Proposal summaries
B2059 - Dual trajectories of adolescent smoking and depression - 15/08/2013
Project outline:
Smoking and depression commonly co-occur in the general population. That is, individuals with depression are more likely to be smokers and smoke more heavily compared to individuals without depression, and smokers are more likely to report depressive symptoms compared to nonsmokers. In adolescents, there is also evidence of this relationship. It has been shown that depression and other mood disorders (e.g., anxiety) in adolescents increase the likelihood of experimental smoking and smoking initiation. Others have demonstrated that tobacco smoking among adolescents leads to increase depressive symptoms, which remit following cessation. Regardless of directionality, it is well-known that smokers with elevated depressive symptoms experience more difficulties when quitting smoking. Furthermore, concurrent depressive symptoms and tobacco use may interact synergistically to produce greater health risks than either disorder alone, especially for heart disease.
Better characterizing the developmental (longitudinal) relationship between these variables, particularly among adolescents, would be a significant contribution to the existing literature and provide evidence for the diversity in comorbidity of adolescent smoking and depression. This is an important area as both smoking and depression are related to increased use of other drugs and illicit substances, mental health distress, and physical health problems. Recently, much research has focused on modelling patterns in substance abuse and mood disorders across early developmental periods, but smoking and depression among adolescents have yet to be modelled in a dual trajectory analysis. Smoking trajectories for this cohort have been previously established and the data lend themselves to modelling trajectories of the development and early course of depression as well. The ALSPAC cohort presents an ideal dataset to be analysed as dual trajectories to model the comorbid development of smoking and depression in adolescents. Further, we can examine sociodemographic predictors and mental, behavioural, and physical outcomes of group membership.
Aims:
1. Examine the co-occurrence of smoking and depression among adolescents using dual trajectory modelling.
2. Explore outcomes between different trajectory groups, including:
a. mood symptoms (e.g., anxiety),
b. substance use (e.g., cannabis), and
c. biological markers (e.g., lung function).
We will use longitudinal latent class analysis to generate trajectories for adolescent smoking and depression, both separately and then in conjunction. Adolescent smoking will be based on self-reported smoking status. Adolescent depression will be based on the self-report MFQ.
Hypotheses:
We hypothesize that severity of tobacco use will be related to severity of depression (to be examined by cross tabulation). More specifically, we expect that adolescents who smoke will endorse higher levels of depressive symptoms, and that logical dual trajectories of adolescent smoking and depression will emerge. We also expect that there will be significant group differences, both in predictor variables (sociodemographics) and outcome variables (substance use, mood symptoms, and biological markers).
Variables:
Exposure variables. Smoking status will be determined by self-report during the clinical interview and depression will be determined by self-reported on the MFQ. These variables will then be modelled by dual trajectories which will elicit specific smoking x depression groups.
Outcome variables. Other substance use (e.g., cannabis), mood symptoms (e.g., anxiety), and biological markers (e.g., lung function). These outcome variables will be applied to both the groups that emerge from the individual trajectory models (smoking and depression) as well as those from the smoking x depression dual trajectory model.
Confounding variables. Smoking status and depression have also been shown to be differentially associated with gender, race, age, education and SES (housing tenure, crowding status and maternal educational attainment). Therefore these covariates will be included in our models. Another variable that has garnered attention recently is traumatic events in childhood, so we will explore the effect of early life stressors (e.g., abuse, deaths) on both smoking and depression.
B2068 - Investigating the effects of disclosure control - 15/08/2013
Aims: To develop an anonymisation policy for ALSPAC to be implemented for use of any release which may include linked NHS data. The policy needs to be submitted with the application of the Information Goverance Toolkit which needs to be in place to continue receiving and gaining further section 251 support. Further to this policy, we aim to explore anonymisation techniques determining the most secure level of anonymisation with the least effect upon the quality of the data for research. Using previous research on datasets which have been anoymised to different levels and using different techniques.
The anonymisation policy, for the IG Toolkit, will need to include the minimum level of anonymisation needed for release files of linked NHS data, k-anonymisation on quasi-identifiers.
Hyptheses: To determine the most secure method of anonymisation with the least impact on the quality of the data for research.
The hypotheses will be explored using a previous research question published by Kate Northstone. The research used to test the impact is as follows:
Maternal fish intake and child dietary patterns and associations with educational outcome at 16 years of age.
Outcomes: Child achieved 5 or more GCSE's at grade C or above, including maths and english.
Primary exposures:
1) Fish intake during pregnancy (none, 1-340g and greater than 340g)
2) Omega-3 intake (none, any actual intake split into tertiles)
3) Child Dietary patterns derived from PCA at 3,4,7,9 and 13 years of age
Confounders:
Gender
Maternal age
Maternal education
Housing
Maternal life events
Birthweight
Gestation
Maternal Smoking
Parity
Maternal and paternal occupation
IMD
Geography.
B2067 - Utilising multiple independent combinations of genetic variants to evaluate potential pleiotropy - 15/08/2013
We aim to develop a method to investigate potential pleiotropy in causal estimates derived using the Mendelian randomization approach. The ALSPAC data will be used as an illustrative example.
Exposure: height, Outcome: FVC lung function (unadjusted for height), instrumental variables: 20 genotypes listed below.
