Proposal summaries
B2205 - Peak lung function and its associations with longitudinal wheezing phenotypes - 20/03/2014
The project aims to identify genetic and environmental factors associated with failure to acquire expected peakk lung function in early adulthood as a prequel to chronic obstructive pulmonary disease, to specify functional and inflammatory outcomes of well-characterised asthma and wheezing phenotypes through chidhood and adolescence, and to test a novel device for measuring lung function using a mobile phone app in a the context of population-based data collection.
The project aims are three-fold:
1. To extend measurement of lung function in the original ALSAC cohort to its physiological peak in early adultood; completing the trajectory of lung function accural during childhood
2. To conduct a detailed assessment of the outcomes adn endotypes of longitudinal chidhood wheezing phenotypes by recruiting a sub-sample for:
(a) Detailed lung function measurements in a respiratory laboratory
(b) Standardised exercise challenge and cardiorespiratory perfomance (VO2max)
(c) Detailed measures of airway inflammation (Exhaled NO, induced sputum collection)
3. To conduct a feasibility and validation study of the use or a novel mobile-phone based lung function app (SpiroSmart) for near-subject testing in a smapel of participants that have had laboratory measurements as part of Aim (1).
B2204 - Early life stress age of puberty and reproductive behaviour - 20/03/2014
Objectives:
1. To provide a multi-faceted understanding of the causal variables underlying behaviour and the psychological correlates that form and mediate individual life history strategies, allowing a strong test of hypotheses of psychosocial acceleration in response to early adversity.
B2203 - Foetal testosterone 2D4D digit ratio and social cognition - 20/03/2014
Foetal testosterone plays a significant role in a wide range of sex-differences. In animal studies it has been found that foetal testosterone influences the development of the of the brain; the hypothalamus, limbic system, and neocortex (Arnold & Gorski, 1984; Breedlove, 1994; MacLusky & Naftolin, 1981). It has also been found to influence behaviours (Goy & McEwen, 1980) and cognitive abilities (Williams & Meck, 1991). Sex differences in behaviour and cognition are also apparent in humans (Baron-Cohen, 2003). Traditionally research in this area has focused on abilities of logic; spatial, mathematical, and verbal ability (Kimura, 1999). More recently investigations have looked at potential social sex differences. Geary (1998), suggested that women exceed men in particular aspects of socio-cognitive ability; non-verbal communication, language and theory of mind. Baron-Cohen (2002) proposed that women have a better ability to identify and understand another's state of mind, emotional state (empathy), and to respond appropriately.
Lower 2D:4D digit span ratio is a sexually dimorphic trait, thought to be indicative of higher testosterone exposure. On average males have a lower digit span ratio than females (Maning, 2002). Growth of the 4th digit, as promoted by testosterone, is thought to occur in a 'respective window' in utero and therefore 2D:4D ratio remains constant through out postnatal development. Subsequently 2D:4D has been deemed a useful biomarker for extent of prenatal testosterone exposure (Maning, 2002). There is an abundance of evidence in support of this view. For example, it has been found that women with congenital adrenal hyperplasia have more masculine span and males with the condition have smaller digit ratios than control males (Okten, Kalyoncu, & Yari?, 2002 ).
Whereas digit span ratio has been associated with numerous mental health disorders- Depression, Psychopathology, ADHD (Bailey & Hurd, 2005; Blanchard & Lyons, 2010; McFadden, Westhafer, Pasanen, Carlson, & Tucker, 2005), most frequently the literature has investigated links with social cognition and autism. Individuals with autism are thought to be subject to a hypermasculined brain, characterised by low empathising and high systemising traits. At the other end of the continuum the so-called feminised brain is characterised by high empathising and low systemising (Baron-Cohen, 2002). Deficits in social cognition and autistic traits have been found to be indirectly associated (via digit span ratio) with prenatal testosterone exposure (e.g. Honekopp, 2012). In support of these findings, more males have autism than females.
