Proposal summaries
B2090 - Statistical methods to improve clinical interpreation of physiological data from real-time monitoring devices - 03/10/2013
The aim of this project is to develop the analysis of complex, high-dimensional, functional data collected from research into sleep, glucose and cardiometabolism. The identification of zeitgebers in sleep/activity, light and temperature, and their prediction of patterns in glucose and melatonin, will be explored. Ambulatory blood pressure is measured using personally-worn devices.
The outcome is blood pressure measured over time and the exposures of interest are age and sex, with adjustment for the usual confounders.
These types of data are becoming more widespread as the technology develops for personal measures of real-time events. The overarching characteristic is that they produce patterns over time. A recent review (Ullah & Finch, 2013) concluded that there is a lack of appreciation of the value of FDA for biomedical problems.
The aim of the proposed project is to develop clinically relevant statistical techniques for analysing real time complex data made available through recent advances in ambulatory physiological monitoring systems, and thereby establish:
1. the strengths and weaknesses of each statistical and methodological technique for generating comprehensive and holistic analyses of real time complex data series;
2. the extent to which these statistical techniques might offer more sophisticated interpretations of real time physiological data recorded from free-living patients, and thereby improve the clinical acuity of aetiological, diagnostic and prognostic investigations; and
3. the most appropriate format(s) in which such techniques might be made available for non-specialist biomedical technicians and clinicians to optimise the impact of these techniques on aetiological, diagnostic, prognostic and therapeutic decision-making.
A dedicated Work Package for each of these three objectives will involve an assessment of empirical evidence drawn from:
Work Package 1. continuously recorded measurements of interstitial glucose concentration, activity, ambient temperature and light from free living pregnant women with gestational diabetes in order to identify any occult glycaemic abnormalities capable of predicting macrosomia and/or abnormal neonatal glycaemic control - data that will support a robust comparison of the different analytical techniques examined;
Work Package 2. clinically relevant real time physiological data series provided by project partners from the commercial (industrial) and public (healthcare) sectors using recent advances in ambulatory monitoring systems for: body temperature; ECG, EMG and EEG; respiration; blood pressure; heart rate; and blood oxygenation - data that will allow the team to assess the generalisable utility of the analytical techniques developed in WorkPackage 1; and developmental workshops with commercial and public sector partners where mechanisms and associated tools for supporting the uptake, application and integration of the analytical techniques developed and tested in Work Packages 1 and 2 will be designed and implemented - data that will ensure that any advanced statistical techniques become available in a format that is accessible and useful to non-specialist biomedical technicians and clinicians.
B2089 - Prenatal lead exposure gene polymorphisms and child temperament - 26/09/2013
We propose to test three specific hypotheses for children experiencing a range of low-to-moderate prenatal BLL concentrations:
1)Higher BLLs will be associated with higher parent ratings of the child on negative temperamental attributes (grizzly, fretful, stubborn, demanding, unresponsive, active) and lower ratings on positive attributes (happy, alert, cuddly, sociable) at 4 weeks of age when the infants also have polymorphisms previously related to negative emotionality or heightened behavioral reactivity.
2)Higher BLLs will be associated with higher parent ratings of activity, approach, intensity, and distractibility at 6 and 24 months among children who also have polymorphisims previously shown to be related to negative emotionality or heightened behavioral reactivity.Higher BLls will be associated with lower scores on rhythmicity, adaptability, mood, persistence and threshold in the presence of the same gene polymorphisms.
3)Higher BLLs will not be associated with negative temperament traits at 6 and 24 months among children who have gene polymorphisms previously shown to be related to altruism or self-regulation.
In addition to gene-environment interactions, we will test for interactions between maternal hemoglobin and lead levels on the same outcomes to understand if maternal nutritional status acts as a protective or susceptibility factor for the assocation between lead exposure and temperament.
B2088 - Metabolomic and Epigenomic Mechanisms in Developmental Overnutrition - 26/09/2013
AIMS
Our overarching aim is to determine the role of metabolomic and epigenomic mechanisms in the relationships between maternal risk factors for developmental overnutrition and offspring adiposity and related metabolic outcomes. We will also determine the effects of these intrauterine mechanisms on greater adiposity and associated metabolic risk into the next generation. Three related aims with specific objectives are detailed below and illustrated in figure 1 of the research strategy.
Aim 1: To determine the role of metabolomic mechanisms in developmental overnutrition, by identifying:
1.1: The associations of established maternal developmental overnutrition risk factors (adiposity in early pregnancy, gestational adipose gain, gestational diabetes (GDM) and continuous measures of fasting and postload glucose and fasting insulin) with maternal pregnancy metabolome, quantified in serum by nuclear magnetic resonance (NMR) spectroscopy.
1.2: The associations of established maternal developmental overnutrition risk factors and pregnancy metabolome with fetal metabolome, quantified in cord serum by NMR spectroscopy.
1.3: The associations of maternal pregnancy and fetal metabolome with offspring adiposity (BMI, waist, skinfolds, fat mass) from birth through to early adulthood, and with metabolic outcomes (fasting glucose, insulin and lipids from mid-childhood to early adulthood; metabolome in infancy and in adolescence).
1.4: The extent to which maternal pregnancy and/or fetal metabolome mediate the associations of established developmental overnutrition risk factors with offspring adiposity and metabolic outcomes.
Aim 2: To determine the role of epigenetic mechanisms in developmental overnutrition, by identifying:
2.1: The associations of established developmental overnutrition risk factors with fetal genome-wide DNA methylation, analysed on cord blood white cell DNA, with the Illumina 450K HumanMethylation array.
2.2: The associations of pregnancy and fetal metabolome with cord blood white cell DNA methylation.
2.3: The associations of cord blood white cell DNA methylation with offspring adiposity and metabolic outcomes.
2.4: The extent to which cord white blood cell DNA methylation differences mediate the associations of established maternal developmental overnutrition risk factors with postnatal offspring adiposity and metabolic outcomes.
Aim 3: To explore the role of developmental overnutrition, including metabolomic and epigenomic mechanisms, on risk of greater adiposity and metabolic outcomes in two generations.
