Proposal summaries
B849 - Smoking during pregnancy and depression is the association causal - 22/07/2009
Smoking has been found to be associated with an increased risk of depression, although the direction of causality is unclear. Munafo et al (2008) found that in ALSPAC smoking cessation was associated with a reduction in depression symptom score. However, this finding could be explained by confounding by other factors, or reverse causation where women who are feeling more positive are more likely to stop smoking. Freathy et al (2009) have identified a genetic variant in the CHRNA5-CHRNA3-CHRNB4) gene cluster which is strongly associated with quitting smoking in pregnancy in ALSPAC, but which is not associated with typical confounding factors.
We would like to use this variant to carry-out a Mendelian randomization analysis to determine whether a causal association between quitting smoking during pregnancy and a reduction in depressive symptom score exists.
We already have data on depression scores and potential confounders which has been used for another analysis of folate and depression so we would only require the genotype data in order to carry-out this analysis.
References:
Freathy RM, Ring SM, Shields B, Galobardes B, Knight B, Weedon MN, Smith GD, Frayling TM, Hattersley AT.A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy. Hum Mol Genet. 2009 May 9. [Epub ahead of print]
Munafo MR, Heron J, Araya R. Smoking patterns during pregnancy and postnatal period and depressive symptoms. Nicotine Tob Res. 2008 Nov;10(11):1609-20.
B846 - Association between analgesia during labour and drug addiction in adult life and neonatal resuscitation and child cancer - 14/07/2009
Previous studies have shown associations between administration of certain drugs during maternal labour and the future development of drug addiction in the offspring during adult life. Administration of nitrous oxide during labour appears to be a risk factor for adult amphetamine addiction in offspring [1], and administration of opiates and/or barbiturates and/or nitrous oxide is a risk factor for opiate addiction [2, 3]. These studies all used the same subjects: 200 amphetamine addicts and 200 opiate addicts born in Stockholm between 1945 and 1966. The addicts were compared to their siblings in a matched case control study. The mechanism contributing to this drug addiction in adults is thought to stem partly from an imprinting process during birth when certain drugs are given to the mother. The unconscious memory of the drugged state at birth might make the individual more disposed to become addicted if exposed as an adult. We are keen to investigate these associations further using the ALSPAC data. We know that there is basic information available on the labour analgesia given to the mothers of the ALSPAC children. We assume that at some stage in the next few years you will be doing projects on drug use / misuse / addiction, and that it would be relatively easy to relate the labour information to prospectively collected data.
There is also a postulated link between neonatal resuscitation with oxygen and an increased incidence of childhood cancers. Data from the Collaborative Perinatal Project (CPP) of nearly 55000 children born between 1959 and 1966 who were followed up until eight years of age were used. An exposure to oxygen for more than three minutes was associated with a greater risk despite controlling for other cancer risk factors [4]. The findings of this study are consistent with a case-controlled Swedish study of 578 children diagnosed with lymphatic leukaemia between 1973 and 1989. Resuscitation with 100% oxygen using a facemask and bag immediately after delivery was significantly associated with more than double the risk of childhood lymphatic leukaemia [5].
ALSPAC data could potentially provide over 6,000 subjects which we would use to further investigate these findings.
References
- Jacobsen B, Nyberg K, Ekland G, Bygdeman, Bygdemann M, Rydberg U. Obstetric pain medication and eventual adult amphetamine addiction in offspring. Acta Obstetrica et Gynecologica Scandinavia 1988; 67(8): 677-82.
- Jacobsen B, Nyberg K, Gronbladh L, Ekland G, Bygdeman, Rydberg U. Opiate addiction in adult offspring through possible imprinting after obstetric treatment. British Medical Journal 1990; 301(6760): 1067-70.
- Nyberg K, Alleback P, Ekland G, Jacobsen B. Socio-economic versus obstetric risk factors for drug addiction in offspring. British Journal of Addiction 1992; 87: 1669-76.
- Spector LG, Klebanoff MA, Feusner JH, Georgieff MK, Ross JA. Childhood cancer following neonatal oxygen supplementation. The Journal of Pediatrics 2005; 147: 27-31.
- Naumburg E, Bellocco R, Cnattingius S, Jonzon A, Ekbom A. Supplementary oxygen and risk of childhood lymphatic leukaemia. Acta Paediatrica 2002; 91: 1328-33.
B857 - Replication of SNPs identified in recent GWAS for intelligence - 10/07/2009
Using an existing IQ GWAS dataset, we have conducted a targeted candidate gene and candidate region analysis for intelligence. We identified several new genes in previously identified candidate regions. We currently have three other replication samples, and would also like to add the ALSPAC study as an independent relication.
We will need to have access (through an ALSPAC collaborator) to the (results of association analysis of) IQ scores of all individuals and to the genotypes of SNPs in three genes that were obtained using the Illumina 317k platform.
B843 - Disability associated with Psychotic Like Symptoms Early life stress and Psychotic symptoms - 06/07/2009
Aims
We wish to investigate two hypotheses:
- Are psychotic symptoms (PLIKS) that occur in adolescence associated with poor social functioning?
- Are life events and other markers of stress in pregnancy associated with PLIKS in adolescence, independently of later stress?
Justification
- Are psychotic symptoms (PLIKS) that occur in adolescence associated with poor social functioning?
There is a great deal of interest in psychotic symptoms occurring in adolescence at present. A number of surveys, including ALSPAC, have documented that these phenomena are quite common and there is some evidence they are linked with future psychotic illness in adults. However, it is not clear whether the psychotic symptoms identified via population based studies such as birth cohorts and surveys are an "illness" in the sense that they lead to problems in the young person. It is possible that young people are reporting these symptoms but are not in anyway "troubled" by them and manage to continue with their education and social life unaffected by the psychotic symptoms. We are not aware of any studies that have investigated this possibility in young people, though Rossler has reported this in adults1. We would propose to examine whether PLIKS are associated with later social functioning in ALSPAC. This would complement the study of Sarah Sullivan (who would also be involved in this project) who is interested in whether early social functioning deficits are associated with PLIKS.
