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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B998 - A graphical model approach to pedigree construction using constrained optimisation - 26/05/2010

B number: 
B998
Principal applicant name: 
Dr James Cussens (University of York, UK)
Co-applicants: 
Dr Nuala Sheehan (Not used 0, Not used 0), Prof Paul Burton (Not used 0, Not used 0), Prof George Davey Smith (University of Bristol, UK)
Title of project: 
A graphical model approach to pedigree construction using constrained optimisation
Proposal summary: 

I am currently preparing a grant application for the MRC Methodology panel with a computer scientist from York, James Cussens (PI), to investigate the potential of powerful graph-learning algorithms for reconstructing pedigrees with maximum likelihood from genetic marker data. This is a problem that I have been working on for a few years with a Norwegian collaborator, Thore Egeland, but our emphasis has been very much on forensic identification applications and we have taken a more traditional statistical genetics approach. A pedigree is a special type of graph in that nodes representing individuals can only have two parents and parents must be labelled as being of opposite sex. Consequently, general graph learning algorithms are not very efficient unless they are suitably modified, although we do not have the additional problem encountered in other applications of having to learn the probabilities on the edges (arrows) between nodes as these derive from our knowledge of the genetic model under consideration. James has been in communication with us for some time and has considered a number of approaches to this specialised graph learning problem. He has decided that an approach using constrained optimisation using integer linear programming is the most promising. Indeed, initial results for a simplified situation whereby all individuals are observed and are totally ordered by age are promising, and much faster than competing methods, so we are quite optimistic.

Classical approaches to pedigree reconstruction developed 40 years ago, such as the sequential algorithm of Thompson ? which is a "greedy algorithm", in our terminology ? typically search for "good" but not necessarily optimal pedigrees by starting with sets of individuals that are most likely to be siblings, then finds the most likely parents for these sibships and moves on from there. The resulting reconstruction in heavily dependent on the decisions made about nuclear families at any given stage. Information on the maximal size of a sibship (which will vary across human populations and differ widely from animal and plant populations), the minimal number of years to reach sexual maturity (generation gap), age differences between parents etc. is incorporated in these algorithms at various stages in order to ensure that a realistic structure is produced. These are all "constraints" and one of our first tasks will be to search the statistical literature for those that are known to be important and then find a way to express them as linear constraints. All these algorithms assume complete data which we will typically not have. Searching over all possible pedigrees with missing individuals is much harder and is the interesting problem for the graph learning community. We will begin with a likelihood approach but will then move to a Bayesian framework where ""hard" prior information e.g. on certain known relationships and "soft" prior information e.g. this population is known to favour first cousin marriages etc. can all be incorporated. We will start with simulated data, moving from classic unlinked microsatellite-type data to linked markers and dense sets of SNPs: the likelihood calculations become more problematic then and we will need to employ Markov chain Monte Carlo methods to approximate likelihoods that are intractable with exact methods.

Besides the fact that this is a really nice graph theory problem, the main medical application is the potential for finding sets of related individuals from large Biobank populations for later linkage studies, or for homozygosity mapping where distantly related individuals are better because the shared environmental effects won't mask the relatively small effects of the rarer variants we're trying to find. Identifying the correct pedigree/relationship is crucial for forensic and population wildlife management applications, of course. It is also important for linkage analysis but is overkill for homozygosity mapping where you just need individuals with reasonable IBD-sharing probabilities. However, these general machine-learning algorithms are extremely efficient so if we can tailor-make one for pedigrees that will work quickly, we can obviously get distant relatives easily. We will then need to check sensitivity to getting the right relationship and investigate how best to choose relatives for homozygosity mapping from any constructed extended pedigree.

This is a methodological project with some very hard problems to solve before we get close to using it for anything. There are obviously ethical issues as to when and where you could do this in practice, but for now, we just want to see if it can be done. We will clearly do most of the work with simulated data but we will need a real dataset to check that what we are finding is not totally due to how we simulated. The main application is aimed at UK Biobank which has referred to the desirability of being able to infer relatives at a later point in its protocol. However, as they are a long way off genotyping, we will need a back-up data set to test things on if we get funded and if Biobank takes more than three years to deliver. Other existing cohort studies are probably not large enough to capture any relatives by chance. Obviously there are very close relationships in ALSPAC which are a bit too easy to find but, given that every birth in Avon over a two year period was included, we thought that there might be siblings or even a few cousins there. Our main intention would be to see if we can recover relationships you already know about - not to find hidden ones - although there is a possibility that the ones you know about are not quite as stated. Obviously all ethical issues will have to be handled as deemed appropriate at the time. In particular, we are not interested in any analysis of the ALSPAC data for relatedness, per se, so nothing will be published without clearing everything beforehand. Also, authorship of any paper that uses the ALSPAC data in any way at all, be it for the machine learning, statistical genetics, forensics or medical communities, will include appropriate ALSPAC investigator(s) and this will be discussed with you as beforehand.

Paul Burton (Leicester) and George Davey Smith (Bristol) are both coming on board as full investigators, not because of their great desire to learn about constrained optimisation but because we feel we need their input and experience to ensure a) that the focus of the research stays on medical applications and b) that anything to do with real data will be handled correctly. Knowing them both, I am confident that they will advise us well. I am being deliberately vague about what data we require because we do not know exactly what we need yet, it will be a long time before we need it and much more information than the above will have to be provided then. George mentioned that Illumina quad GWAS data would be available so once we have the machinery in place to handle dense SNP arrays, access to some of that data would be something to discuss. Right now, for the purposes of the grant application, I would like to be able to say, with your permission, that we are in discussion with ALSPAC collaborators for real data which will be used to test the methods in an appropriate way when we finally get to that stage.

Date proposal received: 
Wednesday, 26 May, 2010
Date proposal approved: 
Wednesday, 26 May, 2010
Keywords: 
Genetics
Primary keyword: 

B1001 - EAGLE consortiums Internalizing Behaviour GWAS meta-analysis - 25/05/2010

B number: 
B1001
Principal applicant name: 
Dr Henning Tiemeier (Erasmus University Medical Center, Rottterdam, the Netherlands, Europe)
Co-applicants: 
Fleur Velders (Not used 0, Not used 0), Camilla Stoltenberg (Not used 0, Not used 0), Dr Beate Glaser (Not used 0, Not used 0)
Title of project: 
EAGLE consortium's Internalizing Behaviour GWAS meta-analysis
Proposal summary: 

Concept: Measurement Person Source Time points

Internalizing behaviour SDQ emotional symptoms mother report Questionnaire 4-13yrs.

continuous measurement

SMFQ mother report Questionnaire 10-16yrs.

continuous measurement

EAGLE-WITHIN-COHORT-ANALYSIS-PLAN-Internalizingbehaviour-170310

In this document:

1. Traits of interest

2. Participating studies

3. Number of subjects

4. Genotyping + Imputation

5. Model of association.

6. Data exchange

7. Analysis plan

8. Secondary analysis

9. Proposed deadline

1. Traits of interest

First round: Internalizing behaviour at preschool age (0-7yrs.) continuous measure (int_cont_preschool)

Second round (data added to first round): Internalizing behaviour at school age (8-17yrs.) continuous measure (int_cont_school)

2. Participating studies (as of 10-09-2009)

Fleur Velders, Henning Tiemeier (Generation R),

Joachim Heinrich (LISA)

Beate Glaser, George Davey Smith (Alspac),

Elena Hyponen, Chris Power (1958BC),

Sandra Louis, Lyell Palmer (RAINE),

Pal Suren, Camilla Stoltenberg (MOBA).

3. Projected number of subjects:

4. Genotyping + Imputation

* Genotyped SNPs (Affymetrix, Illumina, Perlegen)

* Imputation HapMap Phase II CEU SNPs. Preferred release 22 of HapMap, build 36. Predefined marker filters to apply before imputation (HWEPgreater than 10-6, MAFgreater than 0.01, SNP-callgreater than 95%). Suggestion left open to cohorts to apply specific filters but should be reported.

* Analyse all SNPs, no filtering on call rate/HWE/MAF/imputation quality (QC metrics to be reported, and filtering will be done at meta-analysis stage)

5. Model of association

* Additive model (SNP coded as allele dose from 0 to 2), which accounts for genotype imputation uncertainty by use of linear regression onto estimated dose (as included in MACHQTL, ProbABEL, SNPTEST), adjusting for population structure and covariates.