[Note. we have used the following notation in objectives 3.1-3.3: G0=index pregnant women on whom developmental overnutrition risk factors were measured; G1= offspring of G0; G2 = offspring of G1 and their partners]
3.1: We will determine whether the G1 females who have been exposed to higher levels of intrauterine developmental overnutrition, determined by a weighted score of G0 developmental overnutrition risk factors, enter their pregnancies with greater adiposity and more adverse metabolic outcomes than G1 females who are less exposed to developmental overnutrition by their G0 mothers.
3.2: We will determine the associations of G1 female exposure to developmental overnutrition with G2 cord serum metabolome, cord blood white cell DNA methylation, birth weight and infant adiposity.
3.3: We will compare the associations examined in 3.2 to equivalent associations with exposure to different levels of intrauterine developmental overnutrition in G1 males.
B2087 - Methylation of maternal and cord blood as a mechanism in G x E interaction - 26/09/2013
Aims: There are many relationships between features of lifestyle and other exposures to the parents that have been shown to be related to the growth, behaviour and development of the child, but there is rarely a convincing mechanism to explain how they occur. This study aims to determine, for each of the known relationships, whether DNA plays a part in the mechanism.
The hypothesis is that DNA methylation is a mechanism to 'explain' a number of relationships between the environment and measures of growth, cognitive development and behaviour. The presumed mechanism is shown diagrammatically as follows:
Exposure to parents ? Methylation of mother's and/or child's blood ? child outcome
Exposure variables: The proposed study will concentrate on exposures related to toxins (particularly cigarette smoking), ionising radiation (especially X-rays and radon levels in the residential areas in which the parents were born and currently live which can be linked to 3-digit postcode using published data), nutrition (especially related to fish intake and to dietary patterns in pregnancy), and stress (particularly acute stressors during the parents' life-course, chronic stressors using social circumstances, and measures of their anxiety levels). Exposures to the parents and grandparents will be included.
Outcome measurements will concentrate on growth, behaviour, intellectual development and educational attainments (including SATS results as well as the ALSPAC assessments of maths, reading, spelling, scientific understanding and phoneme awareness).
Confounders will be chosen based on the original reports of an association between an exposure and an outcome. It is important to recognise that we are mainly testing the possibility of DNA methylation explaining relationships that have already been reported.
A variety of statistical analyses will be undertaken: (i) relationship between prior exposures to the mother and her parents and methylation of the mother's blood; (ii) relationship between the mother's methylation pattern and that in the cord blood; (iii) relationshipbetween exposures to both parents and grandparents andthe methylation levels of the cord blood; (iv) determination of ways in which these methylation patterns may explain how relevant exposures have influenced outcomes.
B2086 - Does methylation mediate the effect of physical activity on obesity in childhood - 26/09/2013
Background
Evidence implies that there is an association between physical activity and DNA methylation and between methylation and obesity. I will therefore explore the potential mediating relationship of methylation in the relationship between activity and obesity, using epigenome-wide data which have only recently become available on this scale.
Objectives
Primary objectives:
1)Identify methylation variation associated with physical activity and then consider how this variation relates to obesity.
2)Use Mendelian randomisation to investigate causality in any associations between physical activity, differentially methylated regions (DMRs) of the genome, and obesity.
3)Investigate the underlying biological mechanisms that the DMRs may be acting through.
Secondary objective:
1)Explore the relationship between physical activity, DNA methylation variation and cardiovascular health in children.
B2084 - CLOSER SES DATA HARMONISATION - 19/09/2013
The Cohorts and Longitudinal Studies Enhancement Resources (CLOSER) project aims to provide and document a range of key variables that have been harmonised across multiple UK birth cohorts to encourage cross-cohort research on longitudinal data sets and permit compatrisons across as well as within cohort studies. Due to the restrictions on using and holding ALSPAC data (particularly data obtained through linkage) it is our aim to derive standardised measures from education, income and social class variables that are harmonised with derived data from the other cohorts. These variables, once derived, will be deposited back to ALSPAC with accompanying documentation and will not specifically be used for research outputs at this point other than documenting summary statistics. As such, there are no exposure, outcome or confounding variables to outline.
Documentation will be held by CLOSER and made readily available to researchers in an attempt to provide a suitable search platform for commonly requested variables and therefore encourage cross-cohort analysis of data.
B2083 - Use of cancer-related genetic scores to investigate association with intermediate phenotypes - 19/09/2013
Recently, and mostly thanks to genomewide association studies, a large number of DNA polymorphisms have been identified that are associated with cancer risk (http://www.genome.gov/gwastudies/). This has been the case particularly for breast and prostate cancer, and in a smaller proportion for colorectal and skin cancer. If these polymorphisms are combined in an overall score, the score will likely better explain variation in the trait than individual SNPs.
Additionally, several non-genetic cancer risk factors have been uncovered and validated, whilst findings for others have been inconclusive.
Aims & hypothesis
We propose to examine the relationship of genetic scores that reflect variation in cancer risk with exposures that have been associated with the same types of cancer, in ALSPAC children. We are also interested in running hypothesis-generating analyses using the genetic scores and metabolomic data when it becomes available.
In this way we will be able to define potential pathways through which the genetic risk factors exert their actions, and which will also indicate possible targets for treatment.
By examining this relationship in children we expect to identify relevant risk factors while overcoming the problem of reverse causation that may arise when investigating exposures in individuals already affected by the disease.
B2082 - Hypertensive disorders of pregnancy and long term paternal cardiometabolic health - 19/09/2013
Both pre-eclampsia and intrauterine growth restriction are associated with abnormal placentation. For successful placentation, tolerance against partner alloantigens is necessary(1). Several, but not all(2), epidemiological studies suggest that an increased risk of pre-eclampsia and of small-for gestational-age (SGA), may be transmitted through the father.