- Are life events and other markers of stress in pregnancy associated with PLIKS in adolescence, independently of later stress?
The hypothesis that early stress can increase the risk of psychosis is gaining some credence at present. There is relatively little investigation of how stressful events might be related to PLIKS in adolescence. Of particular interest is the possibility that stressful events in pregnancy could have a particular powerful influence on later risk, possibly by an influence on the HPA axis of the foetus. We wish to examine the hypothesis that early life stress is associated with the later development of PLIKS. Part of this investigation should also examine markers of socioeconomic position as these could also be a proxy marker of adversity. Maternal depression and anxiety is also something that is related to stress in pregnancy and would need to be investigated though more difficult to interpret. This project is related to a previous unsuccessful application by Giovanni Salvi for a training fellowship and he is aware of this application.
Resources
It is proposed that Laura Asher and Sarah Dorrington who are on the Academic Foundation programme will help with this proposal. All the variables that are requested have been used by other funded projects including the ESRC large grant and original PLIKS proposal. We therefore think there will be a minimal need for alspac resources apart from preparing a datset.
Reference List
1. Rossler W, Riecher-Rossler A, Angst J, et al. Psychotic experiences in the general population: a twenty-year prospective community study. Schizophr Res 2007;92:1-14.
B848 - ALSPAC Genotyping GWAS in Children 23andMe - 01/07/2009
23andMe, Inc. (the "Company") is excited to support the Avon Longitudinal Study of Parents and Children ("ALSPAC") by providing the genotyping support described in this letter agreement. With the goal of genotyping 11,000 children already enrolled in the ALSPAC study, the Company will provide Illumina Human550+ Quad DNA Analysis BeadChips (each of which can process four samples and analyses approximately 610,000 loci and each of which contain the custom content generated and designed by 23andMe) (the "BeadChips") to process a maximum of 11,000 samples, plus another 1,000 for failures in processing.
The Company will ship that number of BeadChips to process approximately 1,000 samples to the Wellcome Trust Sanger Institute laboratory ("Sanger") and the remainder of the BeadChips to the National Genetics Institute laboratory ("NGI") (collectively the "Laboratories"), at which Laboratories the samples will be genotyped. Sanger's processing fees per sample shall be as set forth on Exhibit A, which cost shall not exceed the actual cost of processing by Sanger as represented by the Sanger. The Company will pay these processing costs as the genotyping occurs and is confirmed to the Company on written invoice. The Company will also pay the processing costs for samples processed by NGI pursuant to the terms of a separate agreement. The University of Bristol represents that only samples of children already enrolled in the ALSPAC study will be shipped to the Laboratories to be genotyped with the BeadChips and that the 11,000 number of samples processed shall only be exceeded to re-process samples that fail processing up to the maximum of 12,000. The Company is aware that genotyping data produced by the Laboratories of the ALSPAC participants under this letter agreement shall be the property of University of Bristol and reintegrated into the ALSPAC dataset.
As consideration for the support described above, each of Bristol University and Sanger, to the extent applicable, agrees that: 1) it shall not utilize the BeadChips except for the purposes set forth in this letter agreement, 2) it shall not utilize any information provided by 23andMe, Inc. to process the BeadChips, including but not limited to decoding files or other services provided to aid in the decoding of the DNA samples using the BeadChips, other than in order to process the BeadChips for the purposes set forth in this letter agreement (the BeadChips and information provided therewith the "Proprietary Information"), 3) shall maintain as confidential the Proprietary Information, applying the same measures to protect such Proprietary Information as it does its own confidential information, and 4) that 23andMe shall be permitted to discuss and announce that it is funding the genotyping of the ALSPAC children and that it may send a Research Fellow to analyze the ALSPAC dataset.
The Company agrees that the Laboratories shall provide the resulting data from the genotyping directly to the University of Bristol and that the Company shall not receive such data from either laboratory. However, if either laboratory requests aid from the Company in processing the data under this letter agreement, the Company shall be happy to provide reasonable assistance.
The University of Bristol agrees that a Research Fellow can be attached to the MRC Centre for Causal Analyses and Translational Epidemiology at the Department of Social Medicine, University of Bristol, where they will be able to analyze the data in the same manner as the other analysts, for a period of up to six (6) months subject to the terms of a secondment agreement to be agreed between University of Bristol and 23andMe.
B842 - Early childhood influences on obesity and cardiometabolic health at age 15 years in ALSPAC - 01/07/2009
Both studies will be carried out by the principal applicant, Dr Adrienne Hughes, during her 6 month sabbatical (August 2009 to January 2010) in collaboration with Professor John Reilly, Professor John McColl and Professor Andy Ness. Professor John McColl (Professor of Statistics, University of Glasgow) will provide advice on statistical analysis and interpretation. Adrienne's department has agreed to cover the costs incurred by ALSPAC as a result of this work.
Background
Early life events are thought to have important influences on later obesity and cardiometabolic health in children, suggesting that strategies to prevent childhood obesity should focus on young children. However, there is a lack of longitudinal studies using large cohorts of contemporary children. Thus, we intend to examine early life influences, such as timing of adiposity rebound and early weight/BMI gain on later obesity and metabolic health at age 15 years using a large cohort of contemporary children, the ALSPAC dataset.
STUDY 1
The aim of this study is to explore the associations between timing of adiposity rebound and later adiposity and cardiometabolic health at age 15 years.
Design and Methods
We intend to use the Children in Focus subsample (unless it is possible to calculate the timing of adiposity rebound for the entire cohort); the timing of adiposity rebound (AR) has previously been identified for the CiF subsample. In the Children in Focus subsample, 219 children had early AR (defined as before 61 months) and 563 children had later AR.
We require the adiposity rebound category (i.e. very early, early or late) for each child in the CiF subsample as well as length/height, weight and BMI from birth to 61 months.
Adiposity outcomes at 15 years will include: BMI (and external SD score), weight (and external SD score), waist, fat and fat free mass measured by DXA (adjusted and raw values), We also required height, age and gender.