B2056 - Assessing the impact of partner smoking on cotinine levels in the ALSPAC mothers - 01/08/2013
Aim
To investigate the impact of partner smoking on maternal cotinine levels during pregnancy.
Hypotheses
Comparison of the magnitude of association of maternal and paternal smoking during pregnancy is a useful method for assessing whether smoking during pregnancy may have an intrauterine effect on offspring outcomes. (1) This has been used in ALSPAC to investigate the impact of smoking during pregnancy on offspring birthweight, blood pressure, trajectories of height and adiposity and attention deficit hyperactivity disorder. (2-4) This method assumes that the effect of passive smoking in utero on offspring of mothers who do not smoke but have partners who smoke is minimal. However, recent work in ALSPAC has demonstrated that maternal smoking is strongly associated with cotinine (a metabolite of nicotine) levels in non-smoking offspring during childhood and adolescence. (5) Therefore, it is possible that exposure to household smoking may be an important determinant of health outcomes. If this is the case, it may be necessary to control for this in comparisons of the effect of maternal and paternal smoking on offspring outcomes.
We aim to investigate the extent to which partner smoking affects maternal cotinine levels during pregnancy. Associations between partner smoking and maternal cotinine will be investigated using linear regression, stratified by self-reported smoking status of the mother. In addition, we will look at associations of partner smoking with cotinine in all mothers, adjusted for maternal smoking status and heaviness. It may be necessary to use cotinine cut offs to validate maternal self-reported smoking status.
Exposure variables
Paternal smoking status and heaviness
Stratify by maternal smoking status
Outcome variables
Maternal cotinine measured during pregnancy
Confounding variables
Age
Maternal BMI
1. Smith GD. Assessing intrauterine influences on offspring health outcomes: can epidemiological studies yield robust findings? Basic & clinical pharmacology & toxicology. 2008;102(2):245-56. Epub 2008/01/30.
2. Howe LD, Matijasevich A, Tilling K, Brion MJ, Leary SD, Smith GD, et al. Maternal smoking during pregnancy and offspring trajectories of height and adiposity: comparing maternal and paternal associations. International journal of epidemiology. 2012;41(3):722-32. Epub 2012/03/13.
3. Langley K, Heron J, Smith GD, Thapar A. Maternal and Paternal Smoking During Pregnancy and Risk of ADHD Symptoms in Offspring: Testing for Intrauterine Effects. American Journal of Epidemiology. 2012;176(3):261-8.
4. Brion MJ, Leary SD, Smith GD, Ness AR. Similar associations of parental prenatal smoking suggest child blood pressure is not influenced by intrauterine effects. Hypertension. 2007;49(6):1422-8. Epub 2007/04/04.
5. Stiby AL, Macleod J, Hickman M, Yip V, Timpson N, Munafo M. Association of Maternal Smoking With Child Cotinine Levels. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 2013.
B2055 - Injection drug use by the age of 21 socio-economic patterning parental substance use and early childhood adversity - 01/08/2013
Aims: The aim of this project is to investigate early risk factors of IDU in ALSPAC. Previous research has suggested that the onset of IDU is associated with family structure (not living with both parents, or in care or a foster home at any point) as well as early conduct problems, particularly school exclusion and childhood contact with the criminal justice system. Moreover, violence, criminality and financial problems in the family have been shown to be associated with increased risk as well as any types of carer substance use (Macleod et al 2012). However, these association have to date only been shown within the context of case control studies (Macleod et al 2012; Conroy et al., 2009; Tomas et al., 1990; Obot et al, 1999). To our knowledge there is no prospective evidence investigating the association between these early life risk factors and IDU in early adulthood.
Outcome variables: self-reported injecting drug use at ages 17 and 21
We will investigate IDU by age 17 and by age 21 and also create an outcome variable indicating IDU by age 21 (combining TF4 data with data from the 21yr questionnaire)
We propose to examine the following co-variates in relation to the outcome:
Indicators of socio-economic positioning
Indicators of early childhood adversity
- Contact with social services (mother self-report)
- "Child at risk" Register (linkage)
- Experience of victimisation (physical, emotional and sexual abuse during childhood)
- Antisocial behaviour
- Conduct disorder trajectories and early measures of conduct problems
- Alcohol, Smoking and substance use up to young adulthood
- Stessful life events in the child
- Post traumatic stress in the child
Educational measures:
- KS1 & KS2
- School exclusion and data on absenteeism (teacher reported, YP self-reported and linkage data)
Parental factors
- Parental substance use including smoking, alcohol problems, drug taking and injection drug use
- Indicators of family involvement with the police/court, criminal convictions
- Cruelty within the family (towards the carer, towards child), financial hardship
References:
Macleod J, Hickman M, Jones J, Copeland L, McKenzie J, De Angelis D, Kimber J & Robertson JR (2012): Early life influences on the risk of injecting drug use: case control study based on the Edinburgh Addiction Cohort. Addiction. Vol.108(4). pp. 743 - 750
Conroy E, Degenhardt L, Mattick RP & Nelson E (2009): Child maltreatment as a risk factor for opiod dependence:comparison of family characteristics and type and severity of child maltreatment with a matched control group. Child Abuse & Neglect. Vol.33. pp. 343 - 352.
