Proposal summaries

These are research proposals that have been approved by the ALSPAC exec. The titles include a B number which identifies the proposal and the date on which the proposals received ALSPAC exec approval.

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B1107 - Maternal and offspring iron genes early infections and growth disentangling causality - 19/01/2011

B number: 
B1107
Principal applicant name: 
Dr Abigail Fraser (University of Bristol, UK)
Co-applicants: 
Prof Debbie A Lawlor (University of Bristol, UK), Dr Laura Howe (University of Bristol, UK), Prof Kate Tilling (University of Bristol, UK), Dr Carolina Bonilla (University of Bristol, UK), Dr Sarah J Lewis (University of Bristol, UK)
Title of project: 
Maternal and offspring iron genes, early infections and growth: disentangling causality.
Proposal summary: 

1. Assess whether there is a causal relationship between maternal iron status and offspring infection in infancy and childhood using maternal genetic variants (adjusted for offspring variants); and estimate its magnitude.

2. Assess whether there is a causal relationships between maternal iron status and offspring growth trajectories using maternal genetic variants (adjusted for offspring variants) that are robustly associated with iron status; and estimate its magnitude.

3. Unpick the direction of association between post-natal iron status (using haemoglobin measured at 8, 12 and 18 months) with childhood infections (measured at 6 and 18 months) and growth trajectories (0-5 years); and use genetic variants that are robustly associated with iron status to test for causality.

Date proposal received: 
Wednesday, 19 January, 2011
Date proposal approved: 
Wednesday, 19 January, 2011
Keywords: 
Genetics, Immunity, Infection, Nutrition
Primary keyword: 

B1106 - Maternal and paternal physical activity in pregnancy and CVD risk factors in offspring - 19/01/2011

B number: 
B1106
Principal applicant name: 
Dr Abigail Fraser (University of Bristol, UK)
Co-applicants: 
Prof Debbie A Lawlor (University of Bristol, UK), Prof Scott Nelson (University of Glasgow, UK), Prof Naveed Sattar (University of Glasgow, UK)
Title of project: 
Maternal and paternal physical activity in pregnancy and CVD risk factors in offspring.
Proposal summary: 

Until several decades ago, physical activity during pregnancy was a cause for concern because of the perceived associated risk of maternal injury and of physiological changes physical activity induces in blood flow, body temperature, and fetal oxygen delivery that could potentially have both short term and lasting detrimental effects on the fetus.(American College of Sports Medicine 2006) More recently, several observational studies have reported beneficial effects of greater levels of physical activity during pregnancy for the pregnant woman, such as a decreased risk of gestational diabetes (Tobias et al. 2011) and preeclampsia.(Magnus et al. 2008;Rudra et al. 2008) Thus guidelines recommend that pregnant women maintain the same level of moderate physical activity as non-pregnant women.(Artal and O'Toole 2003)

However, current evidence is inconsistent on whether exercise during pregnancy is beneficial, harmful, or neutral for the health of the developing fetus.(Kramer and McDonald 2006) These mixed findings are likely to reflect different methods of exposure and outcome assessment, different timing during the pregnancy for exposure and outcome assessments, differences in pre-pregnancy exercise habits between the study populations, and differences in the studies' abilities to control for potential confounding factors. By far the largest observational study to date, including over 90,000 participants in the Danish National Birth Cohort, found a strong and linear association between increasing levels of physical activity in early pregnancy and miscarriage before 18 weeks gestation.(Madsen et al. 2007) As with other behaviours in pregnancy, RCTs in this area are difficult. However, a Cochrane systematic review of randomized controlled trials to promote aerobic exercise during pregnancy concluded that regular aerobic exercise during pregnancy (mostly swimming, static cycling, floor exercises) appears to improve women's physical fitness, but that current evidence was insufficient to draw firm conclusions about its likely overall risks or benefits for the woman or baby.(Kramer & McDonald 2006) The reviewers concluded that larger, better quality trials are needed before confident recommendations could be made about the benefits and risk of exercise during pregnancy.

The long-term effect of physical activity in pregnancy on offspring future health is even less well studied. Two small prospective studies assessed outcomes in offspring of women who exercised regularly throughout pregnancy compared with offspring of active women who did not exercise at 1 and 5 years of age. In the first study,(Clapp, III et al. 1998) which included 104 mother-offspring pairs, weight, length and abdominal and head circumferences at mean age 1 year were similar in offspring of women who did or did not continue regular physical activity throughout pregnancy. In another study by the same group,(Clapp, III 1996) which included just 40 mother-offspring pairs, at mean age 4 years offspring of women who engaged in vigorous physical activity during pregnancy were lighter and had less subcutaneous fat but were of similar height as offspring of women who voluntarily stopped exercising in pregnancy. They also scored higher for oral language skills and general IQ (assessed by the Wechsler Preschool and Primary Scale Intelligence). Motor, integrative and academic readiness skills were similar between groups. In both studies women were matched for pre and post-natal characteristics known to influence outcomes.(Clapp, III 1996;Clapp, III, Simonian, Lopez, Appleby-Wineberg, & Harcar-Sevcik 1998)

Thus, it is unclear whether variation in levels of physical activity during pregnancy is causally (either beneficially or detrimentally) related to long term health outcomes in offspring. Here we propose to study the association of maternal physical activity during pregnancy with CVD risk factors (including BMI, waist circumference, fat mass, blood pressure, lipids, fasting insulin and glucose) in childhood (age 9 and 15), anti-Mullerian hormone (AMH, a measure of ovarian and testicular function, age 15), cognitive function (age 8) and educational attainment (at age 16 years). We will compare the association of maternal physical activity during pregnancy with the association of paternal physical during pregnancy with the same outcomes. If the association of maternal physical activity with offspring outcomes is greater than the paternal one and remains even when controlling for paternal physical activity, this would suggest a causal, intra utero effect. However, if the associations are of similar magnitude and are abolished with mutual adjustment, this would suggest that familial characteristics such as socioeconomic position or genetic variation are more likely explanations. As a further means of examining whether any associations may be due to intrauterine mechanisms we will examine the extent to which any associations are mediated by offspring levels of physical activity. If the associations are largely or completely explained by offspring activity this would suggest that mechanisms are related to postnatal parental effects on the child's participation in physical activity rather than an effect of physical activity in pregnancy on e.g. risk of preeclampsia and placentation and other pregnancy specific factors that affect fetal development and their later cognitive and cardiovascular health. We will also compare the associations of maternal and paternal physical activity in pregnancy with outcomes measured at different ages, in order to assess whether associations are lasting or perhaps diminish with age.

Our request to include AMH as an outcome here is based on its association with metabolic abnormalities (for example: Park 2003) and we wish to extend a previous application (Prof. Lawlor as the main applicant) to examine smoking, gestational weight gain, blood pressure changes, and diabetes/glycosuria as determinants of offspring AMH.

Date proposal received: 
Wednesday, 19 January, 2011
Date proposal approved: 
Wednesday, 19 January, 2011
Keywords: 
Cardiovascular , Cognitive Function, Physical Activity, Pregnancy
Primary keyword: 

B1101 - Analysis of Longitudinal Food RElated Data ALFRED - 17/01/2011

B number: 
B1101
Principal applicant name: 
Dr Jenny Harris (NatCen Social Research, UK)
Co-applicants: 
Title of project: 
Analysis of Longitudinal Food RElated Data (ALFRED).
Proposal summary: 

The major health problems of obesity, diabetes, CVD and cancer have all been related to diet (e.g. WHO, 1990; Block et al, 1992; Department of Health, 1998; Hooper et al 2001). In response to this, key public health campaigns have encouraged people to increase their daily consumption of fruit and vegetables, reduce their intake of salt and saturated fats, and eat more complex carbohydrates, amongst other aspects of diet. In light of these health messages, research based on cross-sectional and longitudinal research data sources suggest, for example, that there have been population level increases in consumption of fruits and vegetables, dietary fibre and poultry, and a decline in consumption of whole milk, butter and red meat (Prynne, Wagemakers, Stephen and Wadsworth, 2009; The Information Centre for Health and Social Care, 2009; Prynne, Paul, Mishra, Greenberg and Wadsworth, 2005) and eating less saturated fat, less trans fatty acids and less added sugar (Bates, Lennox and Swan, 2010).

The Department of Health has tasked NatCen to undertake scoping analysis project (including descriptive data analysis) to identify the type of food related data available from longitudinal sources in order to guide future research and policy priorities. The focus of this project is on longitudinal data in order to explore changes overtime and the factors associated with a change in diet. This will include analysis of the data by key break variables (to include sex, age, whether a family with children aged under 16, socio-economic classification, education/ highest qualification of mother (for datasets including children) and ethnic group (where data includes sufficient numbers)) and key health variables.

In addition, NatCen will be reporting to the Department of Health on the types of food related data currently being collected and suggesting where new data sources need to be developed including advice about questions/modules for inclusion on future surveys going forward.

Main research objectives

What can longitudinal surveys tell us about changes in eating and cooking practices?

The project will use different variables relating to eating and cooking practices to identify healthy and unhealthy practices, and explore how these vary by key sociodemographic variables and change over time. The primary sources for such data are ALSPAC and Whitehall II. These variables will include the types of fats used with vegetables and bread, and for frying and baking, the use of salt in cooking and at the table, frequency of eating takeaways, microwave and convenience meals and whether family meals are shared.

What can longitudinal surveys tell us about changes in choice and access to food?

Here key data relates to the ability to afford quality and variety of food. Primarily using data from the Family and Children's Survey (FACS) we will analyse a number of variables relating to choice and access, including whether the family is able to afford a cooked meal everyday, good quality/brand name food, fresh fruit and fresh vegetables daily and whether child maintenance goes on food. We will then be able to examine the circumstances of those of those with good choice and access to those with worse choice and access.

What can longitudinal surveys tell us about intake of key nutrients and foods?

The Department of Health has identified key nutrients and foods of policy interest for this project. Exact methods of analysis will vary depending on the data collection method used in the datasets accessed. Where possible, we will use will use the UK Dietary Reference Values as our benchmark and focus on recommended intakes for non-starch polysaccharide and percentage of energy from fat, saturated fat and non-milk extrinsic sugars. We may also include intake of Vitamin C, calcium and iron. For foods we will focus on intake of fruit and vegetables and, where age appropriate, relate this to the 5-a-day recommendation. For those surveys that primarily use food frequency questionnaires (such as Whitehall II) it may also be possible to develop a total fat score (classifying respondents as high, medium and low, an approach used in the Health Survey for England 2007).

References

Bates,Lennoxand Swan (2010). National Diet and Nutrition Survey: headline results from year 1 (2008/2009). Food Standards Agency and the Department of Health.

Block, Patterson & Subar (1992). Fruit, vegetables and cancer prevention: a review of epidemiological evidence. Nutr Cancer, 18: 1-20.

Department of Health (1994) Nutritional Aspects of Cardiovascular Disease.London: HMSO

Department of Health (1998) Nutritional Aspects of the Development of Cancer.London: The Stationery Office.

Hooper, Summerbell, Higgins et al (2001). Dietary fat intake and the prevention of cardiovascular disease: a systematic review. BMJ, 322: 757-763.

Prynne, Wagemakers, Stephen andWadsworth(2009). Meat consumption after disaggregation of meat dishes in a cohort of British adults in 1989 and 1999 in relation to diet quality. Euro Journ of Clin Nutr, 63: 660-666.

The Information Centre for Health and Social Care (2008). Health Survey for England 2007- Healthy lifestyles: knowledge, attitudes and behaviours.

The Information Centre for Health and Social Care (2009). Health Survey for England- 2008 trend tables http://www.ic.nhs.uk/statistics-and-data-collections/health-and-lifestyl...