Large registry based studies from Norway and the USA have shown that men born to a pre-eclamptic pregnancy had a higher risk of fathering a pre-eclamptic pregnancy themselves, compared to men unexposed to maternal pre-eclampsia(3-4). Using data from the Norwegian registers, Lie et al. have shown that the increase in risk of a second pre-eclamptic pregnancy was somewhat greater when both pregnancies were fathered by the same individual, though an increased risk of a second pre-eclamptic pregnancy following a first pre-eclamptic pregnancy was observed regardless of the father's identity(5). Furthermore, the risk of pre-eclampsia in any pregnancy was 1.8-fold higher (95%CI: 1.2, 2.6) when the father had previously fathered a pre-eclamptic pregnancy in another woman(5). Similar results were reported in a study in California, that also reported that an increase in the risk of pre-eclampsia was associated with a change in partner amongst women without pre-eclampsia in a first pregnancy(6). In contrast, a similar analysis using data from the Swedish national registers found no important paternal influence on the risk of pre-eclampsia(2). A more recent study using the Norwegian registers found that partner change was associated with a reduced risk of preterm pre-eclampsia and SGA recurrence, and with an increased risk of SGA in a second pregnancy among women who did not deliver a SGA baby in their first pregnancy. However the risk of term pre-eclampsia was not affected by partner change(1).
Using data from the Norwegian registers once more, Irgens et al, found that fathering a first pregnancy complicated by pre-eclampsia pregnancy was not associated with an increased risk of paternal death from cardiovascular causes (term preeclampsia vs term non-preeclampsia HR=1.01, 95%CI: 0.81 & preterm preeclampsia HR=1.07 & 1.03; 95%CI: 0.55, 1.92). In contrast, women with pre-eclampsia had increased CVD mortality (HR=1.65; 1.01, 2.70 and HR=8.12; 95%CI: 4.31, 15.33 for term and pre-term pre-eclampsia versus term non pre-eclamptic women respectively). Authors concluded that whilst paternal genes in the fetus may increase the risk of pre-eclampsia in a particular pregnancy, such genes are probably not related to CVD risk(7). Similarly, Mylestad et al. found no association between fathering a pregnancy complicated by a hypertensive disorder of pregnancy (HDP) and a range of CVD risk factors measured some 18 years post pregnancy using data from the Norwegian HUNT study(8). The findings of these two studies are in sharp contrast with a consistent body of evidence suggesting that women with a history of pre-eclampsia and gestational hypertension (the hypertensive disorders of pregnancy, HDP) are at increased risk of CVD later in life(9).
To the best of our knowledge the study by Irgens et al. is the only one to have examined the association of fathering a pre-eclamptic pregnancy with future CVD risk in men. Our aim is to assess whether men who fathered a pregnancy complicated by HDP, prematurity or SGA have more adverse cardiometabolic health 18 years post-pregnancy compared to men who fathered a normotensive, term non-SGA pregnancy.
Exposures: HDP (normotensive, gestational hypertension, preeclmpsia), preterm delivery and SGA in the ALPSAC index pregnancy;
Potential confounders and mediators: Maternal & paternal age at pregnancy, maternal & paternal prepregnancy BMI, maternal & paternal smoking in pregnancy, parity, household occupational social class, alcohol consumption, physical activity, pregnancy diabetes, birthweight, gestational age.
Outcomes: Paternal adiposity, blood pressure, lipids, glucose, insulin, inflammatory markers, pulse wave velocity.
References
1. Wikstrom AK, Gunnarsdottir J, Cnattingius S. The paternal role in pre-eclampsia and giving birth to a small for gestational age infant; a population-based cohort study. BMJ Open 2012;2(4).
2. Cnattingius S, Reilly M, Pawitan Y, Lichtenstein P. Maternal and fetal genetic factors account for most of familial aggregation of preeclampsia: a population-based Swedish cohort study. Am J Med Genet A 2004;130A(4):365-71.
3. Skjaerven R, Vatten LJ, Wilcox AJ, Ronning T, Irgens LM, Lie RT. Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort. BMJ 2005;331(7521):877.
4. Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo J, et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 2001;344(12):867-72.
5. Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ 1998;316(7141):1343-7.
6. Li DK, Wi S. Changing paternity and the risk of preeclampsia/eclampsia in the subsequent pregnancy. Am J Epidemiol 2000;151(1):57-62.
7. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 2001;323(7323):1213-7.
8. Mykelstad K, Vatten LJ, Salvesen KA et al. Hypertensive disorders of pregnancy and paternal cardiovascular risk: a population based study. Ann Epidemiol. 2011; 21:407-12.
9. Rich-Edwards JW FA, Lawlor DA, Catov JM. Pregnancy characteristics and women's future cardiovascular health: an underused opportunity to improve women's health? Epidemiologic Reviews In Press.
B2081 - Alcohol harms in the family - 19/09/2013
Aims relating to ALSPAC
This project aims to identify the mechanisms by which different levels, patterns and durations of alcohol consumption by one family member impact the health, well-being and life opportunities of other family members.
Hypotheses
Core hypotheses (children):
1. Having a heavy drinking parent in the household will have a negative effect on child outcomes at present and future waves.
2. Negative effects will be more pronounced when (a) the mother rather than father is a heavy drinker and (b) where both parents rather than only one parent are heavy drinkers.
3. Amongst children with a drinking parent, negative effects will be more pronounced where (a) other risk factors are in place, (b) the drinking has an effect on parenting behaviours and (c) the drinking negatively affects the relationships in the household.
4. Negative effects will be less pronounced where heavy drinking is not present at all waves either due to cessation or the drinker leaving the household.
5. Negative effects will be less pronounced where children have protective or resilience factors in place.
Core hypotheses (partners)
1. Having a heavy drinking partner (HDP) will have a negative effect on the other partner's (OP) well-being.
2. Having a HDP will reduce the OP's relationship satisfaction and increase the likelihood of relationship breakdown.
3. Negative effects for the OP will be more pronounced where (a) the OP drinks significantly less/less often than the HDP (b), the OP experiences other concurrent risk factors and (c) the HDP's heavy drinking persists across multiple waves.