6. Data exchange

* See separate RESULTS_FORMAT file for details of results file formatting and file naming.

* Summary statistics to be uploaded to the AIMS system (available?) (link will be provided)

* Only summary statistics will be transferred, not individual level genotype or phenotype data.

7. Analysis outline

* First round: int_cont_preschool

* Second reound: int_cont_school all items:

Internalizing behaviour:

CBCL: broad band scale internalizing problems

SDQ: subscales internalizing behaviour

Rutter: subscales internalizing behaviour

* how to deal with missings? Suggestions:

o allow 25% mssings per scale

o minimum of 10 items per scale

o cohort specific

* Transformation of outcome variable:

o intbeh Z-score = calculate a Z-score

= standardised score

= [value-mean]/standard deviation

(based on the mean and SD internalizing problems score in the sample)

* Model:

o Z-score = SNP + sex + age

- SNP = child genotype

- Sex: coded 1 for male, 2 for female

- Age: at measurement

* Exclusions:

o One of sibling twins or correction

o Non-Caucasian

8. Secondary analyses (for later discussion)

* Dichotomous measurements

9. Deadline

* The proposed deadline for uploading = end of May 2010.

Date proposal received: 
Tuesday, 25 May, 2010
Date proposal approved: 
Tuesday, 25 May, 2010
Keywords: 
Depression, Genetics, Mental Health
Primary keyword: 

B1000 - Gender-specific genomewide association study for circulating levels of fasting glucose and insulin - 20/05/2010

B number: 
B1000
Principal applicant name: 
Dr Reedik Magi (University of Oxford, UK)
Co-applicants: 
Dr Inga Prokopenko (University of Oxford, UK), Dr Nic Timpson (University of Bristol, UK)
Title of project: 
Gender-specific genomewide association study for circulating levels of fasting glucose and insulin
Proposal summary: 

Not available

Date proposal received: 
Thursday, 20 May, 2010
Date proposal approved: 
Thursday, 20 May, 2010
Keywords: 
Genetics
Primary keyword: 

B994 - Association between SNPs of the IGF Axis against antenatal and postnatal growth - 28/04/2010

B number: 
B994
Principal applicant name: 
Priyakumari Parmar (University of Western Australia, Australia)
Co-applicants: 
Prof Lyle Palmer (Not used 0, Not used 0), Dr Craig Pennell (Not used 0, Not used 0)
Title of project: 
Association between SNPs of the IGF Axis against antenatal and postnatal growth
Proposal summary: 

A manuscript has already been prepared assessing the association between SNPs of the IGF Axis and developmental growth

- 165 SNPs were tagged in Raine as being part of the IGF Axis

- 145 SNPs were used in analyses (20 SNPs were excluded for being inHWE disequilibrium, LD, not genotyped properly less than 80%, and MAF less than 10% in HapMap and Raine)

- Longitudinal analyses for antenatal measures: abdominal circumference, head circumference and ratio of head to abdominal circumference

- Cross-sectional analyses for birth weight, abdominal circumference, head circumference and ponderal index (for measurements taken at birth - on day 2 of life)

- Longitudinal analyses of BMI from year 1 to year 17

- A total of 63 SNPs (out of 145 SNPs) gave at least one significant association (p less than 0.05) with a measure of developmental growth (at birth or antenatal level)

- The following table summarises the analyses

Time

Type of analysis

Outcome

Covariates

Birth

(day 2 of life)

Cross-sectional

Abdominal Circumference

Gestational age, parity, placental weight and maternal diabetes

Head Circumference

Gestational age, parity, placental weight and maternal education

Birth Weight

Gestational age, parity, placental weight

Ponderal Index

Gestational age, placental weight, maternal BMI, maternal and paternal age

Year 1

Cross-sectional

Percentile change in weight

Gestational age, parity, placental function, maternal diabetes and breast-feed

Year 1-18

Longitudinal

BMI

Age

The phenotypic data required for the research in this proposal includes all outcomes and covariates outlined in the table above and are listed below:

  • Data on:
    • Maternal and Paternal age and education
    • Maternal smoking status, BMI, hypertension, diabetes and anemia (during pregnancy)
    • Gestational age
    • Placental weight and function
    • Parity
    • Child breast-feed
    • Gender of child
  • At Birth
      • Abdominal circumference
      • Head circumference
      • Birth weight
      • Ponderal index
  • Postnatal
    • Year One of life
      • Percentile change in weight (since birth)
    • Years One-Eighteen

BMI

Date proposal received: 
Wednesday, 28 April, 2010
Date proposal approved: 
Wednesday, 28 April, 2010
Keywords: 
Genetics
Primary keyword: 

B996 - Testing the combined effects of antenatal and postnatal stressful environments on child development - 23/04/2010

B number: 
B996
Principal applicant name: 
Sara Jaffee (King's College London, UK)
Co-applicants: 
Dr Edward Barker (King's College London, UK)
Title of project: 
Testing the combined effects of antenatal and postnatal stressful environments on child development.
Proposal summary: 

Background: A number of studies have shown that maternal stress during pregnancy has effects on

offspring behaviour independent of postnatal measures of maternal stress. However, animal studies have

shown that behavioural development is influenced by the interaction of antenatal and postnatal

environments (Francis et al. 2003). Data are needed to test the co-action of antenatal and post-natal

environments in humans.

Aims: The proposed research has two aims: (1) to identify trajectories of familial risk from the prenatal to

the postnatal period, (2) to 'test whether familial risk trajectories up to age 8 years are associated with

child cognitive abilities and behaviour from 8 to 10 years. The design will provide evidence as to the

relative importance of antenatal versus postnatal environments and test additive versus interactive models

of antenatal and postnatal effects.

Hypothesis 1: We will identify trajectories that reflect (a) consistently low levels of familial risk, (b)

increasing risk from the antenatal to postnatal period, (c) decreasing risk from the antenatal to postnatal

period, (d) stable and high levels of familial risk.

Hypothesis 2a: If antenatal environments have enduring effects irrespective of postnatal environments,

children on the stable, high risk and declining trajectories will have poorer outcomes than children on the

stable, low risk and increasing risk trajectories.

Hypothesis 2b: If postnatal environments have effects on child outcome irrespective of antenatal

environments, then children on the stable, high risk and increasing risk trajectories will have poorer

outcomes than children on the stable, low risk and declining risk trajectories.

Hypothesis 2c: If antenatal and postnatal environments have additive effects, then children on the stable,

high risk trajectory will have the poorest outcomes, children on the stable, low risk trajectory will have

the most positive outcomes, and children on the increasing and declining trajectories will fall intermediate

to the other two groups.

Hypothesis 2d: If antenatal and postnatal environments have interactive effects, then children on the

stable, high risk trajectory will have poorer outcomes than the other three groups.

Analysis: The analysis would involve Cl) estimating trajectories of environmental risk from the antenatal

through the postnatal period up to age 8 years involving a composite index of financial hardship,

domestic violence (as reflected in mothers' reports of conflict with partner and in life events

questionnaire), child harm (as reflected in life events questionnaire), maternal social support, and

maternal depression and anxiety; (2) estimating associations between environmental risk trajectories and

child behaviour (symptoms of antisocial behaviour, depression, and attention deficit/hyperactivity) and

cognitive outcomes (IQ) at 8 to 10 years. Analyses would control for antenatal smoking and alcohol use

as well as parent education and parental history of antisocial behaviour and mental health problems.

Date proposal received: 
Friday, 23 April, 2010
Date proposal approved: 
Friday, 23 April, 2010
Keywords: 
ADHD, Behavioural Problems, Depression
Primary keyword: 

B987 - Facial landmark data and ocular measures in the ALSPAC cohort - 21/04/2010

B number: 
B987
Principal applicant name: 
Dr Jay Self (Not used 0, Not used 0)
Co-applicants: 
Prof Stephen Richmond (Not used 0, Not used 0), Alexei Zhurov (Not used 0, Not used 0), Arshed Toma (Not used 0, Not used 0), Ms Cathy Williams (Not used 0, Not used 0), Dr Kate Northstone (Not used 0, Not used 0)
Title of project: 
Facial landmark data and ocular measures in the ALSPAC cohort
Proposal summary: 

Draft proposal of Initial analyses of available data

Introduction and background

From the development of the bony orbit through to the complex interconnection of neuronal circuitry required for stereoscopic vision, the factors controlling growth and development of the visual system in humans are poorly understood. In such a sensitive and plastic system, developmental anomalies are extremely common. In many circumstances small but timely interventions can result in significant improvements in vision which serve that individual for life.