However, conclusions made by papers investigating digit pan ratio and social cognition are often based on small sample sizes (around 50 participants). Furthermore, a study by Voracek and Dressler (2006) which used a relatively large number of participants (N= 423), found a lack of correlation between 2D:4D and empathising, systemising and autistics traits, using measures developed by Baron-Cohen (2002). The purpose of this research is to better investigate whether a link between foetal testosterone and social cognition exists, specifically the ability to empathise. The aim of the study is, by using such a large data set, to overcome the experimental limitations to which previous studies may have succumb.
The exposure variable will be 2D:4D and outcomes variables will be social communication, non verbal information, theory of mind, friendships, and gender behaviour. If 2D:4D is indicative of in utero testosterone exposure, and this has organisational effects on brain development that are reflected in lateroutcomes, it is predicted that lower digit span ratio will be associated with poorer social communication, non- verbal information, theory of mind scores and friendships scores and more male typed gender behaviours.This hypotheses will be assessed using appropriate regression techniques.
B2202 - DNA methlyation and processing of facial emotion during 75 carbon dioxide anxiety challenge - 20/03/2014
Aims:
To investigate sources for individual variation in emotional face processing during state anxiety.
The majority of research has examined the association between trait anxiety and emotional processing. In contrast, the effects of state anxiety have been understudied. Our laboratory is experienced in the use of anxiogenic challenges that safely and transiently increase anxiety. This involves short (up to 20 minutes) inhalation of air that has higher levels of CO2 than normal air (7.5%). There is substantial individual variation in anxiety sensitivity and emotional processing, and in this study we would investigate whether effects differ on the basis of DNA methlyation patterns, which have recently been identifed as biological markers of early life stress. DNA methylation profiles have already been generated from the peripheral blood of approximately 1000 ALSPAC mothers and children as part of the Accessible Resource for Integrated Epigenomics Studies (ARIES).
B2200 - Replication of DNA methylation and gender association study - 13/03/2014
Aims: To replicate genome-wide sex-specific CpG sites.
B2199 - Metabolomics workpackage of LIFECOURSE Longitidunal Investigation of biological Factors Explaining age-related Cognitive and Cardiometabolic Outcomes Relationship to Survival and effect of Environment Horizon 2020 bid - 13/03/2014
OBJECTIVES (note these will be achieved within the collaboration of greater than 50 studies and greater than 500,000 participants; ALSPAC will contribute to some but not all and for each objective more than one study will always contribute)
1a. To determine how metabolomic profiles change with age from birth through to old age.
1b. To explore the extent to which risk factors from across the life course (diet, physical activity, alcohol, adiposity) alter general age related trajectories
2. To determine the extent to which blood-based metabolic profiles (assessed at different ages), in addition to clinical characteristics, improve stratification of adults into different levels of risk for cardiovascular disease, type 2 diabetes and dementia
3a. To determine the effect of risk factors, such as greater adiposity, low levels of physical activity, poor diet and excessive alcohol consumption, on metabolic profiles at different ages.
3b. To determine the effect of different blood-based metabolic profiles (assessed at different ages) on subsequent risk of adverse cardiometabolic risk factors, CHD, stroke, type 2 diabetes, lower cognitive function and dementia.
3c. To determine the role of blood-based metabolic profiles (assessed at different ages) in the causal pathway between upstream risk factors (such as greater adiposity, low levels of physical activity, poor diet and excessive alcohol consumption) and subsequent cardiometabolic, cognitive and ageing outcomes
B2198 - Exploration of maternal alcohol consumption nutrient intake dietary patterns and infant outcomes - 13/03/2014
Aims:
To explore associations between alcohol consumption levels and patterns, and intake of methyl donor nutrients and dietary antioxidants during pregnancy.
To derive maternal dietary patterns associated with alcohol consumption levels, drink preference and drinking patterns prior to and during pregnancy.
To explore associations between maternal nutrient intake, maternal alcohol consumption, birth outcomes and cognitive development in offspring.