4. Negative effects on the OP will be less pronounced where protective or resilience factors are in place.
Exposure:
Drinking measures
High level of consumption
High score on dependence screeners
Perceived drink problems
Outcome measures:
Child development:
- Cognitive
- Behavioural
- Social
- Psychological/emotional
- Parent/child relationship
Child health:
- Developmental milestones
- Health problems
- Accidents
Adult (mother and partner) well-being:
- Mental health
- General health
- Quality of life
Mother and partner relationships:
- Relationship satisfaction
- Relationship breakdown
- Domestic abuse
Moderators/mediators
Parenting behaviours, style, resources and self-efficacy
Family organisation (e.g. regular mealtimes)
Social support
Parental mental health*
Household composition (e.g. no. of children)
Marital status*
Socioeconomic status
Demographic characteristics (e.g. age, gender, ethnicity)
Financial measures (e.g. income, debt)
Housing situation and characteristics (e.g. social housing, safe environment, neighbourhood deprivation)
Residential area characteristics (e.g. area-level deprivation)
*Indicates risk, resilience or protective factors which are also outcome measures in their own right.
B2079 - Deductions about human traits and health from ABCC11 genotype - 12/09/2013
BACKGROUND
The ABCC11 gene encodes the multidrug resistance protein 8 (MRP8) (Kruh et al., 2007). This protein is involved in transport of many small molecules in normal physiology, in a variety of cellular and biological contexts. There is strong evidence suggesting that genetic variation at ABCC11 has pleiotropic effects. In particular, a functional non-synonymous SNP (rs17822931), also known as 538G-A or G180R, determines human earwax type (Yoshiura et al., 2006) and axillary osmidrosis (Nakano et al., 2009;Martin et al., 2010) and is associated with apocrine colostrum secretion from the mammary gland (Miura et al., 2007). It has also been related to breast cancer risk, although this is more controversial [(Toyoda and Ishikawa, 2010) and references therein].
rs17822931 genotype AA determines dry earwax type, while the presence of at least one G allele (GA or GG) determines wet earwax type. There are marked differences in rs17822931 allele frequencies across ethnic groups (Yoshiura et al., 2006;Toyoda et al., 2009;Toyoda and Ishikawa, 2010). There is a higher frequency of the A allele in East Asians and therefore higher prevalence of dry earwax type. In contrast, the wet earwax type is more prevalent in European and African populations due to higher frequencies of the G allele.
There is a close histological and functional relationship between ceruminous and apocrine sweat glands. This relationship is believed to explain the connection between earwax and axillary odor (Martin et al., 2010). AA homozygous individuals for rs17822931 display little of the characteristic axillary odorants (Preti and Leyden, 2010;Martin et al., 2010). In contrast, a study of Japanese individuals showed that essentially all individuals with axillary osmidrosis were GG or AG for rs17822931 (Nakano et al., 2009). This indicates that the G allele is necessary and sufficient to cause axillary odor, whereas AA genotype effectively marks non-odorous individuals.
In a recent study (Rodriguez et al., 2013) we have shown for the first time that there is a strongly significant (P=3.7x10^-20) differential usage of deodorant according to rs17822931 genotype. This represents the first evidence of a behavioural effect associated with rs17822931, that is directly relevant to the pharmacogenetics of body odour (Brown, 2013).
Two remarkable findings in relation to the behaviour of axillary deodorant use were that nearly 80% of European genetically non-odorous still use deodorant, whereas one in 20 individuals genetically odorous did not use it. This opens the possibility of a more complex scenario to explain the genetic basis of this human behaviour. To explore this possibility, an analysis of association at the whole genome level would therefore be required. However, a genome-wide analysis of genetic factors associated with deodorant usage has not been performed to date.
In addition, the potential role of ABCC11 genetic variation on other traits has not been studied yet. An interesting field is audition. One of the causes of hearing loss, pain and dizziness is cerumen impactation (McCarter et al., 2007). Ear wax impacts on audition and therefore, the involvement of rs17822931 on ear wax determination makes ABCC11 a good candidate for audition variation among individuals. A more controversial role of earwax is its potential involvement on earache. A common idea among GPs is that earwax does not cause earache and that one of effects of ear infection is the melting of earwax. However, in a pilot study in ALSPAC (approved by the executive, B586) we have found a significant association between earache at age 6-30 months and rs17822931. Muc more detailed analyses are required to understand this novel association and with the great depth of phenotypes involved, this needs an RA for at least a few months, it is not "an afternoon's work.". Similarly, the known role of rs17822931 in apocrine glands opens the possibility that ABCC11 could exert another pleiotropic effect, also acting on breast size. An interplay between breast size, breastfeeding and body odour should also be analysed.
HYPOTHESIS
That the functional SNP rs17822931 in ABCC11 has pleiotropic effects on earache and hearing, additional to its known effects on earwax, deodorant use and colostrum secretion.
AIMS
1.- To perform a phenome scan of all earache and hearing related phenotypes in ALSPAC in relation to rs17822931
2.- To conduct Genome-wide Association Studies on all reported and candidate pleiotropic effects associated with rs17822931, with special reference to deodorant use, earache and hearing.
3.- To access to record linkage data in order to gain more information from GP records to be added to the existing variables already available in ALSPAC
REFERENCES
Brown S. The Pharmacogenetics of Body Odor: As Easy as ABCC? J Invest Dermatol 2013; 133: 1709-1711.
Kruh GD, Guo Y, Hopper-Borge E, Belinsky MG, Chen ZS. ABCC10, ABCC11, and ABCC12. Pflugers Arch 2007; 453: 675-684.
McCarter DF, Courtney AU, Pollart SM. Cerumen impaction. Am Fam Physician 2007; 75: 1523-1528.
Martin A, Saathoff M, Kuhn F, Max H, Terstegen L, Natsch A. A functional ABCC11 allele is essential in the biochemical formation of human axillary odor. J Invest Dermatol 2010; 130: 529-540.
Miura K, Yoshiura K, Miura S et al. A strong association between human earwax-type and apocrine colostrum secretion from the mammary gland. Hum Genet 2007; 121: 631-633.
Nakano M, Miwa N, Hirano A, Yoshiura K, Niikawa N. A strong association of axillary osmidrosis with the wet earwax type determined by genotyping of the ABCC11 gene. BMC Genet 2009; 10: 42.