Tomas JM, Vlahov D, Anthony JC (1990): Association between intravenous drug use and early misbehaviour. Drug & Alcohol Dependency. Vol.25. pp. 79 - 89.
Obot IS & Anthony JC (1999): Association of school dropout with recent and past injecting drug use among African American adults. Addicitive Behaviour. Vol. 24. pp. 701 - 705.
B2054 - Antisocial and callous behaviour the role of fish intake and their associated fatty acids - 01/08/2013
Background: Antisocial behaviour in childhood and adolescence has been associated with more serious offending in adulthood [1]. Recent evidence suggests that the consideration of calluous and unemotional traits may further define the psychopathology [2]. It is clear that individuals can have different trajectories with early onset persistent problems identifying a particularly high risk group [3]. Other research has also shown a number of antecedents reflecting child characteristics (such as uncontrolled temperament and low self-esteem), parenting skills and the home environment including inter-parental conflict [4, 5]. Studies have also shown associations between exposures during pregnancy and behaviour many years later [5]. But to date research on dietary influences and in particular the role of omega-3 fatty acids has been limited. What evidence exists warrants further investigation of these issues [6].
Aims: To examine and further refine the phenotype based upon potential comorbid characteristics such as particular facets of behaviour, motor skills, language impairments and IQ. To explore the associations of varying risk groups with fish intake and fatty acids.
Hypotheses: (a) That high intakes of omega-3 as reflected in high fish intakes and high blood levels will lower risk for antisocial and callous behaviour. Such effects may be more strongly associated with DHA.
(b) That the ratio of omega-6 to omega-3 fatty acids reflecting an inflammatory response index may independently increase risk of outcomes.
(c) That the fetal environment as reflected by maternal fatty acids and fish intake may 'program' the child to be more susceptible or more resilient to potential risk factors.
Outcomes: Antisocial and callous behaviour taking account of other comorbid conditions.
Exposures: Fish intake and fatty acids obtained from blood samples.
Confounders: Socio-economic, maternal psychopathology, parenting and the home environment.
Analyses are likely to be untaken in parallel both in the USA and Bristol.
References
1. Benda BB, Corwyn RF, Toombs NJ. Recidivism among adolescent serious offenders: Prediction of entry into correctional system for adults. Criminal Justice and Behavior 28:5 (2001), pp 588-613
2. Rowe R, Maughan B, Moran P, Ford T, Briskman J, Goodman R. The role of callous and unemotional traits in the diagnosis of conduct disorder. Journal of Child Psychology and Psychiatry 51:6 (2010), pp 688-695
3. Barker ED, Oliver BR, Maughan B. Co-occurring problems of early onset persistent, childhood limited, and adolescent onset conduct problem youth. Journal of Child Psychology and Psychiatry 51:11 (2010), pp 1217-1226
4. Bowen E, Heron J, and Steer C. Anti-Social and Other Problem Behaviours Among Young Children: Findings From the Avon Longitudinal Study of Parents and Children. London: Home Office; 2008. Report 02/08.
5. Barker ED, Maughan B. Differentiating Early-Onset Persistent Versus Childhood-Limited Conduct Problem Youth. American Journal of Psychiatry 166:8 (2009), pp 900-908
6. Kohlboeck G, Glaser C, Tiesler C, Demmelmair H, Standl M, Romanos M, Koletzko B, Lehmann I, Heinrich J, for the LISAplus Study Group. Effect of fatty acid status in cord blood serum on children's behavioral difficulties at 10 y of age: results from the LISAplus Study. American Journal of Clinical Nutrition 94:6 (2011), pp1592-1599.
B2046 - Social and genetic trajectories from motor development to academic attainment via energy balance-related behaviour - 18/07/2013
The aim of this project is to examine the effects of infant motor development on adolescent energy balance-related behaviour (EBRB) (physical activity and sedentary behaviour), and to identify learning and development, behavioural and health-related factors that mediate these effects (study I). In addition, we aim to examine the effects of self-reported and objectively measured EBRB on adolescent self-reported and teacher-rated academic achievement, and to identify factors/processes that mediate these effects (study II).
We hypothesise that early infant motor development predicts adolescent EBRB via developmental, behavioural and health-related factors like learning, behaviour/psychopathology, language development, personality, motor abilities and behaviour, anthropometry and various physical and mental health measures. We also hypothesise that EBRB predicts academic attainment via social, psychological and health-related factors like cognitive function, self-esteem, academic motivation and goal setting, interpersonal and social skills, psychopathology and school enjoyment, sleep, stress, obesity and physical fitness.Because of partly explorative nature of the study, mediating variables will be specified during structural equation model (SEM) building.
In study I, infant motor development at the age of 6 and 18 months is the main independent factor. Dependent variables include objectively and subjectively measured physical activity and sedentary behaviour/time. Possible mediating factors include parent-reported, teacher assessed and/or clinically measured learning (e.g. learning abilities and performance), behaviour/psychopathology (e.g. emotional and behavioural problems), language development, personality (e.g. self-concept, sensation seeking and locus of control), motor abilities and behaviour (e.g. gross and fine motor skills), anthropometry (height, weight and fat mass) and physical and mental/psycho-social health measures.