B2197 - The association between stressful life events during pregnancy and offspring mental health - 13/03/2014
Aims&Hypotheses
Theprimaryaimoftheprojectistoexaminethelong-termassociationbetweenmothers'exposuretostressfullifeeventsduringpregnancyandindicesofinternalizing(i.e.,symptomsofdepressionandanxiety)intheoffspring'schildhoodandadolescence. Ourprimaryhypothesisisthatin-uteroexposuretomajor stressfuleventswillbeassociatedwithincreasedriskofdepressive symptomatologyinchildhoodandadolescence,andthatthisassociationwillpersistafteradjustingfortheeffectsofchronicstressorssuchaspoverty,maternalpostnataldepression,andrecurrentstressfuleventsinthepostnatalperiod. Oursecondaryaimwillbetoexaminethelong-termassociationbetweenmothers'exposuretostressfullifeeventsduringpregnancyandindicesofexternalizing(i.e.,behaviouraldisorderssuchasconductproblems)intheoffspring'schildhoodandadolescence.
B2196 - Association of maternal and pre-pubertal 25-Hydroxyvitamin D with post-pubertal Anti-Mllerian Hormone in off-springs - 13/03/2014
Aims
The aims of the study are:
(1) to investigate the prospective association between 25(OH)D concentrations at the mean age of 9.9 years and serum AMH at the mean age of 15 years in a large cohort (N=5,080 with levels of 25(OH)D at age of 7,9, or 11 and N = 3,474 with measured levels AMH at the age of 15 years, once data available we will estimate the exact number of eligible pairs for this analysis).
(2) to investigate the prospective association between maternal pregnancy 25(OH)D concentrations and offspring AMH at a mean age of 15 years in a large cohort (N =7,714 mothers with pregnancy 25(OH)D results and N = 3,474 with measured levels AMH at the age of 15 years).
Depending on the results relating to these two primary aims we will further examine whether any association of maternal pregnancy 25(OH)D with offspring AMH at mean age 15 years is mediated by offspring's own pre-pubertal 25(OH)D.
B2194 - Ageing lungs in European cohorts ALEC - HORIZON 2020 - 06/03/2014
The overall objective of the proposal is to exploit information held within existing cohorts and their population-based biobanks to improve understanding of the determinants of and risk factors for low lung function , respiratory disability and the development of a major cause of disease, disability and death in European adults, namely chronic obstructive lung disease (COPD). Lung function in adult life is a critical objective marker of good lung health, strongly associated with other major chronic diseases (for example cardiovascular disease) and is a major independent determinant of overall health status (physical and mental health, quality of life, exercise capacity, independent living).
We will
1. identify determinants and risk factors (behavioural, environmental, occupational, nutritional, other modifiable lifestyle, genetic) of poor lung growth, excess lung function decline and occurrence of low lung function, respiratory disability and COPD within existing child and adult cohorts
2. validate the role of risk factors for poor lung growth, excess lung function decline and occurrence of low lung function, respiratory disability and COPD through a) integration of data from relevant disciplines (clinical, epidemiological, molecular, genetics, epigenetics) and b) valorisation of knowledge gained from the cohort-related population-based biobanks
3. generate and integrate information on change in DNA methylation patterns with ageing to identify risk factors and validate the role of these risk factors
4. generate a predictive risk score that takes account of the combined effects of factors that cause poor lung growth and lung function decline and lead to low lung function, respiratory disability, and COPD in older adults
This work will provide an evidence base for risk identification that can underpin future preventive and therapeutic strategies and policies.