Preti G, Leyden JJ. Genetic influences on human body odor: from genes to the axillae. J Invest Dermatol 2010; 130: 344-346.
Rodriguez S, Steer CD, Farrow A, Golding J, Day IN. Dependence of Deodorant Usage on ABCC11 Genotype: Scope for Personalized Genetics in Personal Hygiene. J Invest Dermatol 2013; 133: 1760-1767.
Toyoda Y, Ishikawa T. Pharmacogenomics of human ABC transporter ABCC11 (MRP8): potential risk of breast cancer and chemotherapy failure. Anticancer Agents Med Chem 2010; 10: 617-624.
Toyoda Y, Sakurai A, Mitani Y et al. Earwax, osmidrosis, and breast cancer: why does one SNP (538Ggreater than A) in the human ABC transporter ABCC11 gene determine earwax type?FASEB J 2009; 23: 2001-2013.
Yoshiura K, Kinoshita A, Ishida T et al.A SNP in the ABCC11 gene is the determinant of human earwax type. Nat Genet 2006; 38: 324-330.
B2078 - Risk and resilience to educational underachievement associations between education language and social disadvantage - 12/09/2013
Aims:
i. Examine language and communication skills as risk and resilience factors in relation to populations at high-risk of educational underachievement.
ii. Determine the extent to which language skills play a role in educational outcomes at GCSE, once school characteristics and socioeconomic factors have been accounted for.
Hypotheses:
1) Language ability in early childhood will be a significant factor in explaining variation in educational outcomes, once school characteristics and socioeconomic factors have been accounted for.
2) Young people with language difficulties will be less likely to have positive educational outcomes upon leaving school.
Variables:
Exposure variable: Language ability (a composite measure based on WOLD comprehension and expression scores, Children's Communication Checklist scores).
Outcome variable: Educational outcomes at school-leaving age (GCSE or equivalent).
Confounding variable: school characteristics (school census data, for example: number of children eligible for free school meals), socioeconomic background (composite based on home ownership, overcrowding score, and maternal education), child characteristics (e.g. ethnicity, first language).
Method:
Secondary analysis of the ALSPAC data will examine the complex associations between language and educational attainment in order to understand which young people are at risk of educational underachievement in secondary school.
The research team will consist of Dr Sarah Spencer (applicant for the ESRC Future Research Leaders research funding) and Dr Yvonne Wren (academic mentor and advisor on the project). The project will form part of a wider research programme examining the associations between language and learning in secondary schools in areas of social deprivation (working with two school partners).
The ALSPAC data will be discussed with both the project policy steering group and a group of young people (participants in Stage 2) to further develop specific research questions and following analysis. This will ensure that findings are relevant for key policy questions and educational practice. The policy steering group will include representatives from: partner schools (senior management), the third sector (Mary Hartshorne, Head of Quality and Outcomes for ICAN, the children's communication charity), The Communications Trust (Wendy Lee, Professional Director), the think-tank Centre for Labour and Social Studies (CLASS), and the Royal College of Speech and Language Therapists (Mark Hope, RCSLT).
The project will employ a post-doctoral research associate (statistician) to work closely with the research team.
Analysis will include:
- filtering variables where distribution is such that they have no potential in the modelling process;
- grouping of risk and resilience factors based on existing research theory;
- grouping children into those who have and do not have profiles of assessments which indicate the presence of language difficulties;
- calculation of whether the presence of language difficulties decreases the likelihood of achieving five or more GCSE grades at A*-C grade or equivalent (a measure of good educational outcomes);
- running a series of univariable regression analyses to test the strength of associations between exposure and confounding variables with the outcome variable (school attainment);
- multivariable regression modelling to derive a final set of variables independently associated with educational attainment at the end of compulsory schooling.
This project will use the recently analysed language scores taken when children were aged 8 years. These include the built files from the Wechsler Objective Language Dimensions (WOLD). Sarah Spencer was involved in the process of analysing and scoring the WOLD samples, along with colleagues at the University of Sheffield and Dr Yvonne Wren.
Outcomes: Users of the research findings will be provided with a richer understanding of the role of language in educational attainment and how this interacts with socioeconomic factors. Target journal: British Educational Research Journal.
B2077 - Association between paternally inherited GNAS SNP alleles and birth weight - 12/09/2013
Aim: Determine whether variations in the paternally expressed GNAS splice variant XL-alpha S affect normal fetal growth?
Background: The term pseudohypoparathyroidism (PHP) refers to several rare, yet related human disorders. PHP type Ia (PHP-Ia) is characterized by an abnormal regulation of calcium and phosphate homeostasis because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules; affected patients furthermore have developmental abnormalities referred to as Albright Hereditary Osteodystrophy (AHO) and often resistance towards other hormones such as TSH and GHRH that mediate their actions through Gs-alpha-coupled receptors. PHP type Ib (PHP-Ib) is characterized by hypocalcemia and hyperphosphatemia due PTH-resistance, typically without evidence for AHO. PHP-Ia and PHP-Ib are both imprinting disorder that are caused by maternal mutations within or up-stream of the GNAS locus on chromosome 20q13.3. This complex locus encodes the stimulatory G protein (Gs-alpha; GNAS exons 1-13) as well as several splice variants thereof, including XL-alpha S (GNAS exons 2-13, plus an XL-specific first exon), the extra-large form of Gs-alpha that is expressed only from the paternal, non-methylated GNAS allele.
Hypothesis: Are variations in XL-alpha S associated with normal fetal growth?
Very recently, we discovered through a collaboration with colleagues in France that paternal GNAS mutations are associated with intrauterine growth retardation (IUGR) (Richard et al., JCEM, 2013). Interestingly, mutations in GNAS exon 1, i.e. the exon specific for Gs-alpha, do not seem to lead to severe IUGR. This suggests that XL-alpha S, which uses the XL-specific first exon, contributes primarily to growth retardation. Conversely, biallelic XL-alpha S expression, as observed in patients with patUPD20q, is associated with enhanced fetal and probably also post-natal growth.
Our observations, which are surprising, led us to conclude that normal XL-alpha S expression from the paternal GNAS allele is essential for the prevention of IUGR and that XL-alpha S expression from both parental alleles results in much enhanced growth rates.