In study II, independent variables include objectively and subjectively measured physical activity and sedentary behaviour/time from age 7 to 16 years. Dependent variables are academic achievement at age 16 years, including spelling, understanding mathematics and science and school experiences and aspirations. Possible mediating factors include teacher assessed and clinically measured learning (e.g. learning abilities and performance), cognitive function, self-concept and academic self-confidence, interpersonal and social skills and relationships, behaviour/psychopathology (e.g. emotional and behavioural problems), school enjoyment, anthropometry (height, weight and fat mass), physical fitness, as well as physical and mental health measures.
B2044 - Association between mitrochondrial copy number and chronic stress - 18/07/2013
Aims . The aim of this proposal is to determine whether there is an association between mitochondrial (MT) copy number and measures of chronic stress (particularly early childhood chronic adversity). This analysis will only be possible using the ALSPAC sample included in the UK 10K project as I need sequence data to answer this question.
Hypotheses
Based on preliminary data from a case control study of major depression I think that early childhood chronic adversity elevates MT copy number, through an unknown mechanism. From DNA sequence data I have observed that in both cases and controls there is correlation between the following measures and MT copy number: neuroticism, number of stressful life events, childhood sexual abuse.
Variables
A meausure of susceptibility to stress (neuroticism), number of stressful life events (we used the 16 item stressful life events questionnaires), and measures of childhood abuse (we interrogate specifically non-genital, genetal and intercourse). Meaures of MT copy number are obtained from the numbers of reads mapping to the reference MT genome, normalized by the reads mapping to the autosomes (I use read data only from one chromosome to get this measure).
Outcomes
A linear model including age and weight, is used to predict MT copy number.
Confounds
As far as we know, age and weight are the only relevant confounds.
B2050 - Meta-analysis of maternal smoking during pregnancy and methylation in offspring - 18/07/2013
AIMS
To investigate the relationship between maternal smoking habits during pregnancy (i.e. smoking status, sustained smoking/smoking duration, smoking quantity) and DNA methylation levels in cord blood samples from newborn offspring utilising the ALSPAC-ARIES HM450 dataset. This analysis will form part of a meta-analysis across multiple study cohorts.
Overall research question: Is maternal smoking during pregnancy related to CpG site-specific methylation in newborns?
ANALYSIS PLAN
Exposure variable: Four questions have been drawn up to address issues relating to smoking habits throughout pregnancy, timing, dosage and paternal effects. It is acknowledged that not all individual study cohorts will have the relevant data to address all these questions. Hence, each study cohort should address those applicable.
1. Active smoking
a. Sustained active smoking versus no smoking (dichotomous): mothers who smoked during most of the pregnancy/into late pregnancy (2nd/3rd trimester) versus those who did not smoke at all during pregnancy (including those who quit prior to pregnancy).
b. Early pregnancy smoking versus no smoking (dichotomous): mothers who smoked during early pregnancy and quit later versus those who did not smoke at all during pregnancy (including those who quit prior to pregnancy).
c. Ever smoked versus no smoke (dichotomous): mothers who reported smoking at anytime during pregnancy versus those who did not smoke at all during pregnancy (including those who quit prior to pregnancy).
2. Passive smoking
Definition: any indication that mothers were exposed to passive smoking (i.e. partner smoked, other relatives/household members smoked, exposed at home, exposed at work, quantified e.g. greater than 1 hour per day). Perform analysis in non-smokers only, split into passive and non-passive smoking as appropriate (Dichotomous). If possible, perform analyses in the three sets as above.
3. Smoking quantity
Definition: if possible split mothers by 1-9 cigarettes per day, 10+ cigarettes per day, non-smokers (trichotomous). If possible, perform analyses in the three sets as above.
4. Smoking in biological father
If smoking status of biological father is known perform analyses on paternal smoking prior to pregnancy (yes/no, dichotomous).
Outcome variable: DNA methylation utilising the HM450 ARIES data on cord blood samples. If possible, use the raw beta values for all probes i.e. with no normalisations or transformations. Alternatively (or in addition) perform preferred QC and pre-processing analyses as necessary.
Statistical Analysis: Perform robust linear regression with individual CpG site methylation levels as the outcome variable and smoking status as the exposure of interest. Include any potential confounders on a cohort-specific manor. Summary statistics will be provided to Dr Jourbert at NIEHS enabling mixed/random effects modelling in downstream meta-analyses.
Confounders for ALSPAC-ARIES: Definition - any factor associated with the exposure variable (i.e. smoking variable) and plausibly associated with DNA methylation. Assess the potential confounding effects of the following variables and include within the statistical model as necessary: sex, genetic ancestry/ethnical background, social-economical background, maternal age, pre-pregnancy BMI, parity.
Possible Sensitivity analyses: Perform the primary model (sustained vs non-smoke) adjusting for cell composition if possible and adjusting/stratified for preterm birth.
Other stipulations: restrict analyses to singleton births. Do not adjust for gestational age or birth weight in the first instance as these may be on the causal pathway linking smoking, methylation and health outcomes.
B2049 - Socioeconomic distribution of excess weight in children - 18/07/2013
Aim:
We propose to go beyond prevalence-based methods to test the relationship between obesity and parental income amongst children and investigate the differences by race/ethnicity and gender.