World Health Organisation (1990).Diet, nutrition, and the prevention of chronic diseases. Report of a WHO Study Group.Geneva: World Health Organisation

Other data sets to be included in this project-

Freely available datasets

? English Longitudinal Study of Aging (ELSA) (http://www.esds.ac.uk/longitudinal/access/elsa/l5050.asp )

? Families and Children Study (FACS) (http://www.esds.ac.uk/findingData/snDescription.asp?sn=4427)

? British Household Panel Survey (BHPS) http://www.esds.ac.uk/longitudinal/access/bhps/L33196.asp - Youth Cohort

Datasets subject to access application

? Whitehall II

http://www.ucl.ac.uk/whitehallII/

? MRC National Study of Health and Development

http://www.nshd.mrc.ac.uk/

Date proposal received: 
Monday, 17 January, 2011
Date proposal approved: 
Monday, 17 January, 2011
Keywords: 
Nutrition
Primary keyword: 

B1100 - The effect of maternal iron status and intake during pregnancy on cardiovascular disease risk in the offspring - 17/01/2011

B number: 
B1100
Principal applicant name: 
Dr Nisreen Alwan (University of Leeds, UK)
Co-applicants: 
Prof Debbie A Lawlor (University of Bristol, UK), Prof John Deanfield (University College London, UK), Prof Janet Cade (University of Leeds, UK)
Title of project: 
The effect of maternal iron status and intake during pregnancy on cardiovascular disease risk in the offspring.
Proposal summary: 

Objectives:

To examine the association of maternal dietary iron intake (including supplements) and haemoglobin levels during pregnancy with offspring brachial artery endothelial function measured by FMD, arterial stiffness by carotid-radial PWV and brachial distensibility (DC) at age 10 years.

To explore whether the association of maternal dietary iron intake with the offspring vascular phenotype in objective 1 is likely to be due to a causal intrauterine mechanism, by comparing maternal dietary iron - offspring vascular phenotype associations to partner dietary iron intake (assessed ~4.5 years after birth of index child) - offspring vascular phenotype.

To examine the association of cord ferritin with offspring brachial artery endothelial function measured by FMD, arterial stiffness by carotid to radial PWV and brachial distensibility (DC) at age 10 years.

To examine whether the association of maternal dietary iron intake and haemoglobin levels with offspring vascular phenotypes (as in objective 1) are mediated by cord ferritin levels.

To examine whether any of the associations of maternal dietary iron intake, haemoglobin levels or cord ferritin with offspring vascular phenotypes are mediated by offspring birth weight, gestational age, BMI and dietary iron intake.

Date proposal received: 
Monday, 17 January, 2011
Date proposal approved: 
Monday, 17 January, 2011
Keywords: 
Cardiovascular , Nutrition
Primary keyword: 

B1099 - Oxytocin pathways and social development outcomes - 17/01/2011

B number: 
B1099
Principal applicant name: 
Prof Jean Golding (University of Bristol, UK)
Co-applicants: 
Dr Sue Carter (University of Illinois at Chicago, USA), Prof John Davis (University of Illinois at Chicago, USA)
Title of project: 
Oxytocin pathways and social development outcomes.
Proposal summary: 

Specific aims:

Oxytocin plays an essential role in maternal behavior, social bonding, prosocial behaviors, establishment of trust, anxiety reduction, and the modulation of stress. This research is significant in determining the impact of exposures and experiences on oxytocin pathways. Our approach is twofold in seeking to determine the impact of oxytocin on social development trajectory and outcomes. We will examine both exogenous oxytocin administered at birth and effects of exposure and experiences on exogenous oxytocin. Thus there are three factors that are to be studied in oxytocin pathways: exogenous administration, genetic polymorphisms, and epigenetic effects. Finally, our research is significant in examining interactive effects of maternal behavior on the child and the child's behavior on the mother.

1. To determine prosocial and atypical social developmental trajectories and outcomes from infancy through adolescence in the ALSPAC birth cohort and to correlate these findings with indices of OT pathways. We hypothesize that these outcomes will be moderated by (a) exogenous administration of synthetic oxytocin (syntocinon) at birth and dose response, (b) polymorphisms in genes for OT and the OT receptor, genetic and epigenetic regulation of OT receptor expression during development, related perinatal variables, and (c) epigenetic modification of genes in this pathway during development.

2. To empirically derive developmental trajectories from infancy to childhood and adolescence and correlate these trajectories to OT pathways related to:

a. prosocial behavior

b. autistic traits

c. social anxiety

d. social communication deficits

e. anti-social and disruptive behaviors

3. To determine the impact of the following perinatal experiences on social developmental trajectory and outcomes:

a. dosage of synthetic OT (syntocinon/pitocin)

b. caesarian section

c. maternal illness (diabetes, eclampsia) and alcohol and substance use/abuse

d. type of anesthesia or analgesia (e.g. opiates, and "caine" drugs) or other medications administered during the birth process

e. physiologic stress on the mother (e.g. hypertension) and emotional stress (anxiety, depression) in the parents

f. physiologic stress in the newborn e.g. fetal monitoring measures and Apgar score

g. breast feeding (incidence and duration)

h. maternal diet (omega fatty acids)

i. demographic variables ( e.g. parental age, family history of disorder, SES.)

j. post natal experiences (family adversity index, abuse, etc)

4. To examine polymorphisms and unique genetic variants in genes in the OT/vasopressin pathways (peptides, receptors and other factors regulating the release or functions of these peptides) on differences in social behaviors and developmental trajectories listed in Specific Aim 2. Because polymorphisms in the OT receptor are associated with social behaviors we hypothesize that those polymorphisms may modulate human behavior to have a direct effect on developmental trajectories in the ALSPAC cohort.

5. To examine the effects of exogenously administered synthetic OT and its dose response, along with the perinatal variables listed in Specific Aim 3, on the epigenetic expression of genes in the OT pathway on developmental trajectories in Specific Aim 2. We hypothesize that the regulation of the OT receptor (e.g. methylations in the CpG island) may affect social developmental trajectories and that early exposure to synthetic OT will have dose-dependent and long-lasting consequences for gene expression for the OT receptor.

Date proposal received: 
Monday, 17 January, 2011
Date proposal approved: 
Monday, 17 January, 2011
Keywords: 
Development, Epigenetics , Oxytocin
Primary keyword: 

B1096 - Characterisation of autistic-trait related visual processing Fellowship - 13/01/2011

B number: 
B1096
Principal applicant name: 
Dr Beate St. Pourcain (University of Bristol, UK)
Co-applicants: 
Miss Cathy E M Williams (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK), Prof Jean Golding (University of Bristol, UK)
Title of project: 
Characterisation of autistic-trait related visual processing (Fellowship).
Proposal summary: 

There are a series of visual characteristics and visual processing impairments and abnormalities reported for children with autistic symptoms.

There is evidence for abnormal visual processing of colour informationin autistic children. This manifests as poor chromatic discrimination (Heaton, Ludlow, & Roberson, 2008)(Franklin, Sowden, Burley, Notman, & Alder, 2008)(Franklin et al., 2010) but good colour memory (Heaton et al., 2008). Although originally outlined as test of executive functioning, autistic children, children with autism also show less interference effects for colour naming compared with typically developing children on the classic Stroop test e.g. (Simmons et al., 2009), which is probably related to verbal information processing. Some theories suggest that there is an association between verbal ability and perceptual discrimination (Heaton et al., 2008) such that normally developing children apply verbal labels to colours, and are therefore distracted when presented with colours carrying non-typical labels. Children with language difficulties, as typically expressed in autism spectrum disorders (ASD), however are thought to remember colours perceptionally, in other words they do not encode colour verbally, and may therefore have less interference effects compared to typically developing children (Simmons et al., 2009). A considerable body of research reports that children with autism have also impairments in facial recognition and in the understanding of facial emotional expressions (Simmons et al., 2009). This might be related to the finding that ASD children appear to process and/or attend the eye region of faces less effectively than typically developing children e.g. (Rutherford, Clements, & Sekuler, 2007)(Spezio, Adolphs, Hurley, & Joseph Piven, 2007)(Simmons et al., 2009) and more likely fail to form view-invariant face representations (Wolf et al., 2008). In addition, the ability to perform face-eye region special discriminations might be coupled to verbal intelligence (Rutherford et al., 2007). Furthermore, several studies have observed an enhanced ability to perform visual search tasks in autistic patients such as the ability to disembed a target figures from a complex background in the "Embedded Figures Test". Likewise, autistic children show an superior performance in perceptional grouping as well as mental rotation tasks (e.g. Block-Design subtest of the WISC-III; (Shah & Frith, 1993)(Venter, Lord, & Schopler, 1992)(Goldstein, Beers, Siegel, & Minshew, 2001). Latter association was also observed for autistic-like traits (Stewart, Watson, Allcock, & Yaqoob, 2009).

Aim: Assuming the dimensionality of autism, the proposed fellowship aims to understand the mechanisms linkingvisual functioning to autistic symptoms using a general population sample in order to provide guidance for strategies aiming at intervention and treatment of autistic symptoms.

1) We aim to study chromatic information processing, interference processes between colour perception and colour naming, the understanding of facial expressions as well perceptional grouping and mental rotation tasks with respect to autistic symptoms. Findings will be used to create a profile of visual characteristics and impairments which are associated with specific autistic symptoms in the general population. We will use Growth mixture modelling for longitudinal measures of autistic traits and mixture modelling for cross-sectional autistic data to accomplish this task.

Required variables in ALSPAC:

Outcomes:

4 SCDC measures (8-17 years), CCC

Predictors:

Visual processing of chromatic information: L'Anthony desaturated D15, Stroop (8,11y)

Facial expression based tasks:DANVA (8y Happy, Sad, Angry, Fearful faces), CVI related "face recognition" items (13 y) (Williams, 2010)

Perceptional grouping tasks:CVI related "crowded scenes" items (13y) (Williams et.al, 2010)

Mental rotation tasks:WISC-III Block Design (8y)

Moderators: Verbal IQ (8 y); Colour Ishihara test (12y)

Sensitivity analysis:This will performed by adding less autism-specific visual characteristics like refractive error (7,10,11,12,15 y), strabismus (7y) and visual acuity (7, 11y) to the derived mixture models.

2) Given the genetic basis of autism and autism-specific visual tasks (e.g. h2 Stroop = 0.5, Stins et. al, 2009) we also aim to identify genetic variants which are related to both visual and autistic traits.

a. We propose genome-wide analyses using the Stroop test, the DANVA and the perceptional grouping items of the CVI. Replication will be sought internally within ALCPAC by dividing the sample into a discovery and a replication cohort and within independent samples such a QIMR (Faces task). Genome-wide analysis of the Block-Design test is performed within CHIC.

b. Selection of SNPs for functional network work construction will be enhanced through a second step of GWAS analyses where we combine each autistic symptoms score (i.e. CCC and SCDC) with each studied visual trait (Stroop test, the DANVA, the perceptional grouping items of the CVI, in addition to the WISC-block design) into a bivariate outcome to identify SNPs which preferentially affect both visual and autistic outcomes. For this analysis we will select preferentially trait combinations which have been supported through GMM and cross-sectional mixture modelling (see step 1).

c. Functional networks will be constructed with Ingenuity pathway analysis (http://www.ingenuity.com/products/answers.html).

Date proposal received: 
Thursday, 13 January, 2011
Date proposal approved: 
Thursday, 13 January, 2011
Keywords: 
Autism, Vision
Primary keyword: 

B1095 - Epidemiological studies of human transgenerational responses TGR to paternal and ancestral exposures - 12/01/2011

B number: 
B1095
Principal applicant name: 
Prof Jean Golding (University of Bristol, UK)
Co-applicants: 
Prof Marcus Pembrey (University of Bristol, UK), Dr Kate Northstone (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK), Prof Lars Olov Bygren (Ume? University, Europe)
Title of project: 
Epidemiological studies of human transgenerational responses (TGR) to paternal and ancestral exposures.
Proposal summary: 

Biological inheritance from one generation to the next is generally regarded as transmission of genes and other DNA variation from both parents, plus 'maternal effects' either carried within the egg cytoplasm or through the trans-placental passage of nutrients and metabolic signals. Biological inheritance is supplemented by 'cultural inheritance' (including nurturing behaviour and social patterning) from which it needs to be distinguished.