Metabolic health outcomes at 15 years will include: blood pressure, fasting lipids, glucose and insulin.
We also require the following descriptors/potential confounding factors: maternal education and parental obesity.
Statistical Analysis
This will be informed by Professor John McColl, but is likely to involve the comparison of adiposity and metabolic health outcomes at age 15 years between children with early AR vs later AR.
Please note: The cardiometabolic health component (at age 15 years) of this study may have some overlap with Professor Debbie Lawlor and Professor Naveed Sattar's work, which has been discussed with Professor Andy Ness. Thus, we are willing to collaborate with Professor Debbie Lawlor and Professor Naveed Sattar if they and the ALSPAC Executive consider this to be appropriate.
STUDY 2
We intend to use the entire cohort of ALSPAC children as well as the Children in Focus subsample to address the following aims.
The first aim is to examine the persistence of overweight and obesity and progression from overweight to obesity over various time points (e.g. from preschool to age 15 years using Children in Focus, and age 7 years to age 15 years using entire cohort), and also to identify simple predictors of persistence and progression (e.g. parental obesity, socioeconomic status/maternal education).
The second aim is to describe the prevalence of obesity at specified ages (e.g. preschool, age 7, 11 and 15 years) and the incidence of obesity (i.e. development of new cases) over various time points (e.g. from preschool to 11 years using Children in Focus and age 7 to 11 years using entire cohort).
The final aim is to test the hypothesis (suggested in the Early Bird study) that most excess weight/BMI gain occurs by preschool/age 7 years. Early Bird (Gardner et al Pediatrics 2009) examined excess weight gain (change in weight SD score) between birth, 5 years of age and 9 years of age in small cohort of children. The study found that most excess weight was gained by 5 years of age, suggesting that obesity prevention strategies should focus on preschool children. However, this study involved only 233 children and followed children to only 9 years of age, thus we intend to examine how much weight/BMI gain has occurred by specified ages (e.g. preschool, age 7, 11 and 15 years years) using a much larger cohort of contemporary children.
Design and Methods
To address these aims, we intend to use data from the entire cohort of ALSPAC children as well as the Children in Focus subsample. For the entire cohort of ALSPAC children, we require the following data at birth and from age 7 years to age 15 years: weight (external z score), height/length, BMI (external z score), age, gender. We also require the following descriptors/potential confounders: parental obesity, maternal education, ethnicity.
For the Children in Focus subsample, we require the data described above at birth and from infancy and preschool to age 15 years.
Statistical Analysis
This will be informed by Professor John McColl.
B839 - Religious belief and practice their affect on adjustment to traumatic events - 25/06/2009
Although religious practice is well recognised in the American literature as related to positive health, very little research has been carried out in the UK.
I deliberately asked Ursula King to develop questions on religious belief and practice to be administered to the parents in pregnancy (D and PB files) with the aim of assessing how well religious belief related to the ability to look at resilence when major life events had occurred.
This project therefore will compare those with and without religious beliefs in regard to their response to major life events that have occurred subsequent to the religious belief questions being administered. The current suggestion is that this should be the 8 months major life events scale, which considers life events after the birth of the child.
The outcomes to be considered will be those measured between 8 months and 5 years and will include:
1. Maternal depression and anxiety subsequent to 8 months (allowing for prenatal depression and anxiety).
2. Parenting activities and strategies (allowing for prenatal attitudes to parenting).
3. Behaviour of the parent with the child (e.g. the frequency with which the mother is irritated and or loses their temper).
4. Relationship between the parents (allowing for prenatal relationships)
5. Use of alcohol and illicit drugs (compared with prepregnancy and prenatal assessments).
6. Later religious belief (as measured at 61 months).
There are a variety of factors that will be taken into account in the logistic and multiple regression analyses: these will include parental ages, number of other children in the household, social network and social support, parental personality, parental education levels, childhood life events,life events prior to the birth of the child, and other factors that distinguish those who have a belief system from those who do not at the time of pregnancy.
B838 - Scoping study for archiving all correspondence and background information relating to ALSPAC to end of 2005 - 25/06/2009
At the moment, there are a variety of documents in various places in this country relating to the establishment, management, strategy, publicity and workshops of ALSPAC. The Wellcome Trust approached me some months ago in regard to the possibility of archiving all the material from 1985 to 2005 inclusive. I've now had a detailed discussion with Tim Powell, the archivist recommended by the Trust. He then approached the University of Bristol Library who are keen to hold the archived records.
As part of the discussion, it become obvious that archiving could not happen without a detailed documentation and assessment of the various documents available. In brief, the view was that historians would be interested in the following:
* Correspondence with parents
* Correspondence with collaborators and potential collaborators
* Correspondence with members of the public
* Correspondence with funders - including failed & successful grants
* Development of instruments & validation
* Sub-projects
* Publicity (including press releases, cuttings, posters, etc)
* Slides and power point presentations
* Minutes of internal meetings as well as of Advisory Committees and Workshops
There are a number of other sources of information that may be acquired, included records from the University Finance Department, the Vice-Chancellor's records, those of various funders etc.
This is a preliminary list. There are a number of sets of documents in different parts of the country, concerning the early genetic side of the study held by Marcus Pembrey, early records of the Ethics Committee held in a basement by Elizabeth Mumford, major informtion concerning many of the sub-studies which are held by collaborators such as Judy Dunn (London), Susan Golombok (Cambridge), Marian Jongmans (the Netherlands), Gideon Lack (London), Richard Ashcroft (Cambridge).
The project will use a senior member of staff (Karen Birmingham) employed half time within CCAH for 12 months.
Much of this is under discussion at the moment, but an outline for a scoping study to investigate the whereabouts and possbilities inherent is warranted. It is proposed that this scoping study should start early November if at all possible. The project will work with Iain Bickerstaffe in regard to aspects that are related to his expertise and responsibility as well as various members of ALSPAC who have old records.
The project should result in major benefit to ALSPAC in that all information will be documented and held in one place, available to be accessed by ALSPAC staff and collaborators as well as others interested in the history and development of the project.