Hypotheses:
1. a)Using Unconditional Quantile Regression (Joliffee 2011) with BMI Z-scores the independent variable, low socio-economic status will be associated with greater weight at the overweight and obese BMI Z-score thresholds.
b)When accounting for parental weight status (overweight or obese), the coefficient for the effect of income on child BMI Z-scores at the overweight and obese thresholds will be reduced
c) Comparing Ordinary Least Squares estimates for the effect of parental weight status and income on child BMI Z-scores will underestimate the effect at the overweight and obese thresholds.
2. a) The net concentration index for measures of child obesity will be negative
b) A significant proportion of the concentration index for measures of child obesity will be explained by parental and weight status. Including parental obesity status will reduce the independent effect of income on obesity status for children.
The results of this analysis has policy implications. If the coefficient is significant after controlling for parental obesity status, this may indicate that healthy weight initiatives should target poor children. If, however, the coefficient becomes insignificant, policies should target all children and particularly children with overweight or obese parents.
Exposure variables:
Income, parental weight status
Outcome variable:
BMI z-score (calculated using weight, height, gender and age)
Confounding variables:
Socioeconomic measures such as ethnicity, lifestyle behaviours including diet, TV viewing, physical activity, tobacco use, and sleep duration.
Reference List:
Jolliffe, D. (2011). Overweight and poor? On the relationship between income and the body mass index. Economics & Human Biology, 9, 342-355.
B2048 - CLOSER work package one Data harmonisation of measures of biological function and structure across the cohorts - 18/07/2013
Aims:
To facilitate cross cohort work by harmonising measures of biological structure and function across the UK birth cohort studies, starting with weight and height in the 1946, 1958, 1970, 2000 birth cohort studies, plus ALSPAC. To sue the harmonised measures in two demonstration papers that:
1) compare body size distributions and mean trajectories, across different phases of the life course, between cohorts, and
2) investigate how SEP inequalities (using measures harmonised in CLOSER work package 2) in body size trajectories, across different phases of the life course, differ between cohorts. To extend the harmonised dataset to include data from other birth cohort studies (e.g. HCS, SWS, Biobank) and other measures of biological structure and function (e.g. blood pressure and grip strength), if necessary.
B2047 - Modifiable risk factors for depression in adolescents - understanding the role of physical activity and obesity - 18/07/2013
We aim to investigate the association between objective measures of obesity and physical activity and depression in adolescents.
1. To investigate the association between obesity, measured objectively, and depression in adolescents, including the possibility of a bi-directional association
2. To investigate the association between physical activity, measured objectively, and depression in adolescents, including the possibility of a bi-directional association
3. To investigate the inter-relationship of these modifiable risk factors.
B2045 - UK10K Secondary proposal age at menarche - 04/07/2013
As part of an approved UK10K secondary proposal, we aim to perform an age of menarche whole-genome meta-analysis between ALSPAC and Twins UK. A UK10K secondary proposal covers any phenotype not included as a 'core' trait intended to be published as part of UK10K. We aim to analyse menarche and publish as a separate satelite paper at a similar time to the main UK10K effort.
There are two genetic datasets used in this project (that are already available within UK10K):
The ALSPAC UK10K sequence genotypes
Imputed UK10K genotypes from the wider ALSPAC GWAS sample
(We will perform two models, using the same statistical parameters used by the ReproGen consortium.
Model A: Menarche ~ SNP + Birth year
Model B: Menarche ~ SNP + Birth year + BMI (closest to age at menarche)
Model C: Menarche ~ SNP + Birth year + BMI (furthest time point from menarche available)
Similar to the core analyses in UK10K, we aim to perform a 4-way meta-analysis of the following strata:
Discovery sequence genotypes in ALSPAC
Discovery sequence genotypes in Twins UK
Imputed UK10K sequence genotypes from wider GWAS in ALSPAC
Imputed UK10K sequence genotypes from wider GWAS in Twins UK
We plan to share both individual level data (where possible) and summary level SNP results for meta-analysis. Only analysts registered on a UK10K data access agreement will be using the data - currently covers John Perry (KCL side) and Carolina Bonilla (ALSPAC side) for this project.
B2043 - Unwanted pregnancy and psychosis in the offspring An analysis of the data from the ALSPAC - 04/07/2013
Background: Over the last decade, there has been a renewed interest in the role of environmental adversities in the development of psychotic experiences (1-3). It is becoming increasingly evident that such experiences should be understood as "endpoints of atypical developmental trajectories" (5, 6).
In our work at the University of Liverpool, we have also found that communication deviance seems to be especially prevalent in the mothers of psychotic offspring (4). In the same paper, we suggest that disruptions in the child's early development may explain the findings from large birth cohort studies that document subtle developmental asymmetries in children who are later diagnosed with Schizophrenia (10-12).
One risk factor that has been found to be associated with later development of psychosis in the offspring is the unwantedness of the pregnancy (7-9). Unfortunately, these findings have received little attention from the research community and consequently little or no attention has been devoted to explore the potential developmental pathways and mediators that could explain such relationship.
Overall aim: The current study has the primary aim to replicate Myhrman et al.'s findings (7) and secondarily to explore potential mediators of this previously reported association.