However, there is growing evidence in mammals (refs 1- 3,9 and references therein) that sperm carry information about the ancestral environment that can influence the development and health of the next generation(s) through enduring alterations in gene expression. How this information is transmitted is unknown, but epigenetic gametic inheritance is one candidate.

There are human epidemiological TGR data (predominantly male-line with mortality, diabetes, coronary heart disease and metabolic syndrome as outcomes) from three populations;Overkalix in Northern Sweden (4-6), ALSPAC (6) and Taiwan (7).A similar phenomenon could occur down the maternal line, complementing the known 'maternal effects', although the latter present a challenge in terms of confounding. Beyond the importance of enlarging our knowledge of human inheritance, understanding the nature and extent of these transgenerational responses is likely to bring medical and public health benefits.

This project will extend our ALSPAC work on TGR to include additional ancestral exposures and further exploration of sex-specific effects.

Background

The initial ALSPAC data (6) showed that paternal onset of smoking before puberty was associated with a greater BMI at 9 years in sons but not daughters. This triggered sex-specific analysis of the Overkalix data with dramatic results. The paternal grandfather's food supply in mid childhood was only linked to the mortality rate of grandsons, whilst paternal grandmother's food supply was only associated with the granddaughters' mortality rate (6). This was true in 2 of 3 independent cohorts and the TGR persists when the grandchild's early life circumstances were also taken into account (8). There are also father to son affects in the Overkalix data. Recent unpublished ALSPAC analysis shows paternal onset of smoking before puberty continues to be associated with greater BMI in (just) sons until age 15.

Since we published 5 years ago, animal studies have paid more attention to sex differences in TGR with varying results from exposed males linked to affected female offspring (2,3) or to affected offspring of both sexes (1) and with curious three generation male-line effects, namely exposed male, his male offspring (unaffected) and that male's male offspring who are affected (2). But some of these studies had altered diet throughout development of the exposed male ancestor. Other studies, e.g. with short term fasting at different ages of the exposed male, found predominantly affected male offspring (9).

Our collaborative work with Lars Olov (Olle) Bygren suggests humans have an exposure sensitive period in mid childhood (both sexes) and in the fetal/infant period (females), but there is no triggering of TGR in puberty in either sex. Thus we can expect to find different outcomes in descendants (analysed by sex) by comparing paternal or ancestral exposures during puberty with exposures at the above specific times before puberty.

The long-term plan is to; a) test the hypothesis that transmission across the generations in TGR is mediated by elements segregating with the Y(non pairing region) and X chromosome by (epi)genomic analysis, and b) to look for the downstream effects on gene expression in the offspring that are relevant to the outcomes using genome wide DNA methylation association studies. However, more epidemiological evidence of triggers of TGR and sex specific effects are needed to inform these future molecular studies. Meanwhile more understanding of the variables in methylome analysis will accumulate (e.g.10).

Planned studies

* Using the established TGR trigger of paternal smoking before puberty, explore outcomes relevant to metabolic syndrome throughout the development of sons and daughters.

* To test the exposure of the study father in utero (via his own mother smoking in pregnancy) on the outcomes as above in his sons and daughters, particularly in fathers who did not smoke themselves.

* To test the exposure of the study mother in utero (via her own mother smoking in pregnancy) on the outcomes as above in her sons and daughters, particularly in mothers who did not smoke themselves.

In line with animal data, explore 'traumatic events' as a TGR trigger for mental health and behavioural outcomes (as well as metabolic syndrome outcomes) in descendants. These will be of two kinds.

* Study fathers and mothers who suffered the death, separation or divorce of a parent before their own puberty.

* Paternal great grandmother's experience of husband being eligible to go to war in 1939-40 whilst the paternal grandmother was a fetus or infant. Outcomes measured in the children of the study fathers who did and did not have this ancestral exposure.

Look for potential TGR by detecting associations with exposures in the parental or grandparental generation for specific outcomes in the study child. [Unpublished analysis with respect to all childhood cancers reveals an association with the study father's early childhood traumatic circumstances.]

References

1. Carone BR et al (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084-1096.

2. Franklin TB et al (2010) Epigenetic transmission of the impact of early stress across generations. Biological Psychiatry 68, 408-415.

3. Ng SF et al (2010). Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467, 963-966.

4. Bygren LO, Kaati G, Edvinsson S (2001) Longevity determined by ancestors' over nutrition during their slow growth period. Acta Biotheoretica 49:53-59.

5. Kaati, G, Bygren LO, Edvinsson S (2002) Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur J Hum Genet 10, 682-88.

6. PembreyME, Bygren, LO, Kaati G, Edvinsson S, Northstone K, Sjostrom M, and Golding J (2006). Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14, 159-166.

7. Tony H-Hsi Chen TH, Yueh-H Chiu YH, Boucher BJ (2006). Transgenerational effects of betel-quid chewing on the development of the metabolic syndrome in the Keelung Community-based Integrated Screening Program. Am J Clin Nutr 83, 688 -92.

8. Kaati G, Bygren LO, Pembrey M, Sjostrom M (2007). Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet 15:784-90.

9. Anderson LM et al (2006). Preconceptional fasting of fathers alters serum glucose in offspring of mice. Nutrition 22, 327-331.

10. Robinson MD et al (2010). Evaluation of affinity-based genome-wide DNA methylation: effects of CpG density, amplification bias and copy number variation. Genome Res 20, 1719-29.

Date proposal received: 
Wednesday, 12 January, 2011
Date proposal approved: 
Wednesday, 12 January, 2011
Keywords: 
Epigenetics
Primary keyword: 

B1094 - Examining links between mental health problems and epilepsy in childhood and adolescence - 11/01/2011

B number: 
B1094
Principal applicant name: 
Prof Michael Kerr (University of Cardiff, UK)
Co-applicants: 
Dr Ajay Thapar (University of Cardiff, UK)
Title of project: 
Examining links between mental health problems and epilepsy in childhood and adolescence.
Proposal summary: 

Background

The point prevalence of epilepsy in childhood and adolescence has been estimated at between 0.3-0.6%. It has been known for many years from cross-sectional surveys that children with epilepsy have particularly high rates of psychiatric disorders (34.3-37%) when compared to children with other common chronic medical conditions (11-11.3%) and that depression rates especially are particularly high, with reports of upto 26% reported. Depression and depressive symptoms have a high impact on children and adolescents with epilepsy and on their families.

The reasons for the high rates of depression in children with epilepsy are not well understood. One of the most established associations for depression is the female preponderance in prevalence of depression which merges around the time of puberty. This female preponderance is however not found for individuals with epilepsy. A small study found marked differences in gender patterns in depression rates amongst adolescents with epilepsy compared to adolescents with other chronic diseases with adolescent males with epilepsy showed significantly higher rates of depression than males with asthma whereas females with epilepsy were at much lower risk than females with asthma. Moreover there is evidence that that the pattern of depressive symptoms for children and adolescents with epilepsy are also different from that found in the general population.

One possible factor that may explain some of these differences from the general populations is that epilepsy commonly coexists with other neurodevelopmental problems, notably intellectual disability(15-38% of individuals with intellectual disability affected by epilepsy) autistic spectrum disorders, ASD (epilepsy present in 8-28% of those with autism) and Attention Deficit Hyperactivity Disorder, ADHD (ADHD present in 38% of children with epilepsy) that are themselves associated with increased rates of depression. Thus depression risk could be better explained by the cluster of multiple brain/neurodevelopmental problems rather than by epilepsy alone. There are mixed findings from studies on whether it is the presence of other neurodevelopmental problems such as intellectual disability that indexes increased risk of depression amongst adolescents with epilepsy.

It is also not clear whether the association of increased risk of depression is only for those with epilepsy or extends to all those who have experienced non-febrile convulsions. Many children and adolescents experience non-febrile convulsions in a given year but only a minority are labelled as having epilepsy. For many of these children seizures are attributed to a specific cause but for others there is no cause noted and these are labelled as single unprovoked seizures. However there is little long term follow information on this non-epilepsy seizures group as most studies are cross sectional. Moreover detailed characterisation of this group (e.g. co morbidity, prognosis) is lacking although a high prevalence of psychological and social problems are found in individuals labelled as having non-epileptic seizures. Given that both misdiagnosis and underdiagnosis of epilepsy have been identified as issues better characterisation of the non-febrile non -epilepsy group to examine natural history and co morbidity would seem timely.

The overall aim of this proposal is to build on our previous work on adult epilepsy and begin a new programme of neuropsychiatric and psychology research on epilepsy in children and adolescents. The overall scientific aims are to better understand the clinical presentation and processes linking depression with paediatric epilepsy and identify which children are at greatest risk. Longitudinal assessments of epilepsy,non-epilepsy convulsions, asthma and depression across puberty and additional information on commonly co morbid disorders and other psychological and social covariates and outcomes will allow testing of our key hypotheses.

The specific aims of the proposal are

1. To explore whether in children with epilepsy the pattern of depression symptoms and pattern of associations (such as with age, gender, family adversity and social disadvantage) are similar 1) to those for children with asthma) and 2) and to children with non-febrile convulsions but no definite diagnosis of epilepsy

2. To examine the influence of puberty in depression rates for adolescents with depression as compared to adolescents with asthma and adolescents with no other chronic medical condition.

3. To examine the relationship between depression symptoms and adolescent epilepsy. Particularly 1) in temporal order of development of each problem (depression and epilepsy) 2) the effect of co-morbidity (ADHD, Intellectual disability) in explaining any associations uncovered 3) the role of seizure frequency, adjusting for the presence of other co morbid conditions, in predicting depression symptoms.

Practical importance of the topic

There is a paucity of community based mental health research on children with epilepsy particularly focusing on identifying those children at high risk of adverse outcomes. Depression is a key factor determining the quality of life of individuals and their families. This research will provide evidence to inform management strategies for children with epilepsy and should be of help to clinicians and families. For example if a sub-group of children at particular risk of adverse psychopathological outcomes are found this will enable development of appropriate interventions and targeting of clinical resources to this group. If risk pathways to depression in children with epilepsy are different from those in the general population, this would influence clinical management and prevention.

Research design

Samples

This consists of information from parents and children from 14 541 pregnancies. We will include information from children with epilepsy aged between 8 1/2 years and 15 years. Information on epilepsy related convulsions, non-epilepsy non-febrile convulsions, asthma and depression and anxiety are available at 4 data points and will be used for the analysis) We will include all children with epilepsy (31 at age 10) and social class, gender and severity match an equivalent number of children with asthma (selected out of 935 children with asthma) and individuals with non-epilepsy non-febrile convulsions.

Current data required:

Epilepsy: Mother questionnaire reports of convulsions (both attributed to epilepsy and non febrile non-epilepsy and frequency if available ) at ages 103 months, 128 months , 140 months, 157 months and 166 months (KS, KV, KW, TA, TB).

Asthma: Mother questionnaire reports of asthma at ages 103 months, 140 months, 157 months and 166 months (KS, KV, TA, TB)

Depression and anxiety : Mother questionnaire reported depression and anxiety using MFQ items 115 months(KU), 140 months (KW)

Child reported depression and anxiety using SMFQ items: 126 month(focus 10+), 150months (12.5years) (TF1), 13.5 years (TF2) and DAWBA interview 15.5 years (186 months(TF3)).