B840 - Dietary patterns obtained using PCA in partners - 23/06/2009
We wish to examine the dietary patterns in the ALSPAC partners (when children are 47 months of age) which will be obtained using Principal Components Analaysis. This work will feed into project B 716, which examines the association between maternal and child dietary patterns. This work was recently well received at the ICDAM7 conference in Washington and we feel it is important to also take into account any effects of partner's diet.
Before we add partner's patterns into our models forming project B716, we plan to publish a paper first, describing partner's dietary patterns; examining social and demographic associations with them and also examining associations with maternal dietary patterns assessed at the same time.
B834 - DEVELOPMENT OF A TOOL TO HELP PROFESSIONALS IDENTIFY AND TARGET BABIES AND YOUNG CHILDREN AT HIGH RISK OF OBESITY - 18/06/2009
Progressive universalism is a core principal in the Healthy Child Programme and obesity prevention one of its priority areas. Guidance has yet to be developed on how health professionals should identify those babies and toddlers at increased risk for obesity. This is important in order to ensure that valuable resources are targeted for those at highest risk. Factors such as family history, events in pregnancy and family lifestyle may be as important as weight gain.
We propose to come up with a simple tool to help professionals in primary care identify babies at higher risk by analysing data from the ALSPAC cohort. If this initial work looked promising it would need to be validated against other data sets and piloted before it could be introduced into the Healthy Child Programme.
This work has another potential benefit. It would allow a more complex tool to be developed for use by researchers working in the area of antenatal and infant obesity prevention. This would allow them to target babies at highest risk for obesity for epidemiological purposes and recruitment to trials. To date maternal obesity alone has been used as a too simplistic proxy for infant risk.
The project would be coupled with another piece of work for the Department of Health. Analysis of the ALSPAC dataset would also be used to contribute to discussions about the optimum age for measuring children if screening for obesity was introduced during the preschool years.
Both aspects of this work have relevance beyond the UK and extend to antenatal as well as preschool guidance. The Centers for Disease Control and Prevention in the USA has committed support and the funds needed for the first phase of the project. If the initial analysis looks promising application for further funding would proceed in partnership with them.
AIMS:
1. To develop a tool that would be of practical use to clinicians, particularly health visitors (and potentially midwives), to help them identify babies/toddlers at high risk of obesity and ensure that they are targeted for appropriate guidance.
2. To develop a more complex tool to help researchers target populations within cohort studies and for inclusion in trials
3. To advise the Department of Health on the optimal time to weigh and measure preschool children for screening or monitoring purposes
METHODS
A. Development of a simple tool to support anticipatory guidance
PHASE ONE
Literature review
We propose to start by reviewing the literature to explore perinatal and infant factors that are known to be associated with obesity later in life. These include:
* Birth weight (LGA or SGA)
* Rapid weight gain in first year
* One or two parents obese
* Maternal obesity pre- and during pregnancy
* Maternal weight gain during pregnancy
* Maternal age at birth
* Gestational diabetes
* Smoking in pregnancy
* Family history of type2 diabetes and cardiovascular disease
* Race and ethnicity
* SES
* Bottle feeding
Data analysis
The ALSPAC data set will be examined to ascertain the risks for obesity associated with these factors. Obesity at the age of 13 years will initially be used (both on clinical measures and by DEXA scanning). This will be re-assessed once the results at the age of 15 years become available. Some of these variables are fixed for a child (eg ethnicity) and others will vary by age (eg weight at the time of examination). We are likely to use multi-level models to make use of all the data.
We will then assess the extent of the risks for each variable, and for the variables in combination. We will judge whether the final model predicts risk adequately to make it worthwhile to proceed to developing a tool for clinical use.
Development of the clinical tool
The tool will be developed presenting the data in a simple way so that it can be readily used in the clinical situation. This should be of value for identifying babies at risk and for explaining risks to parents directly.
PHASE TWO (Funding to be sought through the CDC if Phase 1 is promising
Piloting and validating the clinical tool
A small number of primary care professionals will be recruited to pilot the tool - health visitors and midwives in the UK, and primary care paediatricians in the USA. We will seek their views about its value and ease of use. If the tool seems promising a properly evaluated trial will be required before more widespread introduction is considered.
Validation is also needed at this stage. We propose to approach the Gateshead Millenium cohort in the UK and the VIVA cohort in Boston to ask if they would like to collaborate to test the accuracy of the tool in these different populations. Other cohorts that might be considered are the Raine cohort in Perth and the Southampton Women's study in the UK.
The research tool
A more complex measure for use by academics and epidemiologists will also be developed. This will be published in the academic literature and offered as a way to identify babies at risk more effectively. This too would require validation against other data sets.
B. Exploration of the predictive value of weight and/or BMI at different time points through the preschool years
The Department of Health is considering whether there might be value in reintroducing growth monitoring during the preschool years. It would be helpful to know if there is an optimal time point for collecting these data for the purposes of providing guidance or more intense input.
The ALSPAC data set will be analysed for the predictive value of weight and BMI at the various time points when weight and height are measured. This will help inform discussion about the value of screening and the best time to measure children taking into account other practical issues such as contact for other reasons.
COLLABORATION BETWEEN THE CDC AND UK DEPARTMENT FO HEALTH
Professor Mary Rudolf, paediatric consultant to the DH and currently on sabbatical at the CDC will work with Dr David Freedman, a senior epidemiologist at the CDC, on the preliminary stages of the project. They may be assisted by an intern at the CDC who will conduct the literature review. A more detailed funding proposal to pilot the tools will be developed if the data analysis shows evidence that a clinical or research tool might be promising.
B837 - Are offspring metabolic vascular and inflammatory phenotypes predetermined by the time of birth - 17/06/2009
We request permission to apply for a research grant to examine cord blood samples in the ALSPAC offspring. This proposal will determine whether offspring metabolic, vascular and inflammatory phenotypes are predetermined by the time of birth. Specifically we wish to measure IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests in cord blood. We are aware that some analysis of cord blood has already been performed in small subsets, specifically leptin in 197 infants1, and IGF-II, soluble IGF2R, insulin, IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 in 199 infants2. Our intention is to extend the measurement of leptin, IGF-I and insulin to the remainder of the ALSPAC cohort and examine additional new analytes.