Project 1
Aims: To investigate the association between unwanted pregnancy and psychotic experiences in the ALSPAC dataset
Hypothesis: It is anticipated that unwanted pregnancy will be associate with increased likelihood of self-reported psychotic experiences in the offspring.
Exposure variable(s): Unwantedness of the pregnancy
Outcome variable(s): Psychotic experiences
Cofounding variable(s): Maternal history of psychosis, family history of psychosis, socio-economic variables.
Project 2
Aims: To investigate potential mediators of the relationship between unwanted pregnancy and psychotic experiences
Hypothesis: It is anticipated that unwanted pregnancy and paranoia in the offspring will be mediated by low self-esteem, poor self-concept and external locus of control
Exposure variable(s): Unwantedness of the pregnancy
Outcome variable(s): Psychotic experiences [e.g. 'delusions of being spied on' (D1) and 'delusions of persecution' (D2)].
Cofounding variable(s): Maternal history of psychosis, family history of psychosis, socio-economic variables.
Project 3
Aims: To investigate potential mediators of the relationship between unwanted pregnancy and psychotic experiences
Hypothesis: It is anticipated that unwanted pregnancy and self-reported psychotic experiences in the offspring will be mediated by neuro- and social-cognitive variables.
Exposure variable(s): Unwantedness of the pregnancy
Outcome variable(s): Social cognition, neuro-cognition and psychotic experiences
Cofounding variable(s): Maternal history of psychosis, family history of psychosis, socio-economic variables.
Planned analysis:
Paulo de Sousa (PhD student) will carry out the statistical analysis. Initially, basic association between symptoms of psychosis (PLIKSi) and unwanted pregnancy will be tested using binary logistic regression. In a second stage, several mediation models will be estimated using Mplus 6.1.
Bibliographic references
1. Bentall RP. Madness explained: Psychosis and human nature. London: Allen Lane; 2003.
2. Bentall RP. Doctoring the mind : is our current treatment of mental illness really any good? New York: New York University Press; 2009.
3. Varese F, Smeets F, Drukker M, et al. Childhood adversities increase the risk of psychosis: A meta-analysis of patient-control, prospective- and cross-sectional cohort studies. Schizophrenia Bull 2012;38(4):661-671.
4. De Sousa P, Varese F, Sellwood W, Bentall, RP. Parental Communication and Psychosis: A Meta-analysis. Schizophr Bull 2013: sbt088v1-sbt088.
5. Bentall RP, Fernyhough C, Morrison AP, Lewis S, Corcoran R. Prospects for a cognitive-developmental account of psychotic experiences. Brit J Clin Psychol 2007;46:155-173.
6. Bentall RP, Fernyhough C. Social predictors of psychotic experiences: Specificity and psychological mechanisms. Schizophrenia Bull 2008;34(6):1012-1020.
7. Myhrman A, Rantakallio P, Isohanni M, Jones P, Partanen U. Unwantedness of a pregnancy and schizophrenia in the child. Brit J Psychiat 1996;169(5):637-640.
8. Herman DB, Brown AS, Opler MG, et al. Does unwantedness of pregnancy predict schizophrenia in the offspring? Findings from a prospective birth cohort study. Soc Psych Psych Epid 2006;41(8):605-610.
9. McNeil TF, Schubert EW, Cantor-Graae E, et al. Unwanted pregnancy as a risk factor for off spring schizophrenia-spectrum and affective disorders in adulthood: a prospective high-risk study. Psychol Med 2009;39(6):957-965.
10. Cannon M, Caspi A, Moffitt TE, Harrington H, Taylor A, Murray RM, Poulton R. Evidence for early childhood, pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Archives of General Psychiatry 2002;59:449-456.
11. Jones P, Rodgers B, Murray R, Marmot M. Child development risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 1994;344:1398-1402.
12. Welham J, Isohanni M, Jones P, McGrath J. The antecedents of schizophrenia: a review of birth cohort studies. Schizophrenia Bull 2009;35(3):603-623.
B2042 - The Role of Epigenetic Processes in the Developmental of Psychotic Experiences and Disorders in a Non-Clinical Population ALSPAC Study - 04/07/2013
Aims of the Proposed Research
Paper 1: To investigate the role of perinatal insults on gene methylation in mother and child pairs, during pregnancy and at birth, respectively.
Paper 2: To investigate the role of gene methylation (genome-wide DNA methylation) in psychotic experiences at age 12 and 18 years, and a diagnosis of psychotic disorder at age 18 years.
Paper 3: To investigate the role of perinatal insults and gene methylation (genome-wide DNA methylation) in psychotic experiences at age 12 and 18 years, and a diagnosis of psychotic disorder at age 18 years.
Hypotheses
Obstetric complications are expected to result in differential methylation of mother and child gene pairs. Similarly, differential gene methylation in ALSPAC children is expected to be associated with psychotic experiences at age 12 and 18 years, and also with diagnosis of psychotic disorder at age 18 years.
An agnostic stance, rather than a targeted approach, will be used to investigate relationships between early adverse exposures, gene methylation and psychotic experiences. Hypotheses regarding specific gene candidates will not be considered prior to conducting the proposed research.