Strabismus (squint) describes misalignment of the visual axis of one eye with respect to the other. It is thought to affect between 2 and 4% of the population and in most cases results in loss of vision and/or loss of stereoscopic vision1. Some squints are convergent and some divergent. In some cases it is not clear why the eye is divergent rather than convergent or visa-versa. Convergence is closely related to many forms of convergent squint as is the refractive condition of the developing eye2. Similarly, the distance between the eyes in the horizontal plane is known to alter the amount of convergence required for binocular vision and the degree of stereopsis in the general population can vary greatly. Therefore, it is possible that by altering the requirement for convergence, the physical distance between the eyes in the horizontal plane is a risk factor for squint and for varying grades of stereoscopic vision.

The factors influencing the growth of the bony orbit and its relationship to development of the globe are also poorly understood. However, it is known that extreme anomalies of globe growth can result in significant growth changes in the developing orbit. For example, in infants with either absent (anophthalmos) or very small globes (microphthalmos) the orbit is known to under-develop such that tissue expanders are sometimes used to treat asymmetry. Conversely, for infants with marked enlargement of the globe (Buphthalmos) which is often related to congenital glaucoma, the bony orbit is enlarged3.

It is therefore evident that extreme variations in the growth of the globe can influence the growth of the bony orbit and resulting facial character. Perhaps more subtle variations in globe size also have an effect on the development of the bony orbit.

Proposed study

ALSPAC is an ongoing population-based birth cohort into which over 14,000 mothers-to-be were recruited in the Southwest of England (http://www.bristol.ac.uk/alspac/). Approximately 11-12,000 children and their families are still participating and the "children" are now on the verge of adulthood (17 - 19 years). ALSPAC has assembled detailed exposure and developmental data on these children and their families in addition to genetic information leading to the production of numerous peer reviewed publications in prestigious journals4.

Data relevant to this proposed study include 3D facial scans for 4200 individuals of the ALSPAC cohort when aged 15, processed and landmarked by Professor Richmond's group in Cardiff. The 3D facial scans were captured using 2 high resolution Konica/Minolta laser scanners. These scans provide exquisite detail of the surface characteristics of each participants face and allow measurement of facial features and comparison with age matched controls to an accuracy of 0.3mm. These data have been 'landmarked' over various periocular structures to allow measurements of anatomical structures such as inter-canthal distance and new landmarks can be created for each scan to measure an infinite number of facial characteristics.

Further relevant data includes assessments of ocular biometry, alignment and stereoscopic vision measurements for the same 4200 children with facial scans, collected at ages 7 - 15 years, thus providing a uniquely detailed dataset of ocular development and facial characteristics in a large sample of children.

We will investigate the hypothesis that mild to moderate variations in globe size alter the growth of periocular structures. From those ALSPAC children with 3D facial scans and ocular biometry for each eye collected at age 15 (n = 2837), approximately 5% (134) have an interocular difference in axial length of 0.5 mm or greater. We will obtain a Left vs Right asymmetry measurement (as in figure 1) for the periocular landmark data and compare the asymmetry of the two groups and therefore the degree of facial asymmetry with the degree of ocular size asymmetry.

Additionally, we will compare the same periocular landmarked data in children (obtained at age 15) with orthoptic measurements obtained at age 7 years (strabismus) or stereoscopic vision (obtained at 7, 11 and 12 years), to investigate the relationship between horizontal distance between the visual axes and the incidence of squint and reduced levels of stereopsis (depth perception). We anticipate that the majority of children with 3D face data will have been examined at age 7: of these approximately 3.5% (estimated n = 140) will have had a strabismus at that age and are highly likely still to be strabismic at 15 as the condition does not spontaneously resolve and even surgery rarely removes all misalignment. We will investigate the hypothesis that the occurrence of ocular misalignments (manifest squints) is modified by the distance between the ocular axes, for example that the risk of convergent strabismus increases as the horizontal distance between the eyes decreases and conversely that the risk of divergent strabismus increases as the eyes are displaced further apart. Stereopsis has been tested at 7, 11 and 12 years and we anticipate that the majority of children with 3D facial data at 15 will have had their stereopsis tested at 7 years, and again at 11 years. We will investigate the hypothesis that, in children with no strabismus, the accuracy of depth perception is related to the horizontal distance between the eyes.

We will perform a variety of statistical analyses looking for associations between these parameters and ocular landmark measurements. The details of the individual tests will be clarified when feasibility and numbers for each individual dataset are ascertained. We anticipate using univariate and subsequently multivariate analyses using appropriate covariates including sex etc. Dr Kate Northstone will act as "data buddy" as part of her funded programme of work with CW and will advise on analytic approaches as needed. Data transfer will take place using a specific procedure designed to collaborate with Prof Richminds group, who unusually have the alspac clinicID as the identifier on the face-shape data they acquired. Thus KN will send Prof Richmond the clinicIDs of all participants for whom we have the specified vision variables; Prof R will then send KN the derived face landmark variables; KN will attach to this file the vision data and will remove clinicID and replace it with a collaborator ID. This stand-alone file can then be analysed in Cardiff or Southampton as appropriate.

Additional statistical support will be sought where necessary from Dr Sarah Ennis from the Bioinformatic Unit at Southampton General Hospital, and Professor Clive Osmond, Professor of medical statistics at Southampton's MRC Epidemiology resource centre

We anticipate acquiring sufficient numbers to investigate the associations of various ocular parameters with periocular facial landmarks. This will provide some exiting information about the complex interaction between physical ocular anatomy, visual development and the interaction of orbital and ocular growth. This could provide some interesting epidemiological data in addition to a greater understanding of visual system development. It is anticipated that this work will lead to the publication of research papers in peer reviewed journals and may provide preliminary data for further work in this cohort perhaps using genetic data.

Date proposal received: 
Wednesday, 21 April, 2010
Date proposal approved: 
Wednesday, 21 April, 2010
Keywords: 
Development, Neurology, Vision
Primary keyword: 

B986 - Facial landmark data ocular development and maternal alcohol consumption in the ALSPAC cohort - 21/04/2010

B number: 
B986
Principal applicant name: 
Dr Jay Self (University of Southampton, UK)
Co-applicants: 
Prof Stephen Richmond (Not used 0, Not used 0), Miss Cathy E M Williams (Not used 0, Not used 0), Dr Marko Kantomaa (Not used 0, Not used 0), Arshed Toma (Not used 0, Not used 0), Alexei Zhurov (Not used 0, Not used 0), (University of Bristol, UK)
Title of project: 
Facial landmark data, ocular development and maternal alcohol consumption in the ALSPAC cohort
Proposal summary: 

We wish to identify those ALSPAC children who have had 3D facial scans, orthoptic assessments, refraction, clinical examination and for whom we have maternal alcohol intake data. We will stratify alcohol exposure as done previously for this cohort into women who drank no alcohol in pregnancy, or less than 1 drink per week, or more than on drink per week (2). In this earlier ALSPCAC paper, effects on child temperament were identified after exposure to greater than 1 drink per week during pregnancy (approx 16% women in that analysis), suggesting there is enough variation in alcohol exposure within the cohort for useful analyses of outcome. We will perform a variety of statistical analyses seeking to examine associations between alcohol exposure and facial anatomical and ophthalmic measurements. For example, category of first trimester alcohol intake as a predictor or modifier of (a) palpebral aperture width (between medial and lateral canthi), (b) distance between the eyes (between the medial canthi) (c) occurrence, direction and magnitude of strabismus (assessed at age 7) and refractive error (outcome data at age 3 for 2000 and at age 15 for approx 5000) and ocular biometry (available for 2900 at age 15).