This work builds on several current studies undertaken by the applicants. First is the analysis of lipids, inflammatory markers, insulin and liver function at age 9, 15 and 17 years. To date we have measured leptin, adiponectin, insulin, lipids, CRP, liver function tests, and IL-6 in non-fasting plasma samples taken at age 9 years old. Analysis of fasting lipids, glucose, insulin, CRP, liver function tests and IL-6 at age 15 years has also recently been completed. Additionally we are currently funded to analyse fasting glucose, insulin, lipids & liver function tests in the cohort at age 17 (Lawlor PI). Secondly, the proposed study will also build on the inspection and abstraction of obstetric data from the ALSPAC cohort and the follow-up studies of the mothers, with funds available and analyses currently being completed on ALSPAC mother's fasting blood for glucose, insulin, pro-insulin, lipids and inflammatory markers now 17 years after the index pregnancy (Davey Smith and Lawlor PIs). Thirdly. the proposed study will also utilise the recently completed genome-wide association study (GWAS) of the offspring (Davey Smith PI) and the recently funded GWAS of the ALSPAC mothers (Lawlor PI), to examine the independent contributions of each genotype and their interaction in the determination of cord analytes. This combination of data, together with the additional data we plan to collect in this proposal, will allow clarification of the role of maternal lifestyle and pregnancy outcome on the offspring metabolic, vascular and inflammatory phenotypes, and whether variations in these phenotypes at birth track into later childhood and early adolescence. Additionally if we can show significant correlations between cord parameters and the same measures in later life, this then provides some rationale for future birth cohort studies to have cord measures as legitimate surrogates.
We would like permission to address the following objectives in relation to cord blood analytes:
a. Describe the distribution of IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests in cord blood.
b. Determine the associations of maternal weight gain in pregnancy, blood pressure change in pregnancy, maternal smoking, alcohol and dietary behaviour in pregnancy, onset of gestational diabetes/glycosuria, mode of delivery, parity and preterm birth on cord IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests.
c. Determine whether variation in maternal vitamin D, parathyroid hormone and calcium levels in pregnancy are associated with cord IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests.
d. Determine the associations of cord IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests with offspring birthweight, placental weight and feto-placental index.
e. Determine the prospective associations of cord IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests with offspring fat mass and change in fat mass and growth trajectories from birth to age 17.
f. Determine the prospective associations of cord IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests with the previously determined repeat measures of these analytes at age 9, 15 and 17 years.
g. Determine the prospective associations of cord IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests with ultrasound assessment of liver fat deposition, liver function tests, lipids, insulin and glucose at age 17.
h. Determine the prospective associations of cord IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests with offspring educational attainment.
i Determine the association of cord IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests with maternal cardiovascular risk profile in later life (lipids, carotid intimal-medial thickness, blood pressure, height, weight, BMI, fat and lean mass, insulin and glucose).
j. With available data (10,000 mothers and 3,000 offspring or larger if additional grants funded) complete a genome wide-association study of cord IGF-I, leptin, insulin, cholesterol, triglyceride, HDL-C, CRP and liver function tests
For objectives g, h, i and j this will be performed on completion of the 17 year clinic, the BHF funded follow up study of the mothers and the GWAS of the mothers (Lawlor PI for mothers follow-up clinic and for maternal GWAS and for grant that funds taking of fasting blood samples and completion of fasting glucose, insulin, lipids, liver function and inflammatory marker tests).
In order to determine the extent to which any associations of maternal characteristics with offspring cord blood levels reflect genetic, intrauterine or background socioeconomic mechanisms we will employ and compare results from three methodological approaches - multivariable regression models; within parental comparisons and Mendelian randomization studies, using maternal genotype adjusted for offspring genotype as an instrumental variable for the causal effect of an intrauterine exposure.
Request for data access to allow generation of pilot data
To facilitate the provision of pilot data for a grant submission, we request permission to examine the previously reported cord analytes of insulin, leptin and IGF-I from the In Focus group1, 2, with subsequent anthropometric and DXA measures at age 9 and 15, and repeat measures of leptin and insulin at age 9, and insulin at age 15 if available.
Background and justification of analytes
Birthweight and fetal insulin
The epidemiologic observations that smaller size or relative thinness at birth and during infancy is associated with increased rates of coronary heart disease, stroke and type 2 diabetes mellitus, in adult life have been extensively replicated3, 4. Although epidemiology studies have largely examined the association of birthweight with adult disease outcomes, because of its ready availability in many datasets, it is increasingly recognised that birth weight is most likely acting as a proxy for other exposures, including maternal diet, smoking, alcohol and other intrauterine exposures and genetic variants.
Birthweight is determined, in part, by fetal metabolic and hormonal responses to intrauterine influences. Pedersen was the first to suggest that maternal hyperglycaemia would result in excessive transfer of glucose to the fetus and the compensatory fetal hyperinsulinaemia would drive fetal growth and deposition of fetal adipose tissue5. We and others have confirmed that in maternal type 1 diabetes maternal hyperglycaemia is associated with fetal hyperinsulinaemia and increased birthweight6. We have also identified that cord insulin is the principal positive associate of the observed increases in both birthweight and neonatal adiposity in offspring of mothers with type 1 diabetes7. More recently, these positive associations have been extended to the euglycaemic range of glucose during pregnancy, with the HAPO study clearly demonstrating that there is positive linear relationship between maternal glucose and birthweight and neonatal adiposity, and that this relationship is mediated by fetal insulin production8, 9. Furthermore, there is some evidence (most convincing from populations, such as the Pima Indians, with very high prevalence of obesity and type 2 diabetes) that higher levels of maternal glucose in pregnancy are associated with greater adiposity and abnormal glucose tolerance in offspring in later life10-12 and can influence the penetrance of genetic syndromes of diabetes13. Consistent with an insulin mediated effect, fetal hyperinsulaemia has been associated with excess adiposity and elevated plasma glucose and insulin during childhood in a Caucasian population14. Given the HAPO results, it is reasonable to wonder the extent to which these associations in later life are present across the whole range of fetal insulinaemia15. Assessment of cord insulin in the ALSPAC cohort will allow us to examine the association of fetal insulin with offspring adiposity and glucose tolerance throughout childhood and adolescence.