To investigate these findings in rare human disorders further and to determine whether the paternal GNAS haplotype is associated with fetal growth, we now propose to re-analyze some of the recently published GWAS data (Horikoshi et al 2013), namely the data from ALSPAC mother-child pairs.
The investigative plan would be as follows:
1) Define the region of interest at the GNAS locus on chromosome 20q13.3 and select SNPs from the maternal and fetal GWAS data within this region.
2) Deduce the paternally inherited allele, where possible, across the GNAS locus for each of these SNPs.
2) Use these deduced paternal allele data to determine whether inheritance of paternal (but not maternal) alleles is associated with impaired growth.
If this provides further evidence for a role of XL-alpha S in fetal development, we would then seek replication of the associations in further studies, e.g. in the EGG Consortium. If the association holds up, we could search in IUGR patients for paternal mutations in exon XL or its regulatory regions, i.e. in the exon specific for XL-alpha S; the identification of such XL-specific mutations would obviously be very exciting, as not much is known about the role of XL in normal human biology. In fact, our recent birth weight data for patients with either paternally or maternally inherited GNAS mutations have provided the first hints regarding its role in humans.
B2074 - The effect of marital relationships on cardiovascular outcomes in men - 10/09/2013
Aims:
To understand the role of marital relationship quality in the development of cardiovascular risk factors
Hypothesis:
Poor quality marital relationships are associated with worsening cardiovascular risk factors.
B2076 - Identifying genetic variants influencing common ENT infections - 05/09/2013
Background: Recurrent ear, nose and throat (ENT) infections and their sequelae (recurrent and chronic illness, high risk for language delay, learning and behavioural problems) are common and costly paediatric health issues caused by complex interactions among pathogenic, genetic and environmental factors. The middle ear, nose and throat may be conceptualized as a unified organ, which are susceptible viral and bacterial infection from similar pathogens. Genetic epidemiological studies (both in the BLATS sample and in Norwegian twin study) have found significant genetic correlations between susceptibility to ENT infection indicating the presence of shared genetic risk factors influencing these illnesses.
Aims: The proposed project aims to identify genetic variants influencing common ENT illnesses. We have previously conducted genome wide association (GWAS) analyses of common ENT infections within the Brisbane Longitudinal Adolescent Twin Study (BLATS) and are seeking to replicate and extend these findings through collaboration with the ALSPAC study.
Exposure Variables: NA
Outcome Variables: As minor ENT infections are very common among children we will analyse surgical interventions performed to mediate these infections to focuss on more severe and reccurent illness. As such ENT illness will be identifed using parental reprts of tonsillectomy, adenoidectomy and myringotomy (the insertion of grommets) derived from the child focused questionnaires at 103 months (8years KS questions A6 b, c and e) and 140 months (11years KW questions A3 b, c and e).
Confounding variables: There are well established sex differences in susceptibility to some ENT illnesses as such sex will be included as a covariate in all analyses.
Analyses: Univariate GWAS analyses of tonsillectomy, adenoidectomy and myringotomy will be conducted by David Evans while he is in Bristol in October 2013. The summary statistics from the analyses of the ALSPAC data will be shared with Sarah Medland and Robyn Choi to allow genome-wide meta-analysis of the BLATS and ALSPAC results.
No raw data or samples will be transfered or shared between ALSPAC and BLATS.
B2075 - Genome-wide association study of red blood cell membrane phospholipids during pregnancy - 05/09/2013
Aim:
To detect genetic variants reliably associated with red blood cell membrane fatty acids (FAs).
Hypothesis:
We hypothesise that variants across the genome will be associated with FA levels during pregnancy.
Variables:
The exposure variable will be imputed maternal genotype, while antenatal FA levels will be the outcome.
Data on 40 different FAs were extracted from antenatal blood samples taken from ALSPAC mothers, these included saturated, omega-3, omega-6 and omega-9 FAs. Genome-wide association analyses will be performed on each of the FAs available in ALSPAC, using a univariable linear regression model, regressing FA level on maternal genotype.
Previous studies have found associations with omega-3 and omega-6 Fas and both the FADS gene cluster on Chromosome 11 and the ELOVL2 gene on Chromosome 6 (1, 2). We propose to investigate whether these findings are consistent among pregnant women, and whether any further associations are found with other FA families.
1. Lemaitre RN, Tanaka T, Tang W, Manichaikul A, Foy M, Kabagambe EK, et al. Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. PLoS genetics. 2011;7(7):e1002193. Epub 2011/08/11.
2. Tanaka T, Shen J, Abecasis GR, Kisialiou A, Ordovas JM, Guralnik JM, et al. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. PLoS genetics. 2009;5(1):e1000338. Epub 2009/01/17.
B2060 - Genetic study of smoking and nicotine dependence - 05/09/2013
Specific Aims:
The aims of this study are two-fold: 1. Identification of genes involved in nicotine dependence as measured by the FTND questionnaire; and 2 identification of genes involved in nicotine withdrawal as measured by the time to first cigarette (TFC), ascertained by the question "how soon do you smoke your first cigarette after you wake up in the morning".
Hypotheses:
If a trait is heritable, such as nicotine dependence, there must be gene(s) that influence the expression of the trait. Our hypothesis is, therefore, that since tobacco smoking and nicotine dependence have been demonstrated to be heritable, these traits must be influnced by some genes. Under this condition, if we collect a sufficient sample size, we should be able to detect some of those genes contributing to the traits by association analyses. To avoid selection bias, we plan to test all genes across the human genome.
Study Design:
We plan to use linear regression to analyze the association between genotypes and phenotypes. In the analyses, genotypes are treated as independent variables and pheotypes as dependent variables. Confounding variables, such as sex, age and population substructure will be used to exclude their effects. To maximize the coverage of the genome, genotype imputation will be performed to include all variants observed in the 1000 genomes project. The results from the ALSPAC sample will be combined with the results from other samples by meta-analysis.