SDQ infirmation from KU(115 months) (includes information on peer problems (e.g. bullying), Hyperactivity symptoms)

Autism, Dyspraxia, Dyslexia- from KU questionnnaire 115 months

DAWBA interview ADHD diagnoses (91 months)

IQ scores

Age (child at assessment)

Gender

Social class

Family history of depression

Lifestyle factors: diet parent reported (KT (103m) KU(115m)) self reported CCM (156 months), sleep (KU 115 m, KV 128m, KW 140m TB 166m)

Date proposal received: 
Tuesday, 11 January, 2011
Date proposal approved: 
Tuesday, 11 January, 2011
Keywords: 
Epilepsy, Mental Health
Primary keyword: 

B1093 - Prenatal exposure to maternal obesity in utero and risk for behavioral problems in childhood - 05/01/2011

B number: 
B1093
Principal applicant name: 
Nadia Micali (King's College London, UK)
Co-applicants: 
Dr Alina Rodriguez (King's College London, UK)
Title of project: 
Prenatal exposure to maternal obesity in utero and risk for behavioral problems in childhood.
Proposal summary: 

Aims and Objectives

To determine whether children of women who were overweight or obese at the time of pregnancy are more likely to receive high ratings of ADHD symptoms as compared to children of women who were normal weight. Importantly, use of the ALSPAC data will allow us to extend previous work by testing potential mechanisms, e.g. maternal dietary intake during pregnancy and child weight, as well as examining longitudinal associations across childhood.

Background

Overweight and obesity are significant public health concerns. Prevalence is continuously escalating and by 2030 it is estimated that as many as 2.16 billion and 1.12 billion adults world-wide will be overweight and obese, respectively (Kelly et al., 2008). Women entering pregnancy are more likely than ever to be overweight or obese, with well-documented deleterious health consequences for both mother and child. Less is, however, known about the possible consequences for child mental health.

The concept of maternal weight in programming of mental health problems in the offspring has been studied primarily from the perspective of underweight and low weight gain in pregnancy. Famine studies in the Netherlands and China show that low maternal weight at the beginning of pregnancy is a risk factor for neurodevelopmental disorders in the adult offspring. Fetal brain development is dependent on maternal energy supply (Hay & Sparks, 1985). Due to the obesity epidemic, recent work has examined mental health consequences for the offspring as a function of maternal overweight/obesity in pregnancy (Rodriguez, 2010a). We were first to report an association between maternal pre-pregnancy overweight/obesity and symptoms of Attention Deficit Hyperactivity Disorder (ADHD) in children (Rodriguez et al., 2008).

ADHD, a neurodevelopmental disorder, is very common and has an estimated world-wide prevalence of 5%. The core symptoms of inattention and hyperactivity are associated with impairment even at sub-clinical levels (Rodriguez et al., 2007). Thus, ADHD and its symptoms pose a public health concern due to the documented negative ramifications to the individual, family, and society.

Our first report showed an association between maternal pre-pregnancy overweight/obesity and core symptoms of ADHD combining data from three prospective cohorts from Sweden, Finland, and Denmark with a pooled sample size of over 12,000 children. The finding was confirmed in another Swedish prospective cohort of younger children using the full symptom description of ADHD (Rodriguez, 2010a). Further, this work also showed a significant association with child negative affect. It was possible to adjust for many confounding factors including maternal depression, stress, socio-demographics, as well as ADHD symptoms in both parents. One possibility that the Rodriguez (2010a) paper examined was whether the child's own weight accounted for the association. This is a plausible link because previous research has pointed to the contribution of maternal pre-pregnancy weight in the programming of child weight (Rodriguez, 2010b). Although the results did not show that child weight accounted for the association, the question remains opened because child weight was assessed as within or outside the normal range, thus it is unknown whether child body mass index (BMI) mediates or accounts for the association.

Hypotheses:

1) Children born to mothers who were overweight or obese at pregnancy will have higher risk of child behavior problems, specifically those related to ADHD according to teachers and mothers.

2) Children exposed to maternal obesity in utero will have consistent behavior problems across childhood.

3) Children's own weight will not mediate the association between prenatal exposure to maternal obesity and child behavior problems.

Methodology

Design: A longitudinal prospective study with contrast groups.

Participants: This study is based on data collected from the Avon Longitudinal Study of Parents and Children, ALSPAC (Golding et al., 2001). ALSPAC is a longitudinal birth cohort study, which enrolled all pregnant women living within Avon, England, due to give birth between the 1st April 1991 and 31st December 1992. It is estimated that approximately 85-90% of those eligible for inclusion chose to participate and the sample has been shown to be representative of the UK population. The core ALSPAC sample consists of 14,541 pregnancies, 69 of which had unknown birth outcomes. Data was obtained on the remaining 14,272 via postal questionnaires. For the purpose of this study women will be excluded if they did not respond to the 12 week questionnaire (2,019) or if they had multiple births (208).

Predictor: Prepregnancy maternal BMI will be calculated using the standard formula (weight in kg/height in m2) and rounded to nearest whole number. Maternal pre-pregnancy BMI will be analyzed as continuously and categorically according to the standard classification of the WHO guidelines for overweight and obesity: normal weight (20-24.99), underweight (15-19.99), overweight (25-29.99) and obese (>= 30).

Outcomes: The main outcome measures will be teacher reports of child behavior at ages 8 and 11 years using the Strengths and Difficulties Questionnaire (Goodman, 2000), a widely-used general screener for psychiatric disorders in community samples. One subscale is devoted to ADHD symptoms.

To assess whether children's own weight contributes to ADHD symptoms we will use data collected yearly on physical development (weight) up to the age of 11 years.

Confounders: Participants reported socio-demographic data, including age, occupation, marital status as well as smoking via self-report at 12 weeks gestation. We will also include psychosocial factors such as maternal anxiety and depression during pregnancy. Birth outcomes such as birth weight and gestational age will be included in the model.

Data Analysis: The hypotheses will be tested using linear and logistic regression analyses in which maternal pre-pregnancy BMI is used to predict behavioral outcomes in childhood. All of the central analyses will include covariates. Data available at several time-points will be initially analysed cross-sectionally; longitudinal and growth modelling will be used as a subsequent step. With the available sample sizes, small to moderate group differences in continuous outcomes can be detected with a power of 90% at the 5% test level. Analyses will take into account missing data.

The results offered by this study will not only provide an opportunity for replication in an independent sample in another geographical region, but more importantly will provide an opportunity for extension and examination of potential mediation by child weight as well as longitudinal analysis of child behavior problems across childhood.

REFERENCES

Golding J, Pembrey M, Jones R. ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology. Paediatric and Perinatal Epidemiology 2001;15(1):74-87.

Goodman R, Ford T, Simmons H, Gatward R, Meltzer H. Using the Strengths and Difficulties Questionnaire (SDQ) to screen for child psychiatric disorders in a community sample. Br J Psychiatry. 2000;177:534-9.

Hay WW, Jr., Sparks JW. Placental, fetal, and neonatal carbohydrate metabolism. Clin Obstet Gynecol. 1985;28(3):473-85.

Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes. 2008;32(9):1431-7.

Rodriguez A. Is prenatal exposure to maternal obesity linked to child mental health? In: Bagchi D, editor. Global View

on Childhood Obesity: Current Status, Consequences and Prevention: Elsevier; 2010, pp157-166.

Rodriguez A. Maternal pre-pregnancy obesity and risk for inattention and negative emotionality in children. J Child Psychol Psychiatry. 2010a;51(2):134-43.

Rodriguez A. Is prenatal exposure to maternal obesity linked to child mental health? In: Bagchi D, editor. Global View on Childhood Obesity: Current Status, Consequences and Prevention: Elsevier; 2010b.

Rodriguez A, Miettunen J, Henriksen TB, Olsen J, Obel C, Taanila A, et al.Maternal adiposity prior to pregnancy is associated with ADHD symptoms in offspring: evidence from three prospective pregnancy cohorts. Int J Obes (Lond). 2008;32(3):550-7.

Date proposal received: 
Wednesday, 5 January, 2011
Date proposal approved: 
Wednesday, 5 January, 2011
Keywords: 
Behavioural Problems, Obesity
Primary keyword: 

B1089 - Ethical aspects of epidemiological research on young people involving linkage to routine individual data PEARL - PhD - 21/12/2010

B number: 
B1089
Principal applicant name: 
Dr Mari-Rose Kennedy (University of Bristol, UK)
Co-applicants: 
Prof John Macleod (University of Bristol, UK), Dr Ainsley Newson (University of Bristol, UK), Dr Amanda Owen-Smith (University of Bristol, UK), Prof Ruud ter Meulen (University of Bristol, UK), Dr Catherine Heeney (University of Oxford, UK)
Title of project: 
Ethical aspects of epidemiological research on young people involving linkage to routine individual data (PEARL) - PhD.
Proposal summary: 

The project is part of a 1+3 year MRC funded PhD at the University of Bristol. The first year has been dedicated to scoping the ethical issues pertinent to data linkage research and conducting a conceptual analysis of these. I plan to investigate the ethical aspects of data linkage research in relation to public health and research ethics, therefore examining the possible benefits and burdens of conducting this type of research and how these are balanced and distributed in both research procedure and outcomes.

Empirical ethics: integrating qualitative, in-depth interviews and grounded theory analysis with ethical analysis will be utilised to examine the Project to Enhance ALSPAC through Record Linkage (PEARL) as a case study.

Three groups of participants will be interviewed:

1. ALSPAC researchers who have utilised or are planning to utilise data linkage in their work

2. Members of the ALSPAC ethics and law Committee (ALEC)

3. Members of the eligible ALSPAC cohort including individuals from groups potentially less likely to consent to data linkage.

Participants will be purposively sampled and members of the eligible ALSPAC cohort will be recruited in consultation with the ALSPAC family liaison team. Approximately 10-15 individuals from each of the three participant groups will be interviewed.

Members of the eligible cohort will be sampled in two ways:

1. According to their previous participation in ALSPAC

2. Specific refusers to data linkage in the PEARL study

Within these two criteria variation according to sex, level of education and ethnicity will be aimed for with attention to individuals from social groups potentially less likely to consent to data linkage (such as individuals with low or high educational levels or from ethnic minorities).

The outcomes of this research will inform recommendations regarding the ethics of conducting data linkage research.

PhD Student: Mari-Rose Kennedy

Project Supervisors: Prof. John Macleod

Dr Ainsley Newson (currently on maternity leave)

Prof. Ruud ter Meulen (temporary supervisor)

Dr Catherine Heeney

Dr Amanda Owen-Smith

Please Note: This project will be collecting new qualitative interview data. Collection of new data from direct assessment was ticked in section 4 of this form as it seemed the most accurate description available in the form for what is intended in this study.

Date proposal received: 
Tuesday, 21 December, 2010
Date proposal approved: 
Tuesday, 21 December, 2010
Keywords: 
Ethics, Qualitative Research
Primary keyword: 

B1091 - Phenotypic Association of Squint Stereopsis and Phychosis - 20/12/2010

B number: 
B1091
Principal applicant name: 
Dr Conor Ramsden (University of Bristol, UK)
Co-applicants: 
Miss Cathy E M Williams (University of Bristol, UK), Dr Nic Timpson (University of Bristol, UK), Prof George Davey Smith (University of Bristol, UK)
Title of project: 
Phenotypic Association of Squint, Stereopsis and Phychosis.
Proposal summary: 

Stereoacuity

Stereoacuity describes the ability to visually perceive depth. It is a product of having two eyes facing in the same direction. Depth perception has an evolutionary advantage and is a feature shared by many successful predators. Stereoacuity allows for better hand-eye coordination and has been attributed with a role in the development of tools by primates and humans1. The ability to see in 3D confers an advantage in modern human life, allowing the performance of complicated manual tasks common to many occupations.

Requirements for stereoacuity are:

* Normal ocular and orbital anatomy

* Overlapping visual fields

* Equal sensory input

* Equal higher central processing

The most common cause of monocular vision in children is lack of overlapping fields caused by a misalignment of the eyes, known as strabismus or squint.

Strabismus

Strabismus (Squint) occurs when there is a failure to align the eyes. It is the most common paediatric ophthalmic condition occurring at a rate of aprox 3% in Caucasian populations.

A constant discrepancy of gaze has the suffix -tropia while an intermittent one is termed -phoria. Either may be convergent or divergent (prefixed by eso- or exo- respectively). Furthermore a squint may be catagorised as a concomitant or incomitant, a description of whether the angel of deviation is constant. These catagorisations lead to a collection of phenotypes and it is currently unclear whether these have disparate aetiologies.