Date proposal received: 
Wednesday, 21 April, 2010
Date proposal approved: 
Wednesday, 21 April, 2010
Keywords: 
Alcohol, Drugs, Smoking
Primary keyword: 

B991 - Acoustic markers to recover the phenotype in residual speech errors A feasibility study - 18/04/2010

B number: 
B991
Principal applicant name: 
Yvonne Wren (North Bristol NHS Trust, Bristol)
Co-applicants: 
Prof Lawrence Shriberg (University of Wisconsin-Madison, USA)
Title of project: 
Acoustic markers to recover the phenotype in residual speech errors: A feasibility study.
Proposal summary: 

Not available

Date proposal received: 
Sunday, 18 April, 2010
Date proposal approved: 
Sunday, 18 April, 2010
Keywords: 
Speech & Language
Primary keyword: 

B990 - Epigenetic Pathways to Conduct Problem Trajectories the Role of Prenatal and Postnatal Environmental Risk Exposures - 18/04/2010

B number: 
B990
Principal applicant name: 
Dr Edward D Barker (University of Alabama, USA)
Co-applicants: 
Dr Jonathan Mill (Not used 0, Not used 0), Prof Barbara Maughan (Not used 0, Not used 0), Prof George Davey Smith (Not used 0, Not used 0), Dr Caroline Relton (Not used 0, Not used 0), Dr Beate Glaser (Not used 0, Not used 0), Dr Susan Ring (Not used 0, Not used 0)
Title of project: 
Epigenetic Pathways to Conduct Problem Trajectories: the Role of Prenatal and Postnatal Environmental Risk Exposures
Proposal summary: 

AIMS

Specific Aim 1: Longitudinal methylomic analyses in each trajectory group

o Perform a hypothesis-free genome-wide screen of DNA methylation in the 200 individuals using the Illumina Infinium 27K Methylation array on bisulfite-treated DNA from samples obtained at birth, age 7 and age 15

o Perform extended fine-mapping verification analyses across specific genomic regions nominated from the microarray screen using Pyrosequening and/or the Sequenom EpiTYPER system in larger numbers of cases and controls.

o Assess the extent to which dynamic patterns of methylation vary across the trajectories

o Is there variation in the epigenetic-regulation of genes in the trajectories relative to controls?

? We would estimate "methylation trajectories" conditional on the conduct trajectories in an attempt to sort "noise" from the potentially informative changes in gene regulation

Specific Aim 2: Examine candidate-gene DNA methylation patterns

o Focus on HPA axis regulatory genes known to functionally inter-relate with serotonin

o e.g., corticotropin-releasing hormone (CRH), CRH receptors, CRH binding proteins, pro-opiomelanocortin (POMC), steroid hormone biosynthetic enzymes, etc.).

o Focus on testosterone (androgen) receptors, androgen biosynthesis pathways, monoamine/catecholamine-related genes (e.g., monoamine oxidase, transporters)

o Quantitative analysis of DNA methylation across gene promoter regions using using Pyrosequening and/or the Sequenom EpiTYPER system .

o Perform extended fine-mapping verification analyses across specific genomic regions nominated from the microarray screen using Pyrosequening and/or the Sequenom EpiTYPER system in cases and controls.

o Assess the extent to which dynamic patterns of methylation vary across the trajectories

o Is there variation in the epigenetic regulation of genes in the trajectories relative to controls?

We would estimate "methylation trajectories" conditional on the conduct trajectories in an attempt to sort "noise" from the potentially informative changes in regulation

Specific Aim 3: examine associations between DNA methylation trajectories and environmental

risk exposures from gestation though to adolescence

3.1 Data collection.

DNA from samples obtained at birth, age 7 and age 15

3.2 Existing Data Required

Environmental risk data are listed in the previous section. The genes we propose to genotype for the candidate methylation scans are listed in the next section.

3.4 Data Analysis.

See specific aims (above). Epigentic analysis will take place at the The Institute of Psychiatry Psychiatric Epigenetics Group, King's College London.

Date proposal received: 
Sunday, 18 April, 2010
Date proposal approved: 
Sunday, 18 April, 2010
Keywords: 
ADHD, Behavioural Problems, Genetics, Epigenetics , Environmental Exposure
Primary keyword: 

B985 - A genome-wide study of CNVs gene expression and quantitative traits in the ALSPAC population cohort - 15/04/2010

B number: 
B985
Principal applicant name: 
Dr Panos Deloukas (Wellcome Trust Sanger Institute, London, UK)
Co-applicants: 
Prof Emmanouil Manolis Dermitzakis (University of Geneva Medical School, Switzerland, Europe), dR Matthew Hurles (Wellcome Trust Sanger Institute, London, UK), Dr Nigel Carter (Wellcome Trust Sanger Institute, London, UK)
Title of project: 
A genome-wide study of CNVs, gene expression and quantitative traits in the ALSPAC population cohort
Proposal summary: 

Summary and timescale

As part of an established colaboration between the University of Bristol and the Sanger Institute we have collected whole genome data on gene expression, SNP and copy number variation in 1,000 individuals belonging to the ALSPAC population cohort. We propose to use these data sets to study the relationships between genetic variation, gene expression regulation and complex traits.

We seek permission to obtain the three data sets generated throught the ALSPAC - Sanger Institutte collaboration from the 1,000 densely-phenotyped individuals namely

- intensity data of the CNV array used to profile the above individuals

- intensity data of the 48,000 transcripts assayed using the Illumina Expression BeadChip platform. The data will be normalised and gene expression levels will be determinrd as part of the down stream analyses.

- genotypes of the 317K or 660K SNP arrays

We will associate gene expression data against CNVs and SNPs to identify genetic variants that influence gene regulation in both cis and trans, and characterise the nature of these associations. We will further associate these data sets with the 20 primary phenotypes outlined in Table 1 with

(i) expression levels of 48,000 transcripts

(ii) SNPs and CNVs

We would like to request at this stage

Sex Child

Body weight Child Clinic latest age

Height Child '' latest age

Expression array data (intensities) Child

Genotype data (317K or 660K array) Child

CNV array data (intensities)

Date proposal received: 
Thursday, 15 April, 2010
Date proposal approved: 
Thursday, 15 April, 2010
Keywords: 
Genetics
Primary keyword: 

B984 - Prevalence and risk factors of hyperacusis in children at age 11 years - 12/04/2010

B number: 
B984
Principal applicant name: 
Dr Amanda J Hall (University of Bristol, UK)
Co-applicants: 
Dr Melanie Parker (Not used 0, Not used 0)
Title of project: 
Prevalence and risk factors of hyperacusis in children at age 11 years
Proposal summary: 

Background:

Hyperacusis is defined as oversensitivity to some everyday sounds (lowered threshold of discomfort to sounds). Children may complain that their ears hurt when exposed to some sounds, typically high pitched or unexpected loud noises. For some children, this can be extremely distressing and can have a significant effect on behaviour. Phonophobia is defined as a fear of sound and in the most extreme cases, the lowest level of the particular sound can trigger what appears to be a disproportionate reaction, with physical symptoms of anxiety, tantrums and avoidant behaviour.

Certain groups of patients are known to be at greater risk of experiencing hyperacusis. It is a common and often disabling condition in Williams Syndrome and has been associated with abnormal cochlear function (Gothelf et al, 2006). It is the commonest sensory perceptual abnormality in children who are on the Autistic Spectrum, with prevalence ranging from 15-100% (Gomes et al, 2008). In these children there is little evidence of peripheral audiological abnormality (Gravel et al, 2006). Research has shown that there are more likely to be central causes for the unusual reactions to auditory stimuli in these children (Khalfa et al, 2001; Orekhova et al, 2008; Jones et al, 2009).

A recent study of 506 children between the ages of 5 and 12 years has used a questionnaire to assess the prevalence of hyperacusis in typically developing children (Coelho et al, 2007a). This identified that hyperacusis was reported by 3.2% of children. The same population was also asked questions related to tinnitus (Coelho et al, 2007b). 37% of children reported hearing a noise inside their head and 17% described it as annoying. Risk factors for experiencing tinnitus included young age, hearing loss and hyperacusis.

The ALSPAC data offers a unique opportunity to establish the prevalence of hyperacusis in a large population of children and to evaluate whether there are any significant associations with early life history, including detailed hearing data.

Research aims and objectives:

1. To determine the prevalence of hyperacusis in the ALSPAC cohort at age 11 years

2. To investigate risk factors for hyperacusis, specifically to examine:

a) Child factors: gender, prematurity, birthweight, migraine, special educational needs (ASD, ADHD & other conditions), meningitis & encephalitis, head injury requiring hospitalisation

b) Auditory function: hearing and acoustic reflex thresholds, current and historical otitis media with effusion, tinnitus

c) Socioeconomic factors: socioeconomic status, maternal education and housing tenure

Methods:

At the age 11 Focus clinic, approximately 7000 children were asked about sensitivity to sound, known as hyperacusis. Pilot analysis showed that approximately 3 % of these children reported hyperacusis of which 60% had experienced it for at least a year. Children were also asked whether they experienced noises in their ears (tinnitus) and pilot analysis showed that children with hyperacusis were more likely to report tinnitus than children without hyperacusis.