B2073 - Determining novel causal risk factors for CVD An original genome-wide Mendelian Randomisation approach - 29/08/2013
Background:
There are now many powerful GWAS based on large sets of meta-analysed data from multiple studies and the number of GWAS in literature is rapidly increasing. These studies provide robust effect estimates for the associations of single nucleotide polymorphisms (SNPs) across the genome with phenotypes of interest. For example, associations for all SNPs across the genome in relation to anthropometric phenotypes are available from the GIANT (Genetic Investigation of ANthropometric Traits) consortium involving meta-analysed data on up to 250,000 individuals (1-3). The GIANT GWAS observed many loci predicting variation in BMI (32 loci) and fat distribution (29 loci) at genome-wide significance level.
However, many loci will exist beyond those established using the stringent genome-wide cut-off level that are in reality reliably related to the phenotype of interest. Data from the GIANT height GWAS (N=183,727 individuals) identified 180 loci associated with height at genome-wide significance levels, explaining 10% of the phenotypic variation in height. However, the authors further estimated, based on recently developed methods (4), that there were in fact 697 loci (95% CI: 483-1040) with effects greater or equal to those identified from the GWAS which would explain a total of 15.7% of the phenotypic variation in height. Preliminary data from the GIANT consortium supports the conclusion that many of the associations that were observed but did not reach genome-wide significance are in fact real associations (J. Hirschhorn, Personal Communication).
Furthermore, when all SNPs across the genome are fitted simultaneously and the variance explained by all the SNPs together is estimated, 45% of the phenotypic variance in height can be explained (5).Together with the fact that for SNPs explaining 0.01% variation there is 99% power to get the direction of the association correct in a sample size of 129,000 individuals, this suggests that robust GWAS with large sample sizes can reliably inform the development of genome-wide polygenic instruments.
The inclusion of a potentially vast number of 'risk-alleles' across the genome would therefore explain significantly more phenotypic variation than instruments based on individual genetic variants or several established genetic variants together. As such, genome-wide polygenic scores provide a platform from which to develop a novel application of the Mendelian Randomization approach using genome-wide instruments that would incorporate a much larger proportion of genetic information than has otherwise been explored previously, resulting in considerably greater power for detecting causal effects for novel phenotypes of interest.
Aims:
The aims of this project are to develop and apply an original genome-wide Mendelian Randomization approach in order to: i) identify of novel causal risk factors for adult CVD, and ii) examine their impact on childhood and adolescent CVD-related traits
Hypotheses:
We hypothesise that the application of genome-wide allele scores for indexing traits known to be related to CVD-related phenotypes, such as adiposity, lipids and inflammation, will accurately index CVD risk and that these scores can subsequently be extended to explore more novel predictors such as iron status, fatty acid profile and uric acid.
Exposure variables:
genome-wide SNP data and phenotypic data for established CVD-related phenotypes (BMI, lipids, inflammatory markers) and novel predictors in CVD (iron status makers, fatty acids, uric acid)
Outcome variables:
Blood pressure, flow-mediated dilation, intima-media thickness
Confounders:
Maternal eduation, paternal education, family income, parental occupational class, child IQ, maternal smoking
References:
1. Speliotes EK, Willer CJ, Berndt SI, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42(11): 937-48
2. Lango Allen H, Estrada K, Lettre G, et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 2010; 467(7317): 832-8
3.Heid IM, Jackson AU, Randall JC, et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 2010; 42(11): 949-60
4. Park JH, Wacholder S, Gail MH, et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat Genet 2010; 42(7): 570-5
5.Yang J, Benyamin B, McEvoy BP, et al. Common SNPs explain a large proportion of the heritability for human height. Nat Genet 2010; 42(7): 565-9
B2072 - Association between perinatal risk factors and child cognitive and emotional development - 29/08/2013
Aims:
There is growing evidence that perinatal maternal depression is associated with impairments in child cognitive development. However, there is very little empiracal evidence of the long term impact. There is only one small UK study which has investigated the association between postnatal depression and academic achievement at the end of school. Data from large prospective studies is therefore needed. Furthermore, the developmental trajectory of cognitive impairment is unclear and can only be tested in longitudinal studies with repeated assesment of cognition across domains
B2071 - Evaluation of prenatal and perinatal risk factors for obsessive compulsive disorder in the ALSPAC pre-birth cohort - 29/08/2013
Although obsessive compulsive disorder (OCD) is clearly known to have a strong genetic component, twin and family studies have consistently demonstrated a significant role for additional, non-genetic factors in the pathogenesis of the disease(Pauls, 2008). Despite this, only four studies have examined the potential contributions of various non-genetic factors in the development of OCD. In these studies, excessive maternal weight gain, hyperemesis of pregnancy, medication use during pregnancy, nuchal cord, hypoxia at birth, unspecified problems during pregnancy or in the perinatal period, and assisted delivery (forceps or Caesarean section) were associated in at least one study with increased risk of OCD(Geller et al., 2008, Grisham et al., 2011, Sampaio et al., 2009, Vasconcelos et al., 2007). In contrast, tobacco or illicit drug use during pregnancy, primiparity, low birthweight, hypertension or pre-eclampsia, and preterm birth were not found to be OCD risk factors. However, these studies had multiple limitations; all but one were retrospective, and the one prospective cohort study only examined a few variables. Therefore, there is a great need to examine a variety of candidate non-genetic OCD risk factors in a prospectively collected, population-based sample.
We have previously examined the relationship between pre- and perinatal risk factors for Tourette Syndrome (TS), a neurodevelopmental disorder that is etiologically and clinically related to OCD, in the ALSPAC cohort (Mathews, in press). We found that inadequate maternal weight gain during pregnancy, parity, and maternal alcohol and cannabis use were all associated with increased risk for TS or chronic tics (CT). Other pre/perinatal exposures that had previously been reported, most notably maternal prenatal smoking and low birth weight, were not associated with TS or CT in the ALSPAC cohort.
We propose to utilize the ALSPAC cohort to study non-genetic risk factors for OCD in a prospective manner, using the same approach used to study TS/CT, through the following specific aims:
Aim 1: Examine the association between previously reported prenatal and perinatal OCD risk factors and those previously found to be identified with TS/CT and the presence of OCD using a nested, case-control design within the longitudinal, prospective, population-based ALSPAC sample.