There is a definite heritable element to strabismus and this has been displayed in ALSPAC2 for convergent squint (OR 2.39 for a positive family history of esotropia).

A previous (unpublished) analysis of genome wide associations of Single Nucleotide Polymorphims (SNP) with squint and stereo was conducted within ALSPAC (ref B711) to tease out the heritable element of the condition. The strongest association was with a SNP in a gene on Chromosome 1 - PDE4B.

PDE4B

PDE4B gene is located on chromosome 1p31. Its gene product is one of a family of enzymes that regulate intracellular pathways via cAMP. It has been proven to be expressed in brain tissue3.

Most significantly, in this context, PDE4B is a well characterised susceptibility locus for schizophrenia and bipolar affective disorder3-5.

Squint, Stereo and Schizophrenia

Minor Physical Anomalies scales such as the Waldrop scale have been identified as phenotypic markers to aid in the diagnosis of schizophrenia. Although the original Waldrop scale did not include squint, it has been modified to incorporate squint with more accurate predictive power6.

Squint has also been shown to be an independent risk marker for schizophrenia7,8.

Additionally, binocular depth perception has been shown to be reduced in psychiatric illness9.

PLIKSi

The Psychosis Like Symptoms Interview is an interview assessment of children reporting episodes of hallucinations, feelings of persecution, delusional symptoms and though disorder.

Children who report such symptoms have been shown to be at a higher risk of developing psychiatric illness9.

Questions Raised

Is there any association between squint/stereo and psychiatric illness?

How to Answer this Question

ALSPAC is uniquely placed as it has both phenotypic data on squint, stereo and psychiatric variables as well as genotypic data. As such we propose an investigation into the following

* Assoc squint & stereo phenotypes and schizophrenia phenotypes (PLIKSi)

1 Foundations of Binocular Vision, a clinical perspective, Steinman, 200

2 Williams, C., Northstone, K., Howard, M., Harvey, I., Harrad, R. A., & Sparrow, J. M. (2008). Prevalence and risk factors for common vision problems in children: Data from the ALSPAC study. Br J Ophthalmol, 92(7), 959-64.

3 Fatemi, S. H., King, D. P., Reutiman, T. J., Folsom, T. D., Laurence, J. A., Lee, S., et al. (2008). PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. Schizophr Res, 101(1-3), 36-49.

4 Numata, S., Ueno, S., Iga, J., Song, H., Nakataki, M., Tayoshi, S., et al. (2008). Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the japanese population. J Psychiatr Res, 43(1), 7-12.

5 Millar, J. K., Mackie, S., Clapcote, S. J., Murdoch, H., Pickard, B. S., Christie, S., et al. (2007). Disrupted in schizophrenia 1 and phosphodiesterase 4B: Towards an understanding of psychiatric illness. J Physiol, 584(Pt 2), 401-5.

6 Yoshitsugu, K., Yamada, K., Toyota, T., Aoki-Suzuki, M., Minabe, Y., Nakamura, K., et al. (2006). A novel scale including strabismus and 'cuspidal ear' for distinguishing schizophrenia patients from controls using minor physical anomalies. Psychiatry Res, 145(2-3), 249-58.

7 Schiffman, J., Maeda, J. A., Hayashi, K., Michelsen, N., Sorensen, H. J., Ekstrom, M., et al. (2006). Premorbid childhood ocular alignment abnormalities and adult schizophrenia-spectrum disorder. Schizophr Res, 81(2-3), 253-60.

8 Toyota, T., Yoshitsugu, K., Ebihara, M., Yamada, K., Ohba, H., Fukasawa, M., et al. (2004). Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Hum Mol Genet, 13(5), 551-61.

9Gunawardana 2010 schizo research - in press.

Date proposal received: 
Monday, 20 December, 2010
Date proposal approved: 
Monday, 20 December, 2010
Keywords: 
Genetics
Primary keyword: 

B1090 - The diagnosis of childhood disorders clinical and social implications MERGED WITH B0521 - 20/12/2010

B number: 
B1090
Principal applicant name: 
Ms Virginia Russell (University of Exeter, UK)
Co-applicants: 
Prof Jean Golding (University of Bristol, UK), Prof Alan Emond (University of Bristol, UK), Dr Kapil Sayal (University of Nottingham, UK)
Title of project: 
The diagnosis of childhood disorders: clinical and social implications (MERGED WITH B0521).
Proposal summary: 

Core research question:

Does identification/diagnosis of children with attention deficit hyperactivity disorders in their communities help improve core symptoms?

Background to proposed research:

Biomedical research suggests that attention deficit hyperactivity disorder (ADHD) is partially genetically and neurologically determined, leading to recommendations that a clinical diagnosis should be made as early as possible to treat and manage this condition. Current clinical trends show diagnosis is given more frequently and at younger ages than previously. Although the evidence for the effectiveness of the pharmaceutical intervention methylphenidate is well established as an effective intervention for ADHD, its use is controversial, particularly in young children.

There is little evidence-base that early diagnosis confers an advantage. Specific early school-based screening and intervention programmes for ADHD have not consistently improved children's outcomes.My own previous work in collaboration with Jean Golding and Colin Steer has shown that children with autistic traits in the ALSPAC cohort who were diagnosed had worse outcomes as adolescents in core autistic symptoms than those who had equally severe symptoms as preschoolers, but remained undiagnosed. We were not able to follow the developmental trajectories of core autism symptoms in detail other than in measures prosocial behaviour, where diagnosis and subsequent interventions in the community apparently made no difference to the developmental trajectory of this trait.

The proposed research will extend the methodology used for autistic traits to examine ADHD. We will identify ADHD diagnoses from clinical medical records of children with SEN or parent and teachers reports of doctors diagnoses of ADHD, and the group of children in the cohort reported as having an ADHD diagnosis will be identified.

This will allow us to define a control group with similar ADHD symptoms levels to those with a diagnosis. - as recorded by parents, teachers and/or medical records- see above. We will then examine social and demographic factors that may be associated with lack of diagnosis, as well as comparing outcomes between the groups.

Methodology:

The main study will focus on four key areas, although there will be scope for flexibility to allow for new developments:

[A] Identifying behavioural traits most predictive of receiving a diagnosis.

Hypothesis:

There will be a group of impaired (but undiagnosed) children in the ALSPAC cohort.

This will involve backwards 2 stage logistic regression to find behavioural traits associated with receiving a clinical diagnosis, then defining a composite 'attention deficit, hyperactivity' trait with appropriate weightings, which matches diagnostic criteria as closely as possible. We will find the ADHD diagnoses from a combination of parent report, teacher report and the IDI data which reports ADHD diagnoses for children with SEN at school action plus or statement level. We may also utilise the DAWBA 'pseudo diagnoses' where children were rated as having ADHD, and determine what proportion were actually diagnosed with ADHD in their communities.

[B] Defining an undiagnosed control group with equivalent symptoms to those with diagnosis.

The group will consist of children with impairment at the same levels as those with diagnosis (in the top 5%, of a composite 'attention deficit, hyperactivity' trait, for example) but who have not been given any Special Educational Needs (SEN) provision. We will examine the sensitivity and specificity of the composite ADHD trait in predicting diagnosis, and we will identify an impaired (control) group who did not receive SEN provision.

[C] Looking at social and demographic factors to see if any predict diagnosis.

Hypothesis:

Social and demographic factors will influence access to diagnosis.

Regression/association will be used to determine which factors in a child's background predict whether a diagnosis is applied or whether they fall into the control group. Gender, geographic region, measures of socio economic status, maternal age at birth, maternal mental health and other factors will be examined.

[D] Comparing outcomes in the two groups up to adolescence, and with the general population of the cohort.

Hypothesis addressing core research question:

Diagnosis of ADHD and subsequent intervention has an effect on clinical and social outcomes, compared with the undiagnosed group with similar symptoms.

We would hope that children receiving diagnosis of ADHD and receiving evidence based treatment (stimulant drugs and / or SEN provision) will have better outcomes than children who were not diagnosed and did not have SEN provision. This stage will compare measures of core symptoms, in diagnosed group, or not diagnosed control group, and in the general population. In addition, we will look at psychological measures such as well being, bullying, self esteem, friendships, and other salient measures such as impact on carers and children as the children reach adolescence. Trajectories of traits throughout the children's lifetimes will also be compared where data resolution allows.

The research proposed for this fellowship will take place at the host institution (Peninsula College of Medicine & Dentistry, Exeter), with an initial placement of one year at the University of Bristol Centre for Child and Adolescent Health, focusing on epidemiological and statistical techniques with ongoing collaboration on the qualitative project with the school of Social Science at Exeter University. A second period of up to one year (broken into short chunks) will be a placement at the international centre for epidemiological research with the larger longitudinal cohort in Denmark, depending on agreements and data availability. Preliminary enquiries have been made to The Danish National Birth Cohort (n=100,000+) who seem enthusiastic to collaborate.

The proposal as a whole responds to calls for community-based, multidimensional studies of outcome in childhood disorders so that current clinical practice can be robustly married with evidence based research. Please note that this research will be part of a larger fellowship proposal made to the Wellcome trust. The deadline for submission of this proposal is 21st January, so I am hoping to secure agreement with ALSPAC before submitting it.

Date proposal received: 
Monday, 20 December, 2010
Date proposal approved: 
Monday, 20 December, 2010
Keywords: 
ADHD, Autism
Primary keyword: 

B1092 - Childhood and early adolescent outcomes of early childhood grandparental care - 17/12/2010

B number: 
B1092
Principal applicant name: 
Prof Barbara Maughan (King's College London, UK)
Co-applicants: 
Title of project: 
Childhood and early adolescent outcomes of early childhood grandparental care.
Proposal summary: 

As increasing numbers of women return to work in their child's first year of life, research and policy interest in the effects of non-maternal care has increased. To date, most attention has focused on group care, where evidence suggests some enhancement of aspects of children's cognitive development, but also (for some children at least) some increased risk of aggressive and disobedient behaviours.

Although a significant minority of very young children are cared for in group settings, in practice informal care from family and friends is much more common. In the Millennium Cohort Study (MCS), for example, although approaching a quarter of the babies of working mothers were in group care at 9 months of age, approaching 60% were receiving 'informal' care. Of these, by far the largest group (35% of all children of working mothers) were looked after by grandparents (Hansen & Hawkes, 2009). Followed at age 3, children cared for by grandparents in infancy showed superior vocabulary development by comparison with children in other non-maternal care settings, but higher levels of difficulties in relationships with peers (Hansen & Hawkes, 2009).

In a previous study (Fergusson et al, 2008) we used the extensive data available on child care arrangements in ALSPAC to identify children cared for by grandparents at 8, 15 and 24 months of age. As in MCS, we found that this pattern was common: 44% of ALSPAC children were regularly cared for by their grandparents at each age. We identified family and maternal characteristics associated with the use of grandparent care, and traced its associations with risk for emotional/behavioural difficulties (as assessed by the Strengths and Difficulties Questionnaire) at age 4. Children cared for by grandparents had somewhat elevated rates of both hyperactivity and peer difficulties, though these variations seemed at least partly attributable to variations in the types of families using grandparent care.

There has been some work looking at the longer-term outcomes of different types and quantities of early childcare (Belsky et al, 2007). In theUS, for example, there may be an association between extensive non-relative care and problem behaviours at 8 and 11 years. So far as we are aware, however, no studies have yet tracked the impact of early grandparent care beyond the preschool years. This study is designed to fill that gap. Specifically, we propose to examine (i) indicators of behavioural adjustment/psychiatric disorder across childhood and early adolescence; and (ii) indicators of early language development (not examined in our previous study), and later cognitive abilities and school progress. We will contrast children who did and did not receive early grandparent care on this range of outcomes, controlling for previously identified confounders/selection effects, and assess the extent to which early grandparent care is associated with long-term risks or advantages for children's development.