We intend to explore the characteristics of children reporting hyperacusis to determine possible risk factors for this condition. We will use univariate and multivariate logistic regression to determine whether those with hyperacusis have common factors in their early medical history (see objective 2a). We will also determine whether there are any differences in pure tone and acoustic reflex thresholds. Finally, we will examine socioeconomic factors.

Date proposal received: 
Monday, 12 April, 2010
Date proposal approved: 
Monday, 12 April, 2010
Keywords: 
Hearing
Primary keyword: 

B997 - Childhood health and facial markers of developmental instability - 07/04/2010

B number: 
B997
Principal applicant name: 
Mr David Lawson (London School of Hygiene and Tropical Medicine, UK)
Co-applicants: 
Prof Ian Penton-Voak (Not used 0, Not used 0), Nicholas Pound (Brunel University of London, uk), Prof Stephen Richmond (University of Cardiff, UK), Arshed Toma (University of Cardiff, UK)
Title of project: 
Childhood health and facial markers of developmental instability
Proposal summary: 

CHILDHOOD HEALTH AND FACIAL MARKERS OF DEVELOPMENTAL INSTABILITY

Summary:

Facial scan data on the ALSPAC cohort has been collected by Prof Richmond and his team at Cardiff University. We seek permission to analyse this data to produce hypothesised markers of development instability (e.g. facial symmetry, see below) and to link this data with childood health data already obtained by Dr Lawson under an existing project (Project B number: B227 - e,g, Lawson and Mace 2008, 2009).

Background:

Small random deviations from perfect symmetry in normally bilateral traits are referred to as fluctuating asymmetry (FA). Low levels of FA are believed to be an indicator of developmental stability (Van Valen, 1962) ? an organism's ability to buffer against stressors such as pathogens, toxins, and mutations (Moller & Swaddle, 1997; Polak, 2003). Across taxa higher FA is associated with greater morbidity, reduced fecundity, and higher mortality and in humans symmetry is associated with attractiveness. For example, bodily FA is negatively associated with face (Gangestad, Thornhill & Yeo, 1994), voice (Hughes, Harrison & Gallup, 2002), and odour attractiveness (Thornhill & Gangestad, 1999).

Although considerable research effort has addressed the consequences of both bodily and facial symmetry on various outcomes (such as intelligence, personality and attractiveness; Penton-Voak et al, 2001; Pound et al, 2007), the basic assumption of this work -effectively, that symmetry reflects good developmental health - remains untested formally. The ALSPAC sample provides both health data and facial scans from which symmetry measures can be obtained, allowing a rigourous test of this relationship between health and asymmetry.

Hypotheses to be tested:

By investigating the associations between a putative marker of developmental instability (facial asymmetry determined from the 3D facial scans using a landmark based morphometric technique ) and childhood health indices (from Dr. Lawson's previous work), we aim to test the hypothesis that asymmetry results from challenges to health during development

Date proposal received: 
Wednesday, 7 April, 2010
Date proposal approved: 
Wednesday, 7 April, 2010
Keywords: 
Depression, Mental Health
Primary keyword: 

B976 - Understanding the pathways between childhood adversity and psychosis-like symptoms in adolescence - 04/04/2010

B number: 
B976
Principal applicant name: 
Dr Helen Fisher (King's College London, UK)
Co-applicants: 
Prof Dieter Wolke (University of Warwick, UK), Andrea Schreier (University of Warwick, UK), Prof Marcus Munafo (Not used 0, Not used 0), Dr Stanley Zammit (University of Bristol, UK), Prof Glyn Lewis (Not used 0, Not used 0), Prof Barbara Maughan (King's College London, UK), Dr Peter McGuffin (King's College London, UK)
Title of project: 
Understanding the pathways between childhood adversity and psychosis-like symptoms in adolescence
Proposal summary: 

Aim: To explore whether psychological and psychopathological factors mediate the association between childhood adversity and psychosis-like symptoms in adolescence.

Background:

An increasing body of research has demonstrated an association between adverse childhood experiences and psychotic disorders (e.g., Bebbington et al., 2004; Fisher et al., 2010; Janssen et al., 2004; Shevlin et al., 2007a). As psychosis is considered to be a quantitative continuum from normality through attenuated psychotic symptoms to full clinical disorder (Chapman & Chapman, 1980; van Os et al., 1999), an underlying aetiological continuum is also assumed to exist (Johns & van Os, 2001; Myin-Germeys et al., 2003). Indeed, childhood adversity has also been linked to sub-clinical expressions of psychosis (e.g., Freeman & Fowler, 2009; Gracie et al., 2007; Lataster et al., 2006; Morgan et al., 2009; Nishida et al., 2008; Shevlin et al., 2007b; Thompson et al., 2009), including amongst the ALSPAC cohort (Schreier et al., 2009). These findings suggest that investigating samples with psychosis-like symptoms (PLIKS) may provide useful insights into clinical psychosis. However, little is known about the mechanisms underlying the adversity - psychosis association.

DIRECT: Traumatic events in childhood could directly increase the risk of developing PLIKS, perceptual aberrations or reality impairment (Allen et al., 1997; Honig et al., 1998). Indeed, genetic studies have demonstrated a role for environmental factors in psychosis proneness (Linney et al., 2003), and Cougnard et al. (2007) found that childhood abuse was associated with the initial appearance of PLIKS. These sub-clinical hallucinations or delusions could be considered to be traumatic reactions to severe adversity whose content is directly reminiscent of the adversity (Read et al., 2005). Such direct connections have been reported in between 3% - 50% of individuals studied (Gracie et al., 2007; Hardy et al., 2005; Read & Argyle, 1999). Therefore, a direct pathway between childhood adversity and PLIKS may be operating but perhaps only for a small minority of individuals.

INDIRECT: A range of indirect pathways have been suggested, including psychological mechanisms (low self-esteem, external locus of control, insecure attachment style) and the development of other mental health problems (depression, anxiety, PTSD). For instance, Gracie et al. (2007) showed that negative perceptions of the self and others partially mediated associations between lifetime trauma and PLIKS in a general population sample, but contradictory results were reported by Freeman and Fowler (2009). Insecure attachment styles are also prevalent amongst individuals who have experienced childhood abuse (Alexander et al., 1998) and patients with psychotic disorders (Dozier et al., 1991), especially those with a history of abuse (Tait et al., 2004), suggesting another possible indirect pathway. Furthermore, some studies have reported that the association between childhood abuse and psychosis is attenuated if depression is included as a confounder (Bebbington et al., 2004; Shevlin et al., 2007a), whilst Freeman and Fowler (2009) recently reported that anxiety mediated the association with paranoid delusions amongst abused individuals. Psychotic symptoms have also been hypothesised to emerge after the experience of post-traumatic stress disorder in those exposed to childhood adversity (PTSD; Braakman et al., 2009; Pepper & Agius, 2009). A range of other potential mechanisms may also be operating (e.g., stunted brain development, substance misuse, epigentic changes, gene x environment interactions, dysregulation of the HPA axis, hostile attributions, etc.) but these are beyond the scope of the proposed analysis.

Therefore, further exploration of the pathway(s) between childhood adversity and psychosis is required to test these different mechanisms. Moreover, the handful of studies that have explored this issue to date (e.g., Fowler & Freeman, 2009; Gracie et al., 2007; Whitfield et al., 2005) have all relied on cross-sectional samples, thus preventing temporal relationships from being accurately established.

Hypotheses:

(i) reported exposure to individual and multiple childhood adversities (peer victimisation, sexual abuse, domestic violence, physical abuse, parental loss, emotional abuse, harsh discipline and neglect) will be associated with separation anxiety, low self-esteem, an external locus of control, and higher levels of depression, anxiety and PTSD symptoms;

(ii) in turn these factors will predict greater endorsement of PLIKS at ~13 years; and

(iii) both psychological and psychopathological factors will explain a significant proportion of the variance in the pathway between the adverse childhood experiences and PLIKS with a direct pathway accounting for only a small proportion of the variance.

Analysis:

Single variables for each form of adversity will be constructed based on the presence of that adversity at any of the time points assessments were conducted versus absence across all time points. The mediation of the childhood adversity - PLIKS association by psychological and psychopathological factors will be investigated using a structural equation modelling framework in Mplus. The major advantage of this approach over path analysis is that measurement error arising from repeated assessments of the variables and missing data can be dealt with directly. Specifically two models will tested for each form of childhood adversity:

(i) full mediation of the relationship between childhood adversity and presence of suspected or definite PLIKS by separation anxiety, self-esteem, locus of control, depression, anxiety and PTSD symptoms; and

(ii) partial mediation such that a direct pathway from adversity to PLIKS is also present.