B2041 - Epigenetic processes mediating between early environment development and psychopathology - 04/07/2013
Summary of aims and objectives: This study will capitalise on environmental, biological and
behavioural data that, together with sequential DNA collections over four time points, from infant
and child saliva, are already available from the Wirral Child Health and Development Study
(WCHADS). This is an MRC funded cohort recruited in pregnancy and followed, so far, to age 5
years, established to identify prenatal, infancy and early childhood risks for child psychopathology.
There is a strong focus on early processes underpinning risks for the conduct disorders, but with
emerging findings also in internalising symptoms. The study has limited funding for genotyping but
none for epigenetics. It is distinctive among cohort studies in using a two stage design that enables
detailed observational and experimental data obtained during pregnancy, infancy and childhood to
be conducted on an epidemiological sample. We are not aware of any other studies that combine
such intensive measurement with sequential DNA collection early in life. We will carry out
comprehensive analyses of DNA methylation allowing us to develop a detailed picture of the
epigenome and gene regulation over early development and in relation to continuities and
discontinuities in early experiences, and stable and changing behavioural phenotypes. The case for
the application is made on the basis of the distinctiveness of the data available from this sample,
and also the degree of overlap and complementarity with collaborating studies, which will allow for
data sharing and replication of novel findings. So far collaborations on methylation analyses have
been established with Barker & Mills (NIH funded study) who have a study of methylation pathways
to conduct disorder using a subsample of ALSPAC participants; Generation R Holland, Teiemier;
McGill University, Canada, Meaney, O'Donnell. We also anticipate collaborative data sharing with a
much wider range of groups, especially those that have identified methylation over regions of
interest later in life, and wish to examine the contributions of early experiences in those regions.
Specific aims include a) to provide evidence on methylation patterns mediating links between
prenatal and early postnatal environmental exposures and later biological and behavioural
outcomes, b) examine the role of differential methylation in explaining gene by environment
interactions in early development, c) use environmental predictors to identify novel environment
sensitive regions of the genome for further study in relation to behavioural phenotypes, d) make use
of our repeated DNA and observational measures to extend findings in other studies, e.g. examine
earlier methylation patterns through infancy in pathways to conduct disorders identified in a
subgroup of the ALSPAC cohort (NIH; Barker & Mills) on the basis of methylation estimated at birth
and later childhood at ages 7 and 9 years.
B2040 - Exploring the developmental overnutrition hypothesis using an allelic score as an instrumental variable - 04/07/2013
AIMS - To determine whether there is a causal, independent intra-uterine effect of maternal BMI and glycemic profile on offspring adiposity and glycemic profile over the lifecourse
HYPOTHESIS - The developmental overnutrition hypothesis describes how intra-uterine conditions affect lifelong risk of offspring obesity. High maternal glycose, free fatty acid, and amino acid concentrations to which the fetus is exposured during pregnancy are proposed to result in permanent changes in appetite control, neuroendocrine functioning, or energy metabolism, leading to increased birth size and greater adiposity in later life. Since maternal BMI is positively associated with insulin resistance and glucose intolerance, and therefore higher plasma concentrations of glucose, fetal overnutrition is more likely among mothers with greater BMI during pregnancy.
EXPOSURE VARIABLES - Maternal pre-pregnancy BMI and glycemic profile during pregnancy (antenatal glucose/insulin)
OUTCOME VARIABLES - Offspring adiposity (BMI and DXA measure) from age 9 to 17
CONFOUNDING VARIABLES - maternal smoking, maternal age at delivery, paternal BMI, parental occupation, parental education, maternal parity, child sex
MEDIATORS - Offspring birthweight
INSTRUMENTAL VARIABLES - allelic score for maternal BMI and glycemic profile, generated from adiposity and insulin/glucose single nucleotide polymorphisms respectively.
B2028 - Analyses of Disparity in Energy intake Metabolism and Adiposity ADEMA A genome-wide association study - 20/06/2013
Aims
We aim to phenotypically refine measures of adiposity and metabolism to encapture a number of individuals that may potentially be described as metabolically healthy obese or metabolically unhealthy non obese and to then explore the potential common genetic variants that are specifically associated with these disparate profiles in ALSPAC Children. We are interested in further analysing other cohorts (TWINS UK) for similarities in these disparities. We also aim to assess replication of our GWAS and to perform a Meta analysis to improve power of results.
B2038 - Infant antibiotic exposure and childhood bone mass - 20/06/2013
Background.
The intestinal microbiota has coevolved with the human genome, and numerous studies suggest that the gut microbiome and human physiology and metabolism are integrated. The composition of the gut microbiota has been associated with immune development and regulation (1), lipid deposition (2), and plasma glucose levels (3). In humans, treatment with vancomycin is associated with development of adiposity (4) and exposure to antibiotics in early life was recently linked to increased body mass index in childhood (5).
Potential effects of the gut microbiota on bone metabolism have only been investigated in a limited number of studies. In mice, absence of gut microbiota leads to increased bone mass and fewer osteoclasts in the trabecular bone as well as a lower number of CD4 positive cells and osteoclast precursor cells in the bone marrow. Colonisation of germ free mice normalised bone mass and the number of CD4 positive cells in the bone marrow (6). Furthermore, treatment of mice with penicillin, vancomycin or the combination of vancomycin and ampicillin is associated with increased bone mass and size (7).