B2195 - Comparison of a developmental time series of expression against the expression individuals with autism spectrum disorder - 06/03/2014
This is a very simple and brief study that is a follow-on to a study that we published previously on gene
expression in individuals with autism spectrum disorder (Kong SW, Collins CD, Shimizu-Motohashi Y,
Holm IA, Campbell MG, Lee I-H, et al. (2012): Characteristics and predictive value of blood
transcriptome signature in males with autism spectrum disorders. PLoS ONE. 7:e49475.) that we have
appended to this application. The aim of this study is to identify the developmental location of every one
of our subjects with Autism Spectrum Disorder (ASD) in gene transcriptome space. We hypothesize that
individuals with more severe autistic features will be more delayed (in their transcriptomic age relative to
their chronological age) than those who have less severe features (against the ADI/ADOS metrics that we
have for each subject). We will proceed with creating a principal component analysis of the ALSPAC
individuals based on the rank normalized expression data. This will provide a multidimensional map of
development of expression for these individuals. The expression data of the ASD individuals will be also
rank normalized and then these individuals will be projected into the ALSPAC expression space for those
genes present on both platforms used (for the ASD study and the ALSPAC study). Prior studies we have
conducted suggest that the effect of age on transcription will be located in the first two principal
components which will allow us to measure the developmental displacement of each ASD individual
relative to the ALSPAC group. We will have to examine gender as a confounding variable as well as the
scores of the SCDC questionnaire for ALSPAC subjects.
B2178 - School exclusion in ALSPAC early markers concurrent needs later outcomes - 27/02/2014
Aims
To explore the distribution and correlations of school exclusion in children and young people in ALSPAC, with particular focus on early risk markers, concurrent needs, developmental trajectories and later outcomes.
B2193 - IQ and A-level achievement do children with the highest IQs obtain the best A-levels - 27/02/2014
Aim:
The aim of this project is to examine the variance in A-level grade outcomes that is attributable to child IQ, and to what extent this is modified by parental characteristics.
B2192 - Development of health risk in childhood and adolescence Gene-environment interactions and its underlying mechanisms - 27/02/2014
AIMS:
Health risk behaviors related to substance (ab)use and externalizing problem behavior threaten the healthy development of children and adolescents. Specifically, early onset substance use and conduct problems are key predictors of later addiction and clinical-level antisocial personality disorder. These are greatly debilitating conditions for any individual, but also the societal costs associated with these conditions are enormous. Harsh or inconsequent discipline, lack of warmth and sensitivity, abuse by parents, and parents' dependence on substance use are among the strongest predictors of substance (ab)use and conduct problems in childhood and adolescence.
Previous research over the past decade has indicated that family risks may have a particularly detrimental effect in children carrying specific genotypes, that regulate the activity within dopaminergic, serotonergic, GABAergic, and cholinergic pathways. In our proposal, we aim to identify gene-environment interactions that predict health risk behaviors in childhood and adolescence - focusing on genetic risk on the one hand, and on specific family and parenting risks on the other hand. Although the field of GxE research holds great promise, until now it has proven difficult to replicate GxE findings. This has two main causes: first of all, a lack of statistical power in most correlational studies focusing on GxE (e.g., Duncan & Keller, 2011) and secondly, a lacking specification of possible explanatory mechanisms underlying GxE (Dodge, 2010; Weeland, Overbeek, Orobio de Castro, & Matthys, 2014).
Thus, our overall aim is to 1) conduct cross-validated tests of gene-environment interactions related to the development of common addictive behaviors (smoking, alcohol, marijuana) and conduct problems or antisocial behavior in childhood and adolescence, and 2) to test possible mechanisms underlying this gene-environment interplay. With regard to this latter aim, we aim to examine specficially whether children's temperamental traits, such as for instance (but not limited to) levels of (dis)inhibiton and reward and punishment sensitivity, can be identified as explanatory factors underlying the gene-environment interactions that lead up to the development of health risk behaviors.
B2191 - The exploration of environmental and genetic contributions to facial shape - 27/02/2014
Aim:
To employ novel techniques to explore the environmental and genetic contributions to facial shape at 25 years of age and change in face shape from 15 to 25 years of age.
B2190 - Identification of avoidable environmental factors that increase the risk of preterm delivery an exposome approach - 27/02/2014
Hypotheses
The major hypothesis is that there are environmental factors, hitherto unsuspected, that have an effect on the risk of preterm delivery. It is anticipated that such environmental effects may interact with the genetic markers of mother and/or fetus, or work through DNA methylation.