IGF-1
Cord IGF-I is positively associated with birthweight and placental weight2, 7 and IGF-I deletion or reduced receptor expression in humans are both associated with a reduction in birthweight and placental weight16, 17. Conversely, in animal models prolonged administration of exogenous IGF-I to growth restricted fetuses substantially increases body and placental weight18. In offspring of mothers with type 1 diabetes, we have demonstrated a relationship of IGF-I and birth weight independent of insulin7, in keeping with previous observations from the ALSPAC cohort2. Furthermore, we have recently demonstrated that cord IGF-I is the principal correlate of placental sub-structure (data submitted), and that placental and fetal growth closely correlate, even if there is fetal hyperinsulinaemia19. IGF-I is also an associate of feto-placental index in offspring of mothers with type 1 diabetes19, with experimental and epidemiological studies suggesting that mismatch of placental and fetal growth are associated with postnatal abnormalities in cardiovascular, metabolic and endocrine functions 20, 21. Therefore, although IGF-I at birth does not track during childhood22, there is significant potential for an association with later development, through its associations with placental development and matching of fetal and placental growth.
Adiposity and Leptin
Cord leptin strongly correlates with maternal and neonatal adiposity7, 23-27, and also neonatal whole body bone mineral contents and estimated volumetric bone density28. Although neonatal adiposity is largely determined by maternal glycaemia9, maternal smoking has also been associated with a reduction in cord leptin independent of influences on birthweight29. Cord leptin may therefore be influenced by maternal lifestyle behaviour - potentially through an impact on both fetal and placental leptin production. Lower cord blood leptin levels, but not variation in adiponectin levels, have recently been shown to be associated with more pronounced weight gain in the first 6 months of life and higher BMI at 3 years of age30. This is consistent with studies demonstrating that early upward crossing of growth centiles is associated with an increased risk of adiposity in later life31. However, these initial results require replication and currently the relationship between cord leptin and outcomes, including adiposity and skeletal development, in later life remain to be determined.
Inflammatory Markers
CRP and ICAM-1 are increased in adults with obesity32-36 and type 2 diabetes37, 38 and similar relationships also appear to be present in childhood39. We have previously demonstrated that offspring of mothers with type 1 diabetes (OT1DM), have increased fat mass and an associated increased circulating leptin concentration40, 41. Furthermore, we have shown that CRP and ICAM-1 are not only increased in OT1DM but are associated with cord leptin and skin fold thickness42. Notably leptin was also associated with IL-6, a major stimulus for CRP production, raising the possibility that fetal adipose tissue is not only responsible for endothelial activation but induction of a pro-inflammatory phenotype which is already evident by the time of birth. Maternal HbA1c was also associated with CRP supporting a role of maternal glycaemic control in the inflammatory phenotype at birth. This finding of an elevated CRP in OT1DM and relation with maternal glycaemia has now also been replicated43, and the possibility that this extends to lower glucose values given the continuous relationship of glucose to offspring birthweight and adiposity9 requires further investigation. Inflammatory markers are also known to track in childhood44 and to be associated with later metabolic37, 38 and vascular disease45. A single study has found raised inflammatory markers in OT1DM in childhood46. We and others have demonstrated that this inflammatory phenotype is present at birth in OT1DM and that it is particularly related to fetal leptin42, 43. Collectively this raises the possibility that there is potential in-utero effects on sub-clinical inflammatory phenotypes, which directly relate to maternal glycaemia and fetal hyperinsulinaemia and adiposity.
Lipids
With respect to lipids we have also previously determined that maternal diabetes is associated with lower fetal lipids in male offspring, in particular HDL-C (thus significantly higher cholesterol to HDL-C ratio)47. Furthermore, we identified that perturbances in IGF-1 and leptin, rather than insulin - may be the major determinants of HDL-C in-utero47. Lipid metabolism and inflammation are linked via hepatic lipid metabolism with elevations of plasma triglycerides occurring during acute adult inflammatory responses48, consequently, CRP and triglyceride are positively related in children33 and adults49. We have also demonstrated that this relationship is present at birth in OT1DM, with markers; ICAM-1, CRP and IL-6 potentially all acting as independent determinants of triglyceride. The possibility that dyslipidaemia and subclinical inflammation - major determinants of adult disease may coexist at birth, requires further study, particularly if we can identify maternal antecedents which may be modified in the future.
Liver Function Tests
Non alcoholic fatty liver disease (NAFLD) has been described in children and adolescents, with estimates of the prevalence of NAFLD based on unexplained elevated levels of alanine aminotransferase (ALT) or ultrasound range from 2-3% in general paediatric populations50, 51 to between 6-30% in obese children or adolescents52-54. Prevalence estimates in general paediatric populations may underestimate the prevalence in adolescents. A recent post-mortem study provides the most robust evidence of the potential importance of NAFLD in adolescents55. In that study, of 742 US individuals (aged 2-19 years) who had died from external causes (mostly road traffic accidents) the age, gender and ethnicity standardised prevalence of NAFLD (defined as greater than 5% steatosis on histology of the post-mortem liver) was 9.6%, with 3% of the population having non alcoholic steatohepatitis. The prevalence increased with increasing age from 0.7% in those ages 2-4 to 17.3% in those aged 15-1955. A non-human primate model has recently demonstrated that a high fat maternal diet can influence offspring liver function with an increase in fetal liver fat deposition and hepatic oxidative stress - with persistence of this phenotype at 180 days postnatal56. Furthermore, it was suggested that this related to fetal lipid rather than glucose loads. Notably cord leptin and triglyceride are associated in male OT1DM47, raising the possibility that fetal liver fat deposition may occur in conjunction with fetal adiposity. Given the potential long-term importance of NAFLD, identification of whether maternal obesity is associated with derangement of LFTs at birth and if this persists through childhood is important.