Effects on bone health of increasing activity of selective gut microbes, through the use of prebiotics, have been assessed in a number of small laboratory and clinical studies. Compared to placebo, intake of a prebiotic (non-digestible oligosaccharides derived from lactose) increased trabecular bone mass in rats, possibly due to improved utilization of calcium and magnesium (8). In humans, treatment with prebiotics (short- and long-chain inulin-type fructans) has been shown to increase calcium absorption and bone mineralization during pubertal growth, and the effects appears to be modulated by common genetic variations in the vitamin D receptor (9). In addition, prebiotic and antibiotic treatments in humans are associated with changes in the secretion of glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (10, 11) and these gut hormones may play a role in the regulation of bone formation and resorption (12, 13).
The modulation of gut microbiota by antibiotics could potentially affect clinically relevant measures of bone mass and quality in humans, in particular attainment of peak bone mass, and, consequently, the risk of fragility fractures in adulthood.
Aims.
* To investigate if exposure to antibiotics in early life is associated with changes in total body bone mass in childhood.
* To determine if associations between early antibiotic use and subsequent total body bone mass persist after adjustment for potential confounding factors such as altered body composition.
* To examine if exposure to antibiotics in early life is likely to affect the risk of clinical events related to osteoporosis in later life, such as hip fracture, based on associations with hip BMD.
* To study the relative contribution of alterations in cortical bone size, thickness, density and turnover to relationships between early life exposure to antibiotics and bone mass which we observe, based on tibial pQCT scan measurements and CTX results.
Hypothesis.
Early life exposure to antibiotics influences gut microbiota, which changes bone metabolism. These alterations cause increases in bone mass in late childhood.
Exposure variables.
Antibiotics in the first 24 months of life.
Outcome variables.
* Indices of total body bone mass as measured by dual-energy x-ray absorptiometry at ages 9.9, 15.5 and 17.8 years.
* Hip BMD as measured at age 13.5 and 15.5
* Cortical bone indices as measured by tibial pQCT at age 15.5 years and 17.8 years
* CTX at age 15.5 years
Confounding variables.
Sex, height, weight, fat mass, lean mass, smoking in first trimester, breast feeding, Tanner stage, physical activity, vitamin D status, socio-economic status/maternal education, insulin, glucose, lipids, leptin, adiponectin, CRP
References.
1. Sommer F, Backhed F. The gut microbiota--masters of host development and physiology. Nature reviews Microbiology 2013; 11(4): 227-38.
2. Backhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 2004; 101(44): 15718-23.
3. Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013; 498(7452): 99-103.
4. Thuny F, Richet H, Casalta JP, Angelakis E, Habib G, Raoult D. Vancomycin treatment of infective endocarditis is linked with recently acquired obesity. PLoS One 2010; 5(2): e9074.
5. Blustein J, Attina T, Liu M, et al. Association of caesarean delivery with child adiposity from age 6 weeks to 15 years. Int J Obes (Lond) 2013.
6. Sjogren K, Engdahl C, Henning P, et al. The gut microbiota regulates bone mass in mice. J Bone Miner Res 2012; 27(6): 1357-67.
7. Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 2012; 488(7413): 621-6.
8. Weaver CM, Martin BR, Nakatsu CH, et al. Galactooligosaccharides improve mineral absorption and bone properties in growing rats through gut fermentation. Journal of agricultural and food chemistry 2011; 59(12): 6501-10.
9. Abrams SA, Griffin IJ, Hawthorne KM, et al. A combination of prebiotic short- and long-chain inulin-type fructans enhances calcium absorption and bone mineralization in young adolescents. Am J Clin Nutr 2005; 82(2): 471-6.
10. Cani PD, Lecourt E, Dewulf EM, et al. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am J Clin Nutr 2009; 90(5): 1236-43.
11. Francois F, Roper J, Joseph N, et al. The effect of H. pylori eradication on meal-associated changes in plasma ghrelin and leptin. BMC gastroenterology 2011; 11: 37.
12. Tsukiyama K, Yamada Y, Yamada C, et al. Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion. Mol Endocrinol 2006; 20(7): 1644-51.
13. Yamada C, Yamada Y, Tsukiyama K, et al. The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 2008; 149(2): 574-9.
B2037 - Fetal Sex and Maternal Prenatal Psychopathology - 20/06/2013
Rationale: Preliminary analyses in the Generation R project revealed a small but significant association between fetal sex and maternal prenatal psychological distress. Mothers of male fetuses appear to be more anxious and score higher on Global severity scale (GSI) of the Brief Symptom Inventory (BSI) at 20 weeks pregnancy. Mothers were not aware of fetal sex at the time of BSI completion.
Aims: To replicate the above findings in Alspac's large sample.
Hypotheses: We expect to find that fetal sex will predict differences in maternal reported prenatal mood, as per our findings in the Gen R sample.
Predictor variables: Fetal sex.
Outcome variable: Maternal mood (depression and anxiety) in pregnancy (preferrably before determination of fetal sex, but close in time to that point).
Confounding variables (optional): Parity, maternal age, ethnicity, maternal education, pre-pregancy BMI.