Specific aims will determine, using a hypothesis free approach, whether any of the following are associated independently with preterm delivery: lifestyle of parents and grandparents (including smoking, alcohol, drug abuse, caffeine and activity levels); other physical exposures (medications, diet, work-based chemicals, noise, radiation); psychosocial features of parents and grandparents (including stressors based on life events, social circumstances, financial difficulties, domestic abuse, abuse of the parents in childhood); and mental and physical health of parents and grandparents. For all relationships identified, assessments will be made concerning relevant genetic and epigenetic associations, and their interaction with the exposures.
B2189 - Association between infant sleep position and gross motor skills and intelligence in childhood - 27/02/2014
Aim:
To determine if child sleeping position in infancy is associated with gross motor or mental development in childhood.
B2188 - The role of metabolomics in reproductive and perinatal epidemiology - 27/02/2014
OBJECTIVES (note these will be achieved within the collaboration; ALSPAC will contribute to some but not all and for each objective more than one study will always contribute)
1a. To determine how metabolomic profiles change with age from birth through to old age.
1b. To explore the extent to which markers of reproductive health (age at menarche, age at first birth, parity, age at menopause, transition through menopausal transition) alter general age related trajectories
1c. To explore the associations of adiposity and change in adiposity with change in metabolomic profiles with increasing age.
1d. To explore the associaitons of reproductive hormones and change in reproductive hormones with change in metabolomic profiles with increasing age.
2a. To determine the extent to which blood-based metabolic profiles (assessed at different ages), in addition to clinical characteristics, improve stratification of women into different levels of risk for infertility
2b. To determine the extent to which blood-based metabolic profiles improve risk prediction of live birth obtained from IVFpredict.
2c.To determine the extent to which blood-based metabolic profiles (assessed at different pre-pregnancy and gestational ages), in addition to clinical characteristics, improve stratification of women who become pregnant into different levels of risk for hypertensive disorder of pregnancy, gestational diabetes, preterm birth, large for gestational age and small for gestational age.
2d. To develop the best prediction tools for single and combined adverse pregnancy/perinatal outcomes
3a. To determine the role of blood-based metabolic profiles (assessed at different ages) in the causal pathway between greater adiposity and subsequent reproductive and perinatal outcomes
3b. To determine the role of maternal gestational and fetal (assessed in cord-blood) blood-based metabolomics in the causal pathway between maternal gestational adiposity and weight gain and subsequent offspring (and the next generation - grandchildren) adiposity and cardiometabolic health
4a. To determine the extent to which metabolic profiles change as women go throug the menopausal transition and determine whether any change is independent of age related change
4b. To determine the extent to which reproductive hormone changes as women go through the perimenopausal transition are related to menopausal transition changes in metabolic profiles
4c. To determine the extent to which any menopausal transition changes in metabolic profiles result in future cardiometabolic diseases.
B2187 - Changes in oral health behaviour between childhood and adolescence- analysis of data from ALSPAC - 27/02/2014
Aim:
The aim of this data analysis project is to describe the changes in oral health behaviours between childhood and adolescence using data from the Avon Longitudinal Study Of Parents And Children (ALSPAC) survey, by performing a statistical analysis.
B2186 - Genome-wide association study of body perception - 27/02/2014
We have investigated BMI in childhood using different time points in genome-wide association settings. Our results suggest that the genomic profile differs according to the nature of the phenotype being investigated; optimising BMI appropriattely for each age group, so that the correlation of BMI with height is removed, resulted in SNPs in ADCY3 being genome-wide significant while this was not the case when BMI was used without this adjustment (Stergiakouli et al under review).
As an extension of this project we would like to perform a genome-wide association study of body shape perceptions using data from the "Growing up" questionnaire. This questionnaire was completed by the children when they were ~ 77 months and asked them to choose one from a series of pictures which best reflected how they thought their body looked.
We are interested in comparing the results from our previous GWAS of BMI in childhood with a GWAS of body perception. We would also test if top hits from published GWAS on BMI in childhood and adulthood can be replicated using body perception data.