Maternal cardiovascular disease
Lastly, offspring birthweight has also been inversely associated with parental mortality, with a stronger relationship seen in mothers and a dominance of cardiovascular disease57. Given the importance of fetal metabolic and hormonal responses in determining birthweight, we hypothesise that these cord analytes will be associated with maternal cardiovascular disease risk profile in later life independent of birthweight.
Methods
All biochemical analyses will be performed at Glasgow Royal Infirmary, which adheres to UK external quality control for all parameters and is Clinical Pathology Accreditation (CPA) accredited. Plasma total cholesterol, triglyceride and HDL-C will be performed by modification of the standard Lipid Research Clinics Protocol unsing enzymatic reagents for lipid determinations. LDL-C will be calculated from total cholesterol and triglyceride using the Friedwald equation. A high degree of correlation between Friedwald calculated LDL-C and directly measured LDL-C has previously been described for cord blood58. Leptin will be measured by a highly sensitive in-house ELISA with better sensitivity at lower levels than commercial assays59. Insulin will be measured by an ELISA (Mercodia), which does not cross-react with proinsulin and has a lower sensitivity of 6pmol/l, well below the (median 22.4pmol/l, IQR15.0 -38.0) we noted in control offspring in a recent study6. CRP will be measured using a high-sensitivity, 2-site enzyme-linked immunoassay42, 60. IGF-1 will be assayed using a chemiluminescence immunoassay (Nichols Institute Diagnostics, San Juan Capistrano, CA 92675, USA) using standards referenced to WHO 1st International Reference Reagent 1988 (Insulin-Like Growth Factor-1 87/518). The limit of detection is 1*0 nmol/l. Intra- and interassay coefficients of variation (CVs) were 5*5-6.8% and 5*4-7*0%. Liver enzymes will be measured by automated analyser with enzymatic methods (all CVs less than 3%). A total of 500micro-l will be required to be shipped to Glasgow for the assays due to dead space, however it is likely that only ~300micro-l will be used.
We will request in the research grant the cost of a post-doctoral statistician to be employed at the University of Bristol under the supervision of Professors Lawlor and Davey Smith for data management and completion of the statistical analysis.
References
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B836 - Maternal thyroid status and offspring development - 17/06/2009
We request permission to apply for funds to perform assays of thyroid hormones- TSH, free thyroxine (fT4) and thyroid-peroxidase antibody (TPO-Ab)- on the serum residuals from maternal samples collected during pregnancy. There is increasing evidence that even mild abnormalities in maternal thyroid hormone levels during pregnancy are associated with both maternal and fetal adverse outcomes. Evidence also exists that elevated TPO autoantibodies can exert these adverse effects even when the mother is euthyroid in early pregnancy. This proposal will examine the impact of maternal thyroid status on pregnancy outcomes and therefore build on the recent work conducted by Debbie Lawlor examining maternal determinants of offspring health in ALSPAC. In particular inspection and abstraction of obstetric data from 13,733 women will soon be completed with complete data on perinatal outcomes exists for ALSPAC.
We would like to address the following objectives in relation to maternal thyroid status:
a. Describe the distribution of maternal thyroid hormones and antibodies in the first and third trimester.
b. Determine the prospective associations of first trimester TSH, fT4 and TPO with maternal weight gain in pregnancy, blood pressure change in pregnancy, smoking status, onset of gestational diabetes/glycosuria and adverse perinatal events including spontaneous and elective preterm birth, preeclampsia, abruption and stillbirth.
c. Determine the prospective associations of first and third trimester maternal thyroid status gestation with offspring birthweight, gestational age, head circumference, offspring fat mass and change in fat mass, growth trajectories from birth to age 15 and offspring cognitive function assessed at age 10 and educational assessment outcomes.
d. Examine the cross-sectional relationships during pregnancy of TSH, fT4 and TPO with vitamin D, calcium and PTH
e. Determine the prospective association of TSH, fT4 and TPO during pregnancy with maternal cardiovascular risk profile in later life (lipids, carotid intima-media thickness (CIMT), blood pressure, height, weight, BMI, fat mass insulin and glucose).
Background
Maternal thyroid status and perinatal outcomes
Maternal thyroid dysfunction has been associated with adverse pregnancy outcomes including spontaneous miscarriage1-3, fetal death4, preterm delivery5, fetal distress6, small head circumference7, low birth weight7 and impaired neuropsychological development8-10. Thyroid autoantibodies have also been independently associated with increased risk of spontaneous miscarriage and preterm delivery5. The results of individual studies on these perinatal outcomes are, however, controversial, reflecting differences in study design, laboratory data, classification of thyroid dysfunction and populations - in particular the inclusion of women with undiagnosed or insufficiently treated thyroid dysfunction. Therefore although clinical hypo and hyperthyroidism have been associated with various adverse perinatal outcomes, at present the role of subclinical thyroid disease is contentious11, 12. The largest study to date suggested that subclinical hypothyroidism -defined as TSH >=97.5th percentile for gestational age at screening and a fT4 greater than 9pmol/l (0.680 ng/dL)- was associated with placental abruption (relative risk 3.0, 95% CI 1.1-8.2) and moderate preterm birth (relative risk, 1.8, 95% CI 1.1-2.9)13. In contrast a recent prospective, population-based cohort study of 5805 women examining maternal thyroid and autoantibody status suggested that subclinical hypothyroidism as defined as TSHgreater than 95th centile and a fT4 between the 5th and 95th percentiles was not associated with adverse perinatal outcomes14. This second study also benefited from assessment of autoantibody status and demonstrated that TPO positivity, defined as greater than 95th centile (n=288), was associated with increased perinatal mortality (adjusted OR 3.2 (1.4-7.1), and a trend towards moderate preterm birth, but no association with birthweight was observed14. Notably subclinical hyperthyroidism has not been associated with adverse pregnancy outcomes15. An association between TPO seropositivity and preterm delivery has recently been demonstrated in a meta-analysis5, and a single intervention study demonstrated that the rate of preterm delivery may be reduced in TPO positive women by levothyroxine treatment16. These findings suggest that the TPO association with preterm delivery may be mediated via impaired thyroid function but obviously requires further study. To our knowledge no study has examined early pregnancy maternal thyroid status on maternal weight gain, an important confounder of adverse perinatal outcomes.