The ALSPAC study includes an assessment of obsessive compulsive symptoms and associated distress and impairment as a part of the Development and Well Being Assessment (DAWBA) parent interview. This self-report questionnaire was completed by ALSPAC mothers as part of the age 7, 10, and 14 questionnaires. We propose to use a definition of OCD that we have previously used in our work on examining perinatal risk factors for tic disorders; this definition corresponds to a DSM-IV-TR lifetime diagnosis of OCD. The presence of recurrent obsessions or compulsions (defined as a response of "sometimes" or "often" to one or more of the seven available questions about contamination, cleaning, checking, repeating, touching, arranging, or counting symptoms) at any of the three timepoints, is required for a diagnosis, along with sufficient severity and/or impairment to meet DSM-IV-TR criteria. This is defined as symptoms that were severe enough to take up at least an hour a day ("waste a lot of time",) cause significant distress ("upset a great deal"), or cause interference/impairment ("quite a lot" or "a great deal" answered to any of the five questions about interference (with family, friends, school, or hobbies). As is consistent with the DSM-IV-TR criteria, recognition that the symptoms are excessive is not required in children.
Exposures of interest will include prenatal and perinatal factors reported to be associated with either OCD or OCD symptom severity in at least one previous study, as well as those examined in our study of tic disorders, including birth weight, maternal weight gain, Apgar scores, paternal age, hyperemesis of pregnancy, increased maternal stress during pregnancy, maternal smoking, alcohol, illicit drug, and caffeine use, as well as obstetrical complications (such as forceps delivery and neonatal hypoxia).All children who do not meet OCD criteria (or subclinical OCD criteria, as defined by OCD symptoms with minimal impairment or distress), and do not have autism or intellectual disability will be included as controls.Both univariate analysis and multivariate analysis using logistic regression will be performed.We hypothesize that maternal smoking, paternal age and perhaps other environmental variables will be associated with the development of TS/CT in this population.
Aim 2: In the subgroup of ALSPAC subjects with OCD, examine the non-genetic risk factors identified in Aim 1 for association with co-occurring anxiety disorders, ADHD, and symptom severity.
In addition to the OCD assessments, ALSPAC subjects have been screened for DSM-IV diagnoses of other anxiety disorders (separation anxiety, social anxiety, and generalized anxiety), and ADHD at three different time points thus far (ages 7, 10 and 14). In this aim, we will evaluate each subject with OCD for the presence of additional co-occurring anxiety disorders and/or ADHD. We will then perform both univariate and multivariate analyses to test for an association between the presence of co-occurring disorders and the same previously reported prenatal and perinatal risk factors. We hypothesize that at least one of these variables will prove to be associated with OCD-associated comorbidities.
Table 1. Data requested for proposed ALSPAC study.
Concept
Specific Measure
Person
Source
Time Point(s)
Prenatal Risk Factors
Medications, smoking, alcohol, recreational drug use, family history, maternal/paternal age
Mother
Questionnaire
8 weeks gestation to 8 weeks post-partum
Prenatal Risk Factors
Hyperemesis
Mother
Questionnaire
8 weeks gestation to 8 weeks post-partum
Maternal stress
Life Events
Mother
Questionnaire
18 week gestation & 8 weeks post-partum
Perinatal events
Birthweight, Apgar scores, obstetrical complications
Mother
Obstetrical and neonatal record
Birth to 4 weeks
OCD
Checklist/screen for DSM-IV OCD criteria
Child-based
Questionnaire
Ages 7, 10, 14
ADHD
Checklist/screen for DSM-IV ADHD criteria
Child-based
Questionnaire
Ages 7, 10, 14
Anxiety disorders
Checklist/screen for separation anxiety, generalized anxiety, and social anxiety
Child-based
Questionnaire
Ages 7,10, 14
REFERENCES:
Geller, D. A., Wieland, N., Carey, K., Vivas, F., Petty, C. R., Johnson, J., Reichert, E., Pauls, D. & Biederman, J. (2008). Perinatal factors affecting expression of obsessive compulsive disorder in children and adolescents. J Child Adolesc Psychopharmacol 18, 373-9.
Grisham, J. R., Fullana, M. A., Mataix-Cols, D., Moffitt, T. E., Caspi, A. & Poulton, R. (2011). Risk factors prospectively associated with adult obsessive-compulsive symptom dimensions and obsessive-compulsive disorder. Psychol Med, 1-12.
Mathews, C. A., Scharf, J. M., Miller, L.L., Macdonald-Wallis, C., Lawlor, D.A., Ben-Shlomo, Y. (in press). Association between pre- and perinatal exposures and Tourette syndrome or chronic tic disorders in the ALSPAC cohort. Br J Psychiatry.
Pauls, D. L. (2008). The genetics of obsessive compulsive disorder: a review of the evidence. Am J Med Genet C Semin Med Genet 148C, 133-9.
Sampaio, A. S., Miguel, E. C., Borcato, S., Batistuzzo, M., Fossaluza, V., Geller, D. A. & Hounie, A. G. (2009). Perinatal risk factors and obsessive-compulsive spectrum disorders in patients with rheumatic fever. Gen Hosp Psychiatry 31, 288-91.
Vasconcelos, M. S., Sampaio, A. S., Hounie, A. G., Akkerman, F., Curi, M., Lopes, A. C. & Miguel, E. C. (2007). Prenatal, perinatal, and postnatal risk factors in obsessive-compulsive disorder. Biol Psychiatry 61, 301-7.
B2069 - Androgens in maternal serum during gestation and child androgen levels in autism spectrum conditions and autistic traits - 29/08/2013
Aims: 1) To test if maternal free and total testosterone are elevated during pregnancy in autism spectrum conditions (ASC), and are correlated to number of autistic traits. 2) To test if maternal androgen levels mediate the reported relationship between gestational complications (i.e. hypertensive and hyperglycemic disorders of pregnancy) and autism risk. 3) To test if children with ASCs have elevated levels of androgens, and if number of autistic traits are correlated with elevated levels of androgens during childhood and adolescence.