The weighted least-squares estimator will be used to analyse the models as some of the variables are likely to be non-normally distributed and it is robust to data missing at random. The two models will be compared using a chi-square test to determine whether including the direct pathway substantially improves the fully mediated model. The proportion of the variance accounted for by the direct and indirect pathways will also be reported to assess the degree of prediction. Potential confounders (age, gender, ethnicity, social class, IQ, family history of schizophrenia or depression and general family adversity) will be controlled for in the analysis.

Date proposal received: 
Sunday, 4 April, 2010
Date proposal approved: 
Sunday, 4 April, 2010
Keywords: 
Depression
Primary keyword: 

B992 - Are functional SNP variants or polymorphisms related to the dopaminergic system associated with myopia in ALSPAC - 01/04/2010

B number: 
B992
Principal applicant name: 
Ms Cathy Williams (University of Bristol, UK)
Co-applicants: 
Dr Jez Guggenheim (University of Cardiff, UK), Dr Beate Glaser (Not used 0, Not used 0), Mr George McMahon (Not used 0, Not used 0), Dr Kate Northstone (Not used 0, Not used 0)
Title of project: 
Are functional SNP variants or polymorphisms related to the dopaminergic system associated with myopia in ALSPAC?
Proposal summary: 

Myopia is a refractive error in which the eye is too long for the focussing power of the lens and so the image is brought to focus a little way in front of the retina which results in a blurred image for the affected person. In most cases this can be corrected by spectacle or contact lenses and more recently by laser surgery and many billions are spent annually across the world on these interventions. However these treatments do not reduce the excess risk for the myopic individual of other serious eye conditions such as glaucoma, cataract, retinal detachment and macular degeneration and myopia remains a significant cause of blindness in the UK, for example myopia was the 4th most frequent cause of registration for blindness in Scotland in 1990's (1).

In the last century there has been a rapid increase in the prevalence of myopia, particularly in far eastern countries where now the condition is said to have reached epidemic proportions as the majority of young people are myopic in recent surveys, for example over 80% of children leaving school in Taiwan and in Singapore, in the 1990's are myopic (reviewed in 2). In the UK, Australia and US recent data suggest lower prevalences but there is evidence of a cohort effect so that prevalences are increasing with successive generations. Although much data suggests a strongly heritable component to myopia (3), the recent marked increases in prevalence are likely to be driven by environmental exposures and propensity for or intensity of reading (4,5), decreased time outside (6), increased urbanization (7) and changing dietary patterns (8) have all been implicated in observational studies. The problems of confounding and bias however, cause major difficulties for researchers when trying to hypothesize or test causal mechanisms leading to myopia.

By contrast with the epidemiological literature, in experimental animal studies there is strong evidence that manipulation of visual input will produce excessive eye growth leading to myopia, for example by blocking all visual input, or just patterned input, or by using defocussing lenses (9). The myopia-causing effects of imposed defocus can be inhibited by short bursts of light (10) . Dopamine is present in the mammalian retina and is released in response to light exposure (11). Drugs which mimic the action of dopamine prevent the development of myopia in form-deprived eyes (12). In a recent paper it was hypothesised that dopamininergic mechanisms may mediate the protective effect of time spent outside in humans (10) and this question was a "hot topic" at the July 2008 International Myopia Conference (13)

Within ALSPAC, we have already published data that shows the expected associations between increased risk of myopia and increased exposure to reading (4). Unpublished data also show a protective effect of increased tine outside being (3+ hrs vs less, on school summer days) associated with a lesser risk of myopia at 11yr, after adjustment for sex, ethnicity, parental myopia and time spent reading (adjusted OR 0.64; 95% CI 0.49 to 0.86, p = 0.001). Also within ALSPAC work has already been published describing SNPs relating to the dopamine system (in the genes for the enzymes COMT and MAO-A) and examining associations between functional variants in these genes and characteristics of the participants including the children's IQ at 8 (14,15), their emotional status at 6 - 7 years (16) and their hyperactivity at 4 and/or 7 years (17).

We hypothesize that dopaminergic mechisms may be involved in myopia development in humans. We would therefore like to test the following related hypotheses, using data already available in ALSPAC:

1 - that functional variants in the COMT gene, and a polymorphism in the MAO-A gene, are assocated with risk for myopia at 11 and/or 15. The SNPs are rs2075507, rs6269, rs4818, rs4680, rs165599 and rs737865 . We will test these individually and also use the "Nackley haplotype" (18)which gives 6 diplotypes with progessively lesser levels of activity of the COMT gene, therefore greater dopamine availability. We will also test the variant in the MAOA (promoter VNTR AJ004835).

2 - that one or more alleles in the above SNPs mediate (or tag a functional variant that mediates) the observed protective effect of spending more time outside, on myopia development. This will be tested even if there is no main effect in (1) above.

All analyses will include stratifying by sex to look for interaction as dopamine expression/activity varies with sex in several reports.

The results of these analyses will be useful as they will be relatively unaffected by confounding and will provide the first data in humans regarding the potential importance of dopaminergic mechanisms for myopia development in a population of children.

Date proposal received: 
Thursday, 1 April, 2010
Date proposal approved: 
Thursday, 1 April, 2010
Keywords: 
Genetics, Neurology, Vision
Primary keyword: 

B977 - The association between early autistic symptoms and psychotoc-like symptoms in later life - 29/03/2010

B number: 
B977
Principal applicant name: 
Dr Rhys Bevan Jones (Not used -1, Not used -1)
Co-applicants: 
Prof Anita Thapar (Not used 0, Not used 0), Dr Stanley Zammit (Not used 0, Not used 0)
Title of project: 
The association between early autistic symptoms and psychotoc-like symptoms in later life
Proposal summary: 

Background

Bleuler, the Swiss Psychiatrist who coined the term 'schizophrenia', considered autism to be an integral part of the diagnosis of this psychotic disorder. Until recently there has been an overlap in the diagnostic criteria for the disorders, for example in between childhood schizophrenia and autism in the Diagnostic and Statistical Manual of Mental Disorders. There has also been interest in the genetic link between autism and schizophrenia, for example in the overlap in copy number variants (CNVs) in these disorders. Also, clinical observations and case studies have described how those on the autistic spectrum may present with psychotic symptoms in early life - which is referred to in the International Classification of Diseases. However, there are few longitudinal studies in this area.

Hypothesis

The aim of the study is to explore whether those with early autistic symptoms (social interaction and language problems, and unusual behaviours) are more likely to present with psychotic-like symptoms in later life. Secondary analysis would include gender, IQ and family history, and we would refine predictors by looking at specific types of autistic symptom groups.

Methods

Data would be taken from the Avon Longitudinal Study of Parents and Children (ALSPAC), and specifically:

1) Data from children aged 7/8:

Development and Well-Being Assessment (DAWBA) Parent Interview

Section M: Other problems

M1. In her first 3 years of life, was there anything that seriously worried you about:

a) her speech development?

i) has this cleared up completely?

b) how she got on with other people?

i) has this cleared up completely?

c) any odd rituals or unusual habits that were very hard to interrupt?

i) has this cleared up completely?

M3 - SKUSE (Social and Communication Disorders Checklist) questions

How much do the following descriptions apply to your study child?

Over the last 6 months:

a) not aware of other people's feelings

b) does not realise when others are upset or angry

c) does not notice the effect of her behaviour on other members of the family

d) her behaviour often disrupts normal family life

e) very demanding of other people's time

f) difficult to reason with when upset

g) does not seem to understand social skills e.g. interrupts conversations constantly

h) does not pick up on body language

i) does not understand how she should behave when she is out e.g. in shops, or other people's houses

j) does not realise that she offends people with her behaviour

k) does not respond when told to do something

l) cannot follow a command unless it is carefully worded

m) Do you have any other comments or concerns?

2) At age 14:

Data from Psychosis Interview - Psychotic Like Symptoms (PLIKS)

Analysis

I underwent the 'Introduction to Stata' course at the University of Bristol in February 2010 and aim to use this software to analyse the data.