References

Belsky, J., Lowe Vandell, D., Burchinal, M., Clarke-Stewart, K.A., McCartney, K., & Tresch Owen, M. Are there long-term effects of early child care? Child Development, 78, 681 - 701

Fergusson, E., Maughan, B. & Golding, J. (2008). Which children receive grandparental care and what effect does it have? Journal of Child Psychology and Psychiatry 49, 161-169

Hansen, K., & Hawkes, D. (2009). Early childcare and child development. Journal of Social Policy 38, 211-239

Date proposal received: 
Friday, 17 December, 2010
Date proposal approved: 
Friday, 17 December, 2010
Keywords: 
Childcare, Cognitive Function, Mental Health
Primary keyword: 

B1088 - Molecular and life-course aspects of APOE and TOMM40 in cognition - 14/12/2010

B number: 
B1088
Principal applicant name: 
Dr Lindsey Sinclair (University of Bristol, UK)
Co-applicants: 
Prof Ian Day (University of Bristol, UK), Prof Seth Love (University of Bristol, UK)
Title of project: 
Molecular and life-course aspects of APOE and TOMM40 in cognition.
Proposal summary: 

The human APOE gene is located on chromosome 19 (19q13.2) and encodes the protein apolipoprotein E (ApoE).(1) There are 3 known APOE variants, epsilon2, epsilon3 & epsilon4 with single amino acid substitutions occurring at amino acid residue 112 (arginine for cysteine in epsilon4) or 158 (cysteine for arginine in epsilon3).(2) APOE is mainly expressed in the liver, with the brain having the second highest concentration.(2) ApoE is involved in lipid transport around the body, is a constituent of VLDL & HDL particles and of intestinally formed chylomicrons.(2) It also modifies binding of lipoprotein particles containing ApoE to LDL receptors(2) and in the brain is thought to be involved in lipid recycling, neuronal repair and maintenance, with E4 being the least efficient isoform.(3, 4)

Possession of an e4 allele is a strong genetic risk factor for the development of Alzheimer's disease (AD), although the mechanisms remain unclear.(5, 6) Cumulative inefficiences of repair and maintenance may contribute to the increased risk in e4 carriers. Early neuropathological changes of AD including deposition of amyloid-beta (Abeta), FDG PET abnormalities and cognitive changes have been found even in early middle age in e4 carriers, decades before AD is clinically evident.(7-9) Possession of e4 (without diagnosed dementia) is also linked to higher levels of Abeta and neurofibrillary tangles at autopsy,(10, 11) accelerated volume loss,(12) reduced synaptic protein concentration(13) and decreased PET glucose metabolism in areas affected in AD.

A meta-analysis identified that e4 carriage (in the absence of dementia) was associated with significantly poorer global cognitive functioning, episodic memory and executive functioning;(14) however, most of the studies were small, some used insensitive tests, several cognitive domains were less studied, information on confounding variables was frequently lacking and most examined the over-60s only. From the small number of studies of younger age groups there is evidence that e4 may be beneficial for early cognitive function although one study reported that young adult e4 carriers had a thinner entorrhinal cortex.(15-17)

In addition to the link with AD, APOE genotype has been shown to influence LDL-C levels and cardiovascular disease risk with e4 homozygotes having the highest risk and e2 homozygotes the lowest.(18, 19) A non-linear relationship between APOE genotype and stroke was recently reported in a meta-analysis to which members of our group contributed.(20)

Recently the hypothesis that mitochondrial dysfunction precedes the development of AD neuropathology has again gained support.(24) Roses et al recently demonstrated that a variable length polymorphism in TOMM40, a mitochondrial protein essential for protein import, "predicts the age of onset of late-onset Alzheimer's disease".(23, 25) TOMM40 is very close to the APOE gene on Chr19 and they are in linkage disequilibrium. Roses et al proposed that the APOE/AD link may actually be due to a haplotype including a long poly-T repeat in TOMM40.(23) Improving our understanding of the early neurobiological effects of APOE and TOMM40 may help in predicting AD and to enhance the effectiveness of lifestyle-based and targeted pharmacotherapeutic interventions.

Most of our current knowledge regarding APOE and cognition relates to older adults and the end-stage pathology seen in AD. It is currently unclear when the e4-related changes in brain structure and function begin and which changes occur first. There is a dearth of information on e4 effects in earlier adult life, although the existing evidence suggests that there are differences between e4 and non e4 carriers. Even less is known about TOMM40 and pre-dementia changes.

Many other studies in this area have been criticised for using insensitive neuropsychological tests or not examining specific cognitive areas. I intend to carry out a battery of validated, sensitive neuropsychological tests to avoid this problem. Neuropsychological testing using genotype based recall from ALSPAC gives the potential to have much greater numbers ofe4 homozygotes, thus improving statistical power. Few other studies have included such young participants, had access to such a high number of individuals with rare genotypes or sufficient information on potential confounders, e.g. cardiovascular variables, whereas the use of ALSPAC data would permit the inclusion a wealth of information on confounders in addition to greater statistical power.

Date proposal received: 
Tuesday, 14 December, 2010
Date proposal approved: 
Tuesday, 14 December, 2010
Keywords: 
Cognitive Function, Genetics
Primary keyword: 

B1087 - Identification of Epigenetic differences in MZ twins at birth using Dried Blood spots - 14/12/2010

B number: 
B1087
Principal applicant name: 
Dr Vardhman Rakyan (Barts and London School of Medicine, UK)
Co-applicants: 
Title of project: 
Identification of Epigenetic differences in MZ twins at birth using Dried Blood spots.
Proposal summary: 

One of the biggest challenges in complex disease epigenomics is distinguishing cause from consequence. Simply comparing disease-affected vs. unaffected individuals will not reveal whether disease-associated epigenetic variation is causative for, or induced by, the disease. In this respect, comparing epigenetic profiles before and after disease onset would be invaluable, but prospective longitudinal birth-cohort studies are extremely expensive, time-consuming, and hence uncommon.

A Guthrie (or Dried Blood Spot, DBS) card is filter paper spotted with neonatal blood and used to screen for various diseases. For ~20 years, DBSs have been routinely generated in many countries (since 2000, greater than 90% of all neonates in the USA had DBSs made) and often stored indefinitely. This led us to consider whether DBSs can be used to generate whole-genome DNA methylation profiles (DNA methylomes). This would permit large-scale systematic analyses to determine whether disease-associated methylation variants are present at birth i.e. prior to overt disease. Importantly, this retrospective approach could be done at a fraction of the cost and time investment required for prospective studies. But, it would require the development of DNA methylomics methods that work on small amounts of relatively old DNA present in archived DBSs.

We have developed two different high throughput sequencing-based methods for generating DNA methylomes using nanogram quantities of DNA from greater than 10 year old DBSs. First, we developed the mini-MeDIPseq method that allows immunoprecipitation-based DNA methylomics from only 200ng of DNA. Then, we adapted BSseq (bisulfite conversion-based single bp-resolution DNA methylomes) for 100ng of DBS DNA. A range of bioinformatic analyses and comparisons with independent external data confirm the quality of the mini-MeDIPseq and BSseq data.

DBSs are already available for millions of people, of whom tens of thousands are disease-affected, and these numbers are increasing. DBS storage is also becoming more formalized. It is worth noting that spotting blood on filter paper is not limited to neonatal screening, but also used in home/field-based settings, and our methods can be applied to such samples. In summary,DBS-based DNA methylomics will help determine whether methylation variants in disease-affected individuals are present at birth, thus forming the basis of a novel retrospective longitudinal strategy for complex disease epigenomics.

Now, we would like to demonstrate, using the methods we have developed, that MZ twins are born epigenetically different, and that these differences are stable. To do this, we will need Guthrie cards from an MZ twin pair and then a follow up samples take any time between 1 - 13 years after birth. The sex, ethnicity, current age, disease-discordance etc. are of no relevance to this project. It would be good to have information on the chorionicity if available, and as many we would also be very grateful if you could provide samples for 2-3 different MZ pairs.

Date proposal received: 
Tuesday, 14 December, 2010
Date proposal approved: 
Tuesday, 14 December, 2010
Keywords: 
Epigenetics , Genetics, Twins
Primary keyword: 

B1086 - Parental depression and child development assessing the moderating effects of temperament and specific genotypes - 14/12/2010

B number: 
B1086
Principal applicant name: 
Dr Paul Ramchandani (Imperial College London, UK)
Co-applicants: 
Dr Susannah Murphy (University of Oxford, UK), Dr Jonathan Evans (University of Bristol, UK), Dr Nic Timpson (University of Bristol, UK), Prof Michael Meaney (McGill University, ROW), Prof Marinus van Ijzendoorn (Leids Universitair Medisch Centrum (LUMC), Netherlands , Europe), Prof Marian Bakermans-Kranenberg (Leids Universitair Medisch Centrum (LUMC), Netherlands , Europe)
Title of project: 
Parental depression and child development: assessing the moderating effects of temperament and specific genotypes.
Proposal summary: 

Aim

To assess the potential moderating effects of reactive temperament and 5-HTTLPR genotype on the association between parental depression and child behavioural and emotional outcomes.

Background

Parental depression is a consistent and strong predictor of adverse outcome for children. Work within ALSPAC has established that maternal anxiety during pregnancy, and maternal depression both pre- and post-natally, predict an increased risk of behavioural problems in children. These effects have been shown to persist until at least age 7 years. Paternal depression in the postnatal period has also been shown to be independently associated with similar adverse risks for children.

There has been considerable interest in recent years in the hypothesis that some children are differentially susceptible to environmental influence, for better or for worse. According to this conception, the same group of children (usually identified as having reactive temperament, and sometimes by genotype) show worse outcomes in adverse environments compared to non-reactive children, but also better outcomes in response to positive environmental exposures. We have previously explored this hypothesis in collaboration with ALSPAC in relation to paternal influence on children's behaviour (forthcoming publication in Family Science by Ramchandani, Bakermans-Kranenberg and van IJzendoorn). Findings from other studies have also supported the notion that differential susceptibility may occur in relation to reactive temperament, and also in relation to genes related to serotonergic and dopaminergic functioning (notably 5-HTTLPR and DRD4) (van IJzendoorn & Bakermans-Kranenberg, in press; Pluess et al, 2010).

Work undertaken by Professor Michael Meaney with the MAVAN cohort study has found preliminary evidence of a moderating effect of the serotonin transporter gene on the association between maternal prenatal depression and child outcome. We have come together to propose a further investigation with the ALSPAC team to investigate specific candidate genotype by environmental risk factors, focussing on parental depression. The MAVAN cohort could act as a second confirmatory cohort for any findings emerging from these analyses.

We would like to develop this further, using a conservative approach and testing the serotonergic candidate genes, namely:

1) Serotonin Transporter Gene- Promoter Region Polymorphism (5-HTTLPR)

If evidence of interaction and clear differential susceptibility is found, then we would seek to take a biologically informed approach and confirm findings in other relevant functional polymorphisms in genes related to serotonergic neurotransmission.

Resources required

We do not anticipate significant resource being required, as we have an existing dataset containing the key variables needed, with the main exception of the genotype classifications. The lead applicant (Paul Ramchandani) would undertake the analyses in collaboration with the other applicants.

This proposal is deliberately brief, but we are happy to answer any questions and provide further detail as required.

