis, though this is the same for the HAPMAP imputation based analyses) for this procedure)
(ii) Sensitivity analyses (slight alterations to models run for GWAS, but no substantive changes)
(iii) For top SNP variants, expression data available on ALSPAC LCLs will be assessed in efforts to chart cis eQTLs relevant to implicated genetic signals.
B2308 - Exploring the genetic and epigenetic mechanisms of early human language development - 23/10/2014
Aims and objectives
Within this project, we aim to enhance the understanding of genetic and epigenetic factors driving the development of human language, and how these factors impact on later child development. We will 1) investigate the genetic architecture of early linguistic abilities, especially expressive language, with respect to common and moderately rare genetic variation, exploiting detailed information from UK10K(http://www.uk10k.org/) and 1000Genomes(http://www.1000genomes.org/)1.
Aim I: Search for single variant genetic effects through a genome-wide meta-analysis of early linguistic skills
Aim II: DNA-based heritability estimations for early language skills using genome-wide data
Aim III: Identification of pleiotropic effects between early linguistic skills and intellectual and developmental outcomes in middle/late childhood
Furthermore, epigenomic variation at birth is likely to harbour a large proportion of cumulative environmental changes during early prenatal development2.
Aim IV: Search for links between epigenetic changes in newborns and early linguistic skills
B2307 - Association between arterial stiffness of ALSPAC fathers mothers and blood pressure trajectories of their offspring - 23/10/2014
Hypertension represents a major cause of cardiovascular morbidity and mortality, affecting one in three adults worldwide[1]. Intergenerational transmission of blood pressure characteristics has long been demonstrated[2, 3] and may be attributed to a variable combination of genetic and environmental factors[4-8].
Despite some studies demonstrating age-specific effects[9], tracking of cardiovascular traits, including blood pressure, has been shown to persist into adulthood[10]. There has been a suggestion that a stronger maternal-offspring association exists for some cardiovascular risk factors, including hypertension[11-13], although this has not been replicated in other studies[14-16], which has led to speculation that intrauterine influences may contribute to development of risk factors for adult diseases in the offspring[17].
Adolescent blood pressure increases with ageing and the rate of change has been shown to track into later adult life, being associated with higher systolic pressures and thus a greater risk of cardiovascular events[18, 19]. It has been postulated that adolescence provides a critical window for mediating the transition to adult hypertension[20], with the familial aggregation potentially increasing throughout this time[21]. However, there has been limited evidence to support screening and interventions in childhood to prevent later cardiovascular disease[22, 23]. Recent analysis of serial measurements in longitudinal studies have allowed calculation of adolescent blood pressure trajectories, which may facilitate a more accurate depiction of the associations between childhood blood pressure changes and later cardiovascular disease[24], allowing for better stratification of cardiovascular risk and interventions that are targeted[25] rather than population-based[26].
Arterial stiffness, measured non-invasively through pulse wave velocity[27] is independently associated with several cardiovascular risk factors in adults, including systolic hypertension[28, 29]. The main contributors to arterial stiffness are known to be time (age), heart rate and blood pressure[30] - pulse pressure is correlated with arterial stiffness and reflects age-related changes in systolic (increase) and diastolic (decrease) that occur with ageing. Such changes result from the reduced ability to repair damage to collagen and elastin fibres caused by constant expansion and relaxation and may be a reflection of age repair mechanisms more generally[31]. Arterial stiffness is related to ageing in other domains including cognition[32, 33] and thus parental vascular ageing may provide an indicator of an individual offspring's propensity to age across more than just cardiovascular traits, allowing for early interventions that minimise these effects.
The ALSPAC study provides an excellent resource to explore these issues further. In addition to investigating the relationships between blood pressure trajectories and vascular ageing in this study, the project will enable us to clean the existing PWV data. Due to occasional field worker errors and a software upgrade that changed the output fields, it will be first necessary to produce a clean research ready dataset with the arterial stiffness exposures that can subsequently be used by others.
B2304 - Costs and Gains to Postponement How Changes in the Age of Parenthood Influence the Health and Well-being of Children - 16/10/2014
The overarching aim of the COSTPOST project (more detailed summary reported below), which will last for a total of four years, is to investigate the consequences of fertility postponement on a range of outcomes for children and their parents. In particular, the COSTPOST project has been inspired by the fact that since many industrialized countries have experienced a remarkable postponement of first births to older maternal ages, we should know more about its consequences for the well-being of children and their parents.