Date proposal received: 
Monday, 29 March, 2010
Date proposal approved: 
Monday, 29 March, 2010
Keywords: 
ADHD, Behavioural Problems
Primary keyword: 

B978 - Gender role behaviour GWAS meta-analysis - 27/03/2010

B number: 
B978
Principal applicant name: 
Dr Beate St Pourcain (Not used 0, Not used 0)
Co-applicants: 
Prof George Davey Smith (Not used 0, Not used 0), Dr Nic Timpson (Not used 0, Not used 0), Prof Susan Golombok (Not used 0, Not used 0)
Title of project: 
Gender role behaviour GWAS meta-analysis
Proposal summary: 

1. Background

The aim of this study is to perform a meta-analysis of GWAS results on gender role behaviour in young children as assessed by male, female and overall gender Pre-School Activities Inventories (PSAI) scores1. Although gender role behaviour increases during childhood, especially during preschool years, the ranking of sex typed behaviour has been shown to be consistent when assessed at 2.5, 3.5, 5 and 8 years2. Gender role behaviour is heritable (Pre-school children: h2 Boys = 0.34; h2 Girls = 0.573) and may relate to underlying quantitative trait loci (QTL) that are accessible through genome-wise association studies (GWAS). This proposal aims to meta-analyse gender role behavior in children at age 3 and 5 using male, female and overall gender PSAI scores1 that are available in ALSPAC and the Twins Early Development Study.

2. Traits of interest

  • Male gender play score (MGPS)
  • Female gender play score (FGPS)
  • Gender PSAI score (PSAI)

3. Participating studies (as of 27-03-2010): Individuals with GWAS and phenotype data

* ALSPAC (MGPS/FGPS/PSAI 42m: 3022; MGPS/FGPS/PSAI 42m 57m:3023/3012/2980)

* TEDS (MGPS/FGPS/PSAI 3y: ~4000; MGPS/FGPS/PSAI 4y: ~4000)

4. Total projected number of subjects (as of 27-03-2010)

* MGPS/FGPS/PSAI (36m to 42m) ~ 7000 individuals

* MGPS/FGPS/PSAI (48m to 57m) ~ 7000 individuals*

5. Genotyping + Imputation

* Genotyped SNPs (Illumina 317k, 610k)

    • Sample-QC: Individuals removed based on missingness, heterozygosity, relatedness, population and ethnic outliers, and other cohort-specific QC steps.

* For stratification analysis, please generate principal component scores (or MDS) using for example EIGENSTRAT. These will be included as covariates (first 5 PCAs).

* Imputation based on HapMap Phase II CEU SNPs.Preferred release 22 of HapMap, build 36.

    • SNP-QC before imputation: SNPs removed based on missingness (SNP-call greater than 95%), minor allele frequency (MAF less than 1%), Hardy-Weinberg (HWE p-value less than 5E-07);
    • o QC in terms of imputation quality is needed for imputed SNPs.

6. Association analysis

* Assuming unrelated individuals

* Assuming White European samples

* Assuming autosomes only

* Assuming all SNPs are aligned to Hapmap Phase II + strand

* Perform a linear regression for

  • MGPS [36m;42m]
  • FGPS [36m;42m]
  • PSAI [36m;42m]
  • MGPS [48;57m]
  • FGPS [48;57m]
  • PSAI [48;57m]

Complete sample

a) Trait = SNP + Age + Age2 + first 5 PCA

Sex-specific analysis (Males)

b) Trait = SNP + Age + Age2 + first 5 PCA

Sex-specific analysis (Females)

c) Trait = SNP + Age + Age2 + first 5 PCA

We may consider rank-transformation for bimodal PSAI scores.

* Perform association analysis on the dosage score (Additive model): SNP coded as allele dose from 0 to 2 on imputed data only

* Use analysis software that accounts for genotype imputation uncertainty (as included in MACHQTL, ProbABEL, SNPTEST), adjusting for population structure and covariates.

* Analyse all imputed SNPs,no filtering on call rate/HWE/MAF/imputation quality (performed on meta-analysis stage)

Date proposal received: 
Saturday, 27 March, 2010
Date proposal approved: 
Saturday, 27 March, 2010
Keywords: 
Genetics
Primary keyword: 

B979 - Genome-wide association study of laterlaity and peg board times - 25/03/2010

B number: 
B979
Principal applicant name: 
Dr Dave Evans (University of Bristol, UK)
Co-applicants: 
Dr Sarah Medland (Not used 0, Not used 0), Prof George Davey Smith (Not used 0, Not used 0)
Title of project: 
Genome-wide association study of laterlaity and peg board times
Proposal summary: 

Sarah Medland, a collaborator from the Queensland Institute of Medical Research, has found some interesting associations between genetic variants and peg board times in her sample of Australian twins. ALSPAC is one of the few cohorts in the world with this measure and genome-wide association data, and we would like to perform a joint GWAS meta-analysis of peg-board times in both our samples, followed by replication in the remainder of the ALSPAC cohort if necessary. We already have previous ALSPAC exec approval to conduct a GWAS of handedness, and have done so, however the results of this scan have been disappointing to date- possibly due to the crude nature of this phenotype (i.e. "What hand do you hold a pencil in?"). It is possible that a more fine scale quantitative measure like peg board times, might be a cleaner phenotype in which to work with and produce better evidence of association with genetic variants. As an addendum, I am particularly keen to foster these smaller collaborations as it means that ALSPAC features prominently on any high profile publications relating to this work (c.f. our recent 2D4D paper in American Journal of Human Genetics, Medland et al. 2010) whereas this is not always the case when part of larger consortia

Date proposal received: 
Thursday, 25 March, 2010
Date proposal approved: 
Thursday, 25 March, 2010
Keywords: 
Genetics
Primary keyword: 

B980 - EAGLE Communication GWAS meta-analysis - 23/03/2010

B number: 
B980
Principal applicant name: 
Dr Beate Glaser (University of Bristol, UK)
Co-applicants: 
Dr Dave Evans (Not used 0, Not used 0), Dr Nic Timpson (Not used 0, Not used 0), Prof George Davey Smith (Not used 0, Not used 0)
Title of project: 
EAGLE Communication GWAS meta-analysis
Proposal summary: 

Not available

Date proposal received: 
Tuesday, 23 March, 2010
Date proposal approved: 
Tuesday, 23 March, 2010
Keywords: 
Genetics
Primary keyword: 

B982 - Associations of SNPs of the HPA-axis with fetal growth and longitudinal blood pressure trajectories - 22/03/2010

B number: 
B982
Principal applicant name: 
Dr Scott White (University of Western Australia, Australia)
Co-applicants: 
Dr Rae-Chi Huang (Not used 0, Not used 0), Dr Craig Pennell (Not used 0, Not used 0), Prof Lyle Palmer (Not used 0, Not used 0), Prof Laurie Beilin (Not used 0, Not used 0)
Title of project: 
Associations of SNPs of the HPA-axis with fetal growth and longitudinal blood pressure trajectories.
Proposal summary: 

The Developmental Origins of Health and Disease (DOHaD) theory is now well established, linking intrauterine and early-life growth with adult cardiovascular and other disease, with increasing evidence for the role of gene-environment interactions underlying this association. Evidence suggests that much of the variation in fetal growth is mediated by changes within components of the hypothalamic-pituitary-adrenal (HPA) axis. This system is also key in regulating blood pressure and therefore is a clear target for research into the links between fetal growth and adult hypertension.

We hypothesise that genetic variations within the HPA axis will show significant associations with fetal growth trajectories and longitudinal blood pressure trajectories in childhood, adolescence, and adulthood, and may therefore represent one of the genetic mechanisms underlying the developmental origins of hypertension.This study aims to test this hypothesis by identifying associations between single nucleotide polymorphisms in the genes within the HPA axis and:(1) antenatal growth trajectories; and,

(2) childhood and adolescent blood pressure trajectories.

We will identify among these associations genes which are known to relate to adult hypertension.

This project will utilise the resources of two international cohorts:

(1) The Western Australian Pregnancy (Raine) Cohort will be studied for the associations between the SNPs and fetal growth and childhood and adolescent blood pressure trajectories to age 17.

(2) The ALSPAC cohort will be studied for the associations with childhood and adolescent blood pressure trajectories.