Date proposal received: 
Tuesday, 14 December, 2010
Date proposal approved: 
Tuesday, 14 December, 2010
Keywords: 
Genetics, Mental Health
Primary keyword: 

B1085 - Accelerometer measured sedentary behaviour and time spent in self-reported daily activities - 10/12/2010

B number: 
B1085
Principal applicant name: 
Prof Jonathan Mitchell (University of South Carolina, Columbia)
Co-applicants: 
Dr Russ Pate (University of South Carolina, Columbia), Dr Steven Blair (University of South Carolina, Columbia), Dr Marsha Dowda (University of South Carolina, Columbia), Prof Chris Riddoch (University of Bath, UK), Mr Calum Mattocks (University of Bristol, UK), Prof Andy Ness (University of Bristol, UK)
Title of project: 
Accelerometer measured sedentary behaviour and time spent in self-reported daily activities.
Proposal summary: 

Background: It is estimated that children spent 6 to 9 hours per day in sedentary behaviour, as assessed by accelerometry (1). This has important public health implications since sedentary behaviour has been associated with poor metabolic health in children and adults, and early mortality in adults (2-4). While accelerometry provides an objective estimate of total sedentary behaviour, this measure of sedentary behaviour does not provide details on how that time is spent. This is a limitation from a preventive standpoint as it is unknown what behaviours need to be specifically targeted to reduce time spent in sedentary behaviour. It is known from self-reported diaries that there is within and between gender variability regarding sedentary behaviour profiles (5, 6). However it is unknown if sedentary behaviour profiles are associated with more or less total sedentary behaviour as assessed by accelerometry.

Aim 1: To determine if spending time in specific sedentary behaviours associate with total sedentary behaviour, MVPA and adiposity at 14-years-old

Aim 2: To determine if spending time in specific sedentary behaviours at 14-years-old associate with changes in total sedentary behaviour, MVPA and fat mass from 14- to 16-years-old.

Cluster Analysis: Cluster analysis will be used to determine if children belong to similar groups based on their self-reported sedentary behaviours (separately for boys and girls). The time spent in 14 sedentary activities on a typical day was self-reported by the children: none, less than 1hr, 1-2hrs or 3 or more hrs.

Dependent Variable 1: Total sedentary behaviour (accelerometry less than 200cpm, mins/d)

Dependent Variable 2: Total MVPA (accelerometry(cubed)3600cpm, mins/d)

Dependent Variable 3: Fat mass (DXA, kg)

Independent Variable: Sedentary cluster group

Covariates: Maternal education, maternal obesity, birth weight, and length of gestation.

Statistical Analysis: Cross-sectional analysis at 14-years using analysis of covariance (ANCOVA) and Tukey adjustment for multiple comparisons. Longitudinal analysis between 14- and 16-years using linear mixed models to determine if sedentary cluster group is associated with change in total sedentary behaviour, MVPA and fat mass over time. All analyses will be conducted separately for boys and girls.

Model Building:

Model 1 - adjusted for age

Model 2 - adjusted for age + maternal factors

Model 3 - adjusted for age + maternal factors + birth factors

Target Journals: American Journal of Preventive Medicine or MSSE

References:

1. Matthews CE, Chen KY, Freedson PS, et al. Amount of time spent in sedentary behaviors in the United

States, 2003-2004. Am J Epidemiol. Apr 1 2008;167(7):875-881.

2. Ekelund U, Brage S, Froberg K, et al. TV viewing and physical activity are independently associated with metabolic risk in children: the European Youth Heart Study. PLoS Med. Dec 2006;3(12):e488.

3. Healy GN, Dunstan DW, Salmon J, et al. Breaks in sedentary time: beneficial associations with metabolic risk. Diabetes Care. Apr 2008;31(4):661-666.

4. Katzmarzyk PT, Church TS, Craig CL, Bouchard C. Sitting time and mortality from all causes, cardiovascular disease, and cancer. Med Sci Sports Exerc. May 2009;41(5):998-1005.

5. Biddle SJ, Gorely T, Marshall SJ. Is television viewing a suitable marker of sedentary behavior in young people? Ann Behav Med. Oct 2009;38(2):147-153.

6. Gorely T, Marshall SJ, Biddle SJ, Cameron N. Patterns of sedentary behaviour and physical activity among adolescents in the United Kingdom: Project STIL. J Behav Med. Dec 2007;30(6):521-531.

Date proposal received: 
Friday, 10 December, 2010
Date proposal approved: 
Friday, 10 December, 2010
Keywords: 
Physical Activity
Primary keyword: 

B1084 - Cortisol in middle childhood associations with genetic and early environmental risk PhD - 09/12/2010

B number: 
B1084
Principal applicant name: 
Dr Irena Yuri Pikovsky (University of Denver, USA)
Co-applicants: 
Prof Sarah Watamura (University of Denver, USA), Prof Julia Dmitrieva (University of Denver, USA)
Title of project: 
Cortisol in middle childhood: associations with genetic and early environmental risk (PhD).
Proposal summary: 

Individual differences in the hypothalamic-pituitary-adrenal (HPA) axis are important contributing factors for mental and physical health throughout the lifespan (e.g. Fan et al., 2009; Weber-Hamann et al., 2002; Whiteford, Peabody, Csernansky, Warner, & Berger, 1987). Because many individual differences that are important for health are believed to emerge in early childhood, research has focused on identifying individual and environmental variables that may impact basal and stress-reactive HPA axis activity. Elements of the early home environment such as financial strain, family turmoil, exposure to violence, and maternal depression have emerged as reliable predictors of basal cortisol (the primary hormonal product of the HPA axis) in childhood (Essex, Klein, Cho, & Kalin, 2002; Evans 2003; Flinn & England, 1997; Saridjan et al., 2010). However, prior research has primarily used concurrent or retrospective designs and therefore the longitudinal effects of early environmental risk on basal cortisol are relatively unknown. Although some important individual differences in HPA axis activity and development are likely due to genetic differences, studies examining genetic contributions to basal cortisol have found inconsistent results. Some studies suggest that genes such as SLC6A4, COMT, and MAOA may contribute to HPA axis regulation in adults (Brummett et al., 2008; Jabbi et al., 2007, Wust et al., 2009). Developmental research has also found main effects for SLC6A4 on basal cortisol in 9-14 year olds (Chen, Joormann, Hallmayer, & Gotlib, 2009). Interestingly, published work (including papers utilizing ALSPAC data) examining associations among these polymorphisms and mental health in children has often reported null results (Araya et al., 2008; Evans et al., 2008; Haberstick et al., 2005; Munafo, Durrant, Lewis, & Flint, 2009). Both theoretical models and limited prior research suggest that early effects of these polymorphisms on health may occur via a meditational process, such as through differences in HPA axis regulation. Thus genetic and early environmental risk may contribute to HPA axis dysregulation in childhood, which may then contribute to poorer health outcomes. However this meditational model needs to be assessed more thoroughly to extend environmental findings and replicate genetic associations.

Toward that end I have been examining genetic and environmental associations with cortisol in early childhood (2-6 years). This research was for my masters degree and related presentations. In our small sample of children (N = 59) I found that environmental risk (a composite of income, financial strain, life events exposure, maternal age, maternal education, and current maternal depression symptoms) did predict basal cortisol, but genetic risk (according to 5-HTTLPR, COMT, DAT, DRD2, and DRD4) did not (Pikovsky & Watamura, 2010). This suggests that although the early environment exerts its influence on basal cortisol patterns fairly early, effects of the above genetic variations may emerge later, and/or be too small to detect in a sample of this size. Because effect sizes are known to be small and effects likely emerge in middle childhood or later, it would be most useful to assess cortisol in a large sample of children more than six years old, as was done in the ALSPAC study.

The proposed study would examine relationships among genetic risk, early environmental risk, and basal cortisol in middle childhood. I would like to examine polymorphisms in the COMT gene (Val158Met - rs4680, rs2097603, rs6269, rs4818, rs165599), the MAOA promoter VNTR (AJ004833), and the serotonin transporter SLC6A4 (5-HTTLPR and rs25531). These polymorphisms will be used to define genetic risk, which along with environmental risk and their interaction will be used to predict basal cortisol. According to the ALSPAC documentation of child biological samples, cortisol was assessed in 889 participants at approximately 7.5 years of age.

To assess early environmental risk I would like to examine cumulative exposure to a variety of risk factors from approximately 2.5 - 6 years of age. The first of these risk factors is exposure to upsetting events. This was assessed with section D of the child-based questionnaires administered at 42, 57, and 69 months. Additionally, because maternal exposure to stressful events has implications for the child's environment, I would also like to examine mother's recent events exposure assessed at 47, 61, and 73 months. Together, cumulative exposure to upsetting events (child) and stressful recent events (mother) will provide a more comprehensive picture of financial strain, family turmoil, and exposure to violence. Finally, prior research in our lab and others suggests that maternal depression during early childhood is a risk factor for physiologic dysregulation (Essex et al., 2002; Pikovsky & Watamura, 2010), therefore I would like to look at the Edinburgh Postnatal Depression Scale assessed at 33, 61, and 73 months. Information from all three sets of risk factors will be combined via structural equation modelling into a latent Environmental Risk variable that will be used in subsequent analyses.

In addition to the aforementioned study variables, I would also like to look at the following variables as possible controls. Information about illness, medication, and diagnoses is especially important as these may impact cortisol concentrations. Therefore I would like to look at several sections of the child-based questionnaires administered at 91 months. Section A provides detailed information about health and medications. Section N provides information about special needs that may indicate underlying physiologic conditions. Finally, variables KR800 - KR832a provide information about DSM IV diagnoses.

Thank you for considering this data request. If accepted, these dissertation analyses will be supervised by my co-applicants: Sarah Watamura and Julia Dmitrieva. By examining the ALSPAC variables described above I hope to more thoroughly examine the links from genetic and early environmental risk to basal cortisol in early childhood. In doing so I will contribute to the literature on physiologic mechanisms leading to variability in mental and physical health.

Date proposal received: 
Thursday, 9 December, 2010
Date proposal approved: 
Thursday, 9 December, 2010
Keywords: 
Cortisol, Genetics
Primary keyword: 

B1082 - The impact of fathers age on offspring intelligence development and health - 09/12/2010

B number: 
B1082
Principal applicant name: 
Dr Elise Whitley (University of Edinburgh, UK)
Co-applicants: 
Title of project: 
The impact of father?s age on offspring intelligence, development and health.
Proposal summary: 

Changing patterns in education, employment and marriage along with improved reproductive technologies mean that the average age of childbearing in men and women is increasing while the average family size is falling. Although there are potential advantages to these trends, particularly in terms of financial security, there are also disadvantages, many of which are poorly understood at present. The detrimental effect of increasing maternal age on the health and development of offspring is widely recognised but the effect of increasing paternal age remains largely unexplored. However, there is emerging evidence that pregnancies conceived to older men are more likely to end in spontaneous abortion and that their children may be less intelligent, and be at higher risk of adverse outcomes and developmental disorders independent of the age of their mother.1-2 Moreover, these increased risks are not confined to childhood and advanced paternal age has also been reported to be associated with a number of adverse outcomes in adult offspring, most notably schizophrenia and certain cancers (principally breast, prostate and leukaemia).3-5 It is hypothesised that these associations may be due to the accumulation of chromosomal aberrations and mutations during the maturation of male germ cells.6 Later reproduction is also leading to a trend towards smaller families. While it is known that morbidity and mortality often rise with increasing number of siblings, there is also evidence to suggest that children from smaller families, and in particular only children, have a health experience that is out of line with anticipated gradients with number of siblings, specific examples being high blood pressure and asthma.7-8

Although the individual risks from having an older father or fewer siblings may be low, current trends in childbearing mean that these will increase at a population level and it is important that the risks are fully understood to allow appropriate education and to inform social policy changes. The aim of this project is to systematically investigate the effects of increasing paternal age and decreasing family size on the health and development of offspring throughout the life course. Systematic reviews of the available evidence will be carried out along with original research utilising a wide range of existing datasets.

Research plan

The project will involve a diverse range of existing large, good quality prospective datasets that cover the whole of the life-course, in different populations, over a range of calendar periods. These data sets include: ALSPAC, ProtecT, Swedish record linkage studies, Midspan Family Study, Glasgow Students Cohort, Caerphilly Cohort, and Boyd Orr Cohort. Parental age is available in all cohorts, along with a wealth of additional relevant data such as: mortality (Swedish, Midspan, Glasgow Students), cancer (ProtecT, Swedish, Midspan, Glasgow Students), offspring IQ (ALSPAC, Swedish), other mitogenic exposures (ALSPAC, Midspan), and details of family formation (ALSPAC, Swedish, Midspan, Glasgow Students).