Preliminary analysis of the data from the Raine cohort suggests significant genetic associations with all of the proposed outcomes and we aim to replicate these associations within the ALSPAC cohort

Date proposal received: 
Monday, 22 March, 2010
Date proposal approved: 
Monday, 22 March, 2010
Keywords: 
Genetics
Primary keyword: 

B983 - Diet and Bone Density in Children - 21/03/2010

B number: 
B983
Principal applicant name: 
Dr Alexa E Gallagher (University of South Carolina, Columbia)
Co-applicants: 
Dr Susan Steck (Not used 0, Not used 0), (University of South Carolina, Columbia), Dr James Hussey (University of South Carolina, Columbia), Dr Charlotte Atkinson (University of Bristol, UK), Dr Jon Tobias (University of Bristol, UK)
Title of project: 
Diet and Bone Density in Children
Proposal summary: 

Childhood and adolescence represent critical times for bone growth and poor bone accumulation during this period may increase risk of osteoporosis later in life. Diet is a key modifiable factor that influences bone development. With this in mind, I am interested in using data from ALSPAC to explore the influence of three aspects of diet on bone density in children for my doctoral dissertation.

I: Breastfeeding and Bone Density

The first aspect of diet I would like to examine is breastfeeding. The composition of breast milk and the fact that it has been specifically designed for human infants provides reason to believe that breastfeeding may play an early, critical role in future bone health. Breast milk provides infants with the appropriate amount of fat, sugar, water, and protein that they need for healthy growth and development and is able to adapt to the needs of each infant. In addition, it is easier for infants to digest and allows for calcium to be absorbed more easily than formulas, which are often based on cow's milk that forms a hard curd in the infant's stomach that is not easily digested [1].

Few studies have been conducted on this topic and those that have provide conflicting evidence. Jones et al., for example, found that breastfeeding leads to increased bone mass at age 8 [2]. Children breastfed for 3 months or longer had significantly better total body, femoral neck and lumbar spine density [2]. Bishop et al. also found bone density of the radius to be higher in 5 year old children if they had been fed more human milk than infant formula [3]. However, Bishop et al. only studied children born preterm. Contrarily, a study by Harvey did not find any association between breastfeeding during the first year of life and bone density at 4 years of age [4]. In addition, several studies that have focused on breastfeeding and bone density in infancy seem to suggest that bone density is lower at this age in breastfed infants [5]. No studies were identified that examined the long-term effect of breastfeeding on bone density in children over 8 years of age.

Considering this, I am interested in further examining breastfeeding and bone density in children. In addition to examining whether a child has ever been breastfed in relationship to bone density, I would also like to examine breastfeeding duration and exclusivity and determine if the effect is different in preterm compared to fullterm infants.

II: Fruit and Vegetable Consumption and Bone Density

Current Western diets, which are abundant in protein rich foods, grains, and cereals, are considered to lead to increased acidity in the body due to their high content of components such as phosphorus, protein and chlorine [6]. To counteract this increased acidity, it has been theorized that the body draws on the basic salts of the bone (i.e. calcium) to serve as a buffer [7]. In children and adolescents, whose bones are still growing, this increased acid load may lead to achieving a peak bone mass below their genetic potential.

Vegetables and fruits, which contain high levels of basic elements such as potassium, calcium, magnesium and vitamin C [6], are gaining interest as important components of a bone healthy diet. Increased consumption of fruits and vegetables may counterbalance the effects of the more acidic elements of diet and, in turn, protect and promote bone growth. Other explanations for why fruits and vegetables are beneficial to bone include high levels of antioxidants such as beta-carotene and vitamin C, which may act to reduce oxidative stress [8], regulation of osteoblast differentiation and collagen formation by vitamin C or the role that vitamin K "plays in bone mineralization by acting as a co-factor in the carboxylation of the bone protein osteocalcin" [8].

To date, a handful of studies have been conducted on this topic in both adults and children and the findings are promising [6, 8-13]. In a study of 56 girls, for example, Tylavsky et al. reported that girls who consumed 3 or more servings of fruit and vegetables had 6.0% more whole body and 8.3% higher radius bone area than those who consumed fewer than 3 servings [10]. Vatanparast et al reported that higher intakes of vegetables and fruit had a significant effect on total body bone mineral content in boys [11]. They calculated that with the consumption of 10 servings of fruits and vegetables a day compared to one, total body bone mineral content would be 48.6 g higher in their male participants.

I would like to further examine the effect of actual fruit and vegetable (e.g. number of servings or grams of fruits and vegetables per day) consumption on bone density. I would also like to focus on the specific vitamins and minerals (potassium, magnesium, vitamin C, vitamin K, calcium, etc) that are found in fruits and vegetables and believed to influence bone density and examine their effects. Lastly, I would like to examine patterns of food consumption in the child and bone density. Cole et al. took this approach, but looked at patterns of maternal food consumption during pregnancy [14]. They found diets high in fruits, vegetables, and wholemeal bread, rice and pasta and low in processed foods to be associated with increased bone mineral content and areal BMD in children.

III: Protein and Bone Density

Lastly, while there is no doubt that protein, which makes up approximately one third of bone mass, is important for bone growth, there is conflicting evidence regarding how much is beneficial [15]. High protein intakes have been implicated as a potential contributors to an increased acid load, which may increase urinary calcium excretion and, in effect, bone resorption [16]. On the other hand, high protein may be beneficial due to the important role it plays in IGF-1 metabolism, which is important in calcium and phosphorus metabolism. The conflicting evidence, which has been the topic of a number of studies in adults [17-20], also emerges in several epidemiological studies in children. A study of 10 year old girls in China, for example, found higher protein intakes to be negatively associated with bone mineral content [21]. The authors noted that this group of girls also had low calcium intakes. Contrarily, Chevalley et al and Alexy et al report high protein to be beneficial [22, 23]. Alexy et al. reported that protein intake in 6-18 year old children was associated with higher bone mineral content as well as periosteal circumference and polar strength strain. Interestingly, these researchers also estimated dietary acid load using PRAL (potential renal acid load) and found higher PRAL to be associated with decreased bone mineral content and cortical area [23].

Considering the debate that remains regarding protein and bone health, I propose to examine the effects of protein on bone density using the ALSPAC data, paying particular attention to low and high protein consumption. I would also like to examine whether the relationship between protein and bone density is modified by calcium consumption. Lastly, I would like to examine the effect of acid load on bone density using an equation developed by Remer et al that uses protein, phosphorus, potassium, and magnesium [24] and by Frassetto et al that uses the ratio of protein to potassium [25] .

Analysis

The bone measure outcomes for this analysis will be derived from the DXA scans taken during the Focus at 9 clinic (mean age 9.9 years). In statistical modeling, we will use total body bone mineral content, areal bone mineral density and area-adjusted bone mineral content like Tobias et al [26].

For aim 1, we will define infant feeding as was done by Pontin et al (exclusive/predominant breastfeeding, complementary feeding and replacement feeding) [27]. In addition, children will also be categorized according to how long they were breastfed to examine the effects of duration of breastfeeding.

The main exposure data for aims 2 and 3 will come from diet diaries collected at the Focus at 10 clinic (mean age 10.6 years) and from the food frequency questionnaire (FFQ) administered as part of the Focus at 8 clinic (mean age 8.6 years). For aim 2, we will examine fruit and vegetable consumption (servings per day), specific vitamins and minerals (potassium, magnesium, vitamin C, vitamin K, calcium) and patterns of food consumption. Patterns of food consumption have been derived from the FFQ. For aim 3, the main exposure will be protein consumption, which will be examined in terms of grams per day. The ratio of protein to calcium as well as estimates of acid load (PRAL) will also be calculated. To reduce confounding, dietary data will be adjusted for total energy intake.

A number of potentially important confounders will be considered. These include height and weight, which are key to consider because DXA variables are size dependent and any influences of diet on bone could be due to an effect on overall body size. Family characteristics such as social class, housing tenure and maternal and paternal education, race, and occupation will also be included. Physical activity derived by self-report or accelerometer will be important to include. For aim 1, other pregnancy and birth related variables such as maternal age, gestational age, birthweight, and maternal smoking during pregnancy will be examined.

All analyses will be conducted using SAS 9.2. Linear regression will be used to examine the questions presented above. Analyses will most likely be done separately for boys and girls. In addition, a sensitivity analysis will be done to compare results in children with and without puberty information.

Depending on the results that are found, we may extend analyses to later time points, and to other measures such as hip DXA and tibial pQCT

Date proposal received: 
Sunday, 21 March, 2010
Date proposal approved: 
Sunday, 21 March, 2010
Keywords: 
Bones, Diet, Eating disorders
Primary keyword: 

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