This wide range of studies will form a consistent and complementary body of evidence on the short and longer-term effects of paternal ageing and smaller family size on offspring intelligence, development and health, and will also allow identification of critical periods in the life-course and investigation of how these interact with other risk factors. Examples (not an exhaustive list) of some specific hypotheses of interest include:

  • Is greater paternal age associated with an increased risk of neuro-developmental markers of future mental disorder such as low intelligence or delay in obtaining motor milestones? How important is intelligence in setting an individual's life-course in terms of education, future financial attainment and long-term health? These questions will be explored using ALSPAC, Swedish and other datasets.
  • Is increasing paternal age is associated with an increased risk of cancer? This will be examined in ProtecT (prostate cancer), Swedish (leukaemia, lymphoma and testicular cancer), and other datasets.
  • How do offspring risks from mitogenic exposures in the father, e.g. smoking, alcohol, diet and occupation, combine with those from advancing paternal age? This will be explored using ALSPAC, Midspan and other datasets.

* It has been suggested that poorer health in only children may be a result of a more sedentary lifestyle. However, there are alternative hypotheses: Are only children more likely to be born to older parents and have a poorer health experience as a result? Or are only children the result of poor reproductive experience with hereditary factors responsible for poorer health? (e.g. high blood pressure in pregnancy is associated with high blood pressure in offspring; if a negative experience in pregnancy (e.g. eclampsia) results in a decision not to have any further children then this could explain the apparent pattern of increased blood pressure in only children) These hypotheses will be investigated using ALSPAC and other data on maternal health in pregnancy.

* To what extent are paternal age and family size associations confounded with each other and with other factors, in particular, parental intelligence, maternal age and changing social class? The availability of a wide range of datasets from across the life-course will allow a thorough investigation of the impact of these inter-correlated confounding variables through direct statistical analysis, appropriate simulation work and alternative study designs, e.g. in the Swedish studies data are available on both biological and step-fathers; if associations are restricted to biological father's age then, assuming that parents tend to be similar in age, this will provide evidence that the relationship is independent of maternal age.

The specific assemblage of different cohorts provides additional strength and value to the proposal. For example, the use of cohorts, some historical, from a range of calendar periods will allow a comparison of associations over time and insight into the impact of changing attitudes and societal trends in the reasons for delayed parenthood. In addition, several cohorts (e.g. ALSPAC, Glasgow Students) have repeated sweeps of data collection and these will be used to explore the impact of missing data on the results and conclusions of the analyses.

References

1. Bray I, et al. Advanced paternal age: How old is too old? J Epidemiol Community Health 2006;60:851-3

2. Cannon M. Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence The clock ticks for men too. PLos Med 2009;6

3. Sipos A, et al. Paternal age and schizophrenia: a population based cohort study. BMJ 2004;329:1070-3

4. Zhang Y, et al. Parental Age at Child's Birth and Son's Risk of Prostate Cancer. Am J Epidemiol 1999;150:1208-12

5. Hemminki K, Kyyronen P. Parental age and risk of sporadic and familial cancer in offspring: Implications for germ cell mutagenesis. Epidemiology 1999;10:747-51.

6. Crow JF. The origins patterns and implications of human spontaneous mutation. Nat Rev Genet 2000;1:40-7

7. Okasha M, et al. Determinants of adolescent blood pressure: findings from the Glasgow University student cohort. J Hum Hypertens 2000;14:117-24

8. Rona RJ, et al. Association between asthma and family size between 1977 and 1994. J Epidemiol Community Health 1999;53:15-9

Date proposal received: 
Thursday, 9 December, 2010
Date proposal approved: 
Thursday, 9 December, 2010
Keywords: 
Development, Offspring
Primary keyword: 

B1083 - Is pet ownership associated with childhood asthma - 02/12/2010

B number: 
B1083
Principal applicant name: 
Prof John Henderson (University of Bristol, UK)
Co-applicants: 
Dr Liz Paul (University of Bristol, UK), Dr Jane Murray (University of Bristol, UK), Dr Carri Westgarth (University of Liverpool, UK)
Title of project: 
Is pet ownership associated with childhood asthma?
Proposal summary: 

We propose to examine the association between pet ownership, allergic sensitization and asthma, within a cohort of children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). On the basis of the findings of previous studies, we hypothesise that childhood household pet ownership will be associated with childhood asthma and asthma/atopy symptoms, and that these associations will be moderated by a number of factors including child genotype, time and duration of exposure, species of exposure (cats, dogs, other pets), and associated parental behaviours (domestic hygiene practices). By making use of an existing large-scale database, which has detailed records of pet keeping in the prenatal and early-to-middle childhood period, as well as extensive information concerning potential confounding factors, we propose to conduct the most rigorous study to date of the relationship between pet keeping and childhood asthma morbidity.

5.2. Hypotheses

We hypothesise that household ownership of cats, dogs and other pets, prenatally, in infancy and in early-to-middle childhood will be associated with:

1. Sensitisation to aeroallergens at 84 months (7 years);

2. Wheezing illnesses during early childhood up to 81 months of age (6 years 9 months);

3. Doctor-diagnosed asthma by 96 months(8 years);

4. Lung function and bronchial responsiveness at age 96 months (8 years).

We additionally hypothesise:

1. that pet ownership effects on sensitisation to aeroallergens, wheezing illness and asthma are independent of other social and lifestyle variables;

2. age and duration of pet exposure, number and types of pets owned (e.g. cats & dogs, cats only, dogs only, other furry pets., etc.) will moderate these associations;

3. parental hygiene practices (e.g. cleaning frequency and use of household cleaning products) will moderate these associations.

5.3. The study population - The Avon Longitudinal Study of Parents and Children (ALSPAC):

Child health questionnaires: Maternal reports of their children's health were collected using questionnaires issued six months after birth and at annual intervals thereafter. Mothers were asked if, during the preceding 12 months (6 months for the initial questionnaire), their child had 'wheeze with whistling on his/her chest when s/he breathed'. If they answered, "Yes," they were asked to complete a number of supplementary questions detailing the frequency of wheezing episodes, duration of wheezing, associated symptoms of breathlessness or fever, and what (if anything) provoked the wheezing. At 91 & 103 months of age (7 1/2 & 8 1/2 years approximately) they were also asked to report if a 'doctor had ever diagnosed (their) child as having asthma'. From responses to these questions, we reported differences in the epidemiological associations of wheezing illnesses in young children (Sherriff et al., 2001) and we have been able to map these symptoms to early wheezing phenotypes reported from the Tucson Children's Respiratory Study (Martinez et al., 1995).

Household pet ownership questionnaires: Details of pets kept in the household of the child were reported by mothers within the same questionnaires used to obtain details concerning child and maternal health. Respondents were asked "Do you have any pets?" and "How many of the following pets do you have?". Pet types listed included cats, dogs, rabbits, rodents (mice, hamster gerbil, etc.), birds (budgerigar, parrot etc.) and 'other' pets. Two additional categories of pet type (fish and turtles/tortoises/terrapins) were added when the cohort children were 2 years of age and onwards. Pet questions were asked prenatally (when the mother was between 8 and 32 weeks pregnant), at 8 months, and at 21, 33, 47, 85 and 97 months (approximately 2, 3, 4, 7 and 8 years).

Additional Questionnaire information: Measures of numerous potential confounds and moderators of pet ownership-asthma associations were collected using the same and additional maternal questionnaires administered both before birth and at yearly intervals thereafter. ALSPAC variables that have previously been found to be associated with variations in pet ownership include: gender of child, number of people in household, presence of older sibling, type of dwelling, maternal age, maternal and paternal social class, presence of other species of pet and maternal and paternal education (Westgarth et al 2010). ALSPAC variables that have previously been found or are thought to be to be associated with childhood asthma include: maternal and paternal smoking (including total number of hours of exposure to tobacco smoke per week in home), environmental pollution, use of household cleaning products, maternal anxiety during pregnancy, maternal and child diet, child activity levels (Shaheen et al 2002, 2004, 2005; Sherriff et al 2005, 2010; Cookson et al 2009).

Child clinic assessments: A range of clinical and behavioural data were collected between 91 and 103 months of age (approx. 7-8 years), including skin prick test responses to cat (felis domesticus), house dust mite (Dermatophagoides pteronyssinus), and mixed grass pollen. A subsample of the clinic population (approx 2500 children) was also assessed by skin prick test responses to other animals commonly kept as domestic pets (dog, horse, mouse, rabbit, guinea pig and hamster). For genetic analyses, DNA was extracted from maternal blood and from infant cord blood samples at birth, and later supplemented by blood samples drawn at approx. 91 months; such samples are currently available for approximately 10,000 mothers and 10,000 children.

The ALSPAC population is broadly representative of the rest of the British population based on 1991 census data, although participants in the study were more likely to live in owner-occupied accommodation and less likely to have a non-white mother (ALSPAC 2.6%; population of Avon 1970 4.1%; UK census 1991 7.6%). In common with all population-based longitudinal studies, there has been incomplete retention of the cohort with attrition biased towards the more socially disadvantaged groups. However, over 11,000 children actively participated in the study to age 96 months (8 years), providing a large dataset with which to assess antenatal and early life effects on the development of childhood asthma and wheeze.

5.4. Health outcomes (see Hypotheses):

1. Sensitisation to aeroallergens was assessed by skin prick test responses to cat (felis domesticus), house dust mite (Dermatophagoides pteronyssinus) and mixed grass pollen at the age of 91 months (approx. 7 years). A positive skin prick test response (greater than 2mm weal) to any of these three allergens identifies over 95% of atopic children in our population (i.e., positive skin test to any allergen).

2. Doctor diagnosed asthma at approx. 96 months (8 years) was assessed from response to questionnaires completed by the mother.

3. Wheezing illness during early childhood is based on a novel approach to wheezing phenotype characterisation developed by our group from longitudinal analyses of wheeze data using latent class models (Henderson et al 2008). This analytical approach defines the minimum number of wheezing trajectories (classes) that best describe the data and is robust to missing data, providing wheeze phenotype classifications for 11,625 of the study population from birth through 81 months. The best fitting model to our data suggested the presence of 6 classes (5 wheezing classes plus non-wheezers). We have named these five wheezing trajectories Transient Early, Prolonged Early, Intermediate-onset, Late-onset and Persistent Wheezing as shown in the legend. These include classes that have been suggested to be associated with abnormalities of early (including intrauterine) airway development (Stocks and Dezateux, 2003). Our analyses showed strong associations between intermediate and late onset wheezing with bronchial hyper-responsiveness and of intermediate onset and persistent wheezing with allergy to cat and house dust mite. Therefore, it appears that these classes are representative of discrete wheezing phenotypes in early childhood that may have differing natural histories and aetiology (Henderson et al 2008).

4. Lung function and bronchial responsiveness were assessed at a research clinic at approximately 103 months. Spirometry was performed according to American Thoracic Society criteria for acceptability and reproducibility (American Thoracic Society, 1995). Measurements were quality controlled to ensure appropriate selection of the optimal curve from which lung function variables (FEV1, FVC, MMEF, FEF50, FEF75) were derived. Each variable was converted to a scale of gender- age- and height-adjusted standard deviation units based on log-linear regression against age and height, for boys and girls separately and then combined across genders (Chin and Rona, 1992). After completion of satisfactory baseline lung function measurements, bronchial responsiveness to methacholine was measured in consenting children (n=5000) according to the rapid method of Yan et al, (1983) using hand-operated glass nebulisers. For each participant, we measured forced expiratory volume (FEV1) post-saline inhalation (baseline) and 1 minute after each of a sequence of cumulative doses of methacholine.

Date proposal received: 
Thursday, 2 December, 2010
Date proposal approved: 
Thursday, 2 December, 2010
Keywords: 
Asthma
Primary keyword: 

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