Maternal thyroid status and offspring development
Hypothyroidism caused by iodine deficiency during pregnancy has classically been associated with neurodevelopmental disorders in the offspring, as has late treatment of congenital hypothyroidism. More recently, animal studies have highlighted the importance of the supply of maternal thyroxine to the developing fetal brain17, 18. These studies suggest that even transient periods of hypothyroxinaemia can induce irreversible brain damage during development, specifically abnormal cell migration and cytoarchitecture of the somatosensory cortex and hippocampus17, 18. The role of isolated maternal hypothyroidism or isolated hypothyroxinaemia on offspring neurodevelopment in humans has been more controversial. In 1999 Haddow et al demonstrated an association of maternal hypothyroidism with impaired neurodevelopment at age 8 - with offspring IQ scores 7 points lower than those of mothers on treatment and 19% with IQ scores less than 85 as compared to 5% in controls8. Even more strikingly, isolated maternal hypothyroxinaemia (fT4 less than 10th centile, normal TSH) during the first trimester has also been associated with delayed mental and motor function in the offspring at age 1 and 210. These studies have substantial potential public health importance as the prevalence of subclinical hypothyroidism may be as high as 2-5% of the pregnant population12, 13 but the importance on long term development of subtle changes in maternal thyroid function remain disputed. The long term impact of these milder disruptions of maternal thyroid status on offspring development and educational attainment are unknown, with a NICHD study currently recruiting 5000 women to examine the impact of a fT4 less than 3rd centile on language and motor development at age 2. With respect to TPO autoantibodies, a single study has suggested an independent relationship of positive TPO antibodies and cognitive function independent of concurrently measured fT410. Further an increase in sensorineural loss has been demonstrated in children whose mothers have elevated TPO in the first half of pregnancy in the absence of overt maternal hypothyroidism19. It remains possible that both of these findings are mediated ultimately through changes in maternal or fetal thyroid hormone levels.
Fetal production of thyroid hormones is also essential for normal cardiovascular, respiratory and skeletal development. However, fetal thyroid hormone production does not begin until 10 to 12 weeks gestation, with the fetus dependent on maternal thyroid hormones until then. It is increasingly recognised that adverse perinatal events including growth restriction can be determined as early as 12 weeks gestation; with smaller than expected skeletal growth as determined by crown rump length associated with adverse outcomes including low birth weight20. The significance of this early dependence on maternal thyroid function on offspring skeletal growth is unclear; however, in an extreme example of genetically dependent fetal hypothyroidism21, although head circumference (33.8cm) was normal, bone development was systematically immature and birthweight (2650g) and body length (46cm) were reduced. The potential for a long term impact of maternal hypothyroxinaemia on offspring growth is unknown, although normality due to fetal and neonatal thyroid compensation is likely.
Subclinical hypothyroidism and cardiovascular risk
In adults, subclinical hypothyroidism has been associated with risk factors for cardiovascular disease. Specifically there is a weak association between subclinical hypothyroidism and serum lipids starting at a level of TSHgreater than 5mU/l and assuming significance on approaching a TSH level of 10mU/L22. Treatment by levothyroxine is also associated with improvement in lipid parameters23. C-reactive protein (CRP) levels also increase with progressive thyroid failure24, with replacement reducing CRP in one25 but not another study26. Enhanced central aortic pressure and central arterial stiffness have also been reported in patients with subclinical hypothyroidism27, with again improvement by levothyroxine treatment28. Lastly (CIMT) is greater in conjunction with subclinical hypothyroidism29 and hypothyroxinaemia30, with improvement on normalisation of thyroid function29, 31. The clinical importance of these findings remains disputed but given that consideration of universal screening of thyroid function during pregnancy is currently being considered, if positive associations do exist with later CVD risk this would be an important additional reason for screening and opportunity for early intervention.
Maternal thyroid status and other endocrine axes
There is limited data on the interaction of thyroid hormones and vitamin D, with animal models suggesting that Vitamin D may directly alter thyroid function32, although no association between Vitamin D and thyroid function or TPO status were recently found in a study of 642 Indian adults33.
Methods
All biochemical analyses will be performed at Glasgow Royal Infirmary, which adheres to UK external quality control for all parameters and is Clinical Pathology Accreditation (CPA) accredited.
For objectives a-d relevant datasets will be compiled by DA Lawlor and standard linear/logistic regression models used in analyses. For objective e this will be performed on completion of the BHF funded clinic of the ALSPAC mothers (Lawlor PI).
References
1 Stagnaro-Green, A., Roman, S. H., Cobin, R. H., el-Harazy, E., Alvarez-Marfany, M. and Davies, T. F., Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies, Jama, 1990, 264: 1422-1425.
2 Glinoer, D., Riahi, M., Grun, J. P. and Kinthaert, J., Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders, J Clin Endocrinol Metab, 1994, 79: 197-204.
3 Glinoer, D., Soto, M. F., Bourdoux, P., Lejeune, B., Delange, F., Lemone, M., Kinthaert, J., Robijn, C., Grun, J. P. and de Nayer, P., Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions, J Clin Endocrinol Metab, 1991, 73: 421-427.
4 Allan, W. C., Haddow, J. E., Palomaki, G. E., Williams, J. R., Mitchell, M. L., Hermos, R. J., Faix, J. D. and Klein, R. Z., Maternal thyroid deficiency and pregnancy complications: implications for population screening, J Med Screen, 2000, 7: 127-130.
5 Stagnaro-Green, A., Maternal Thyroid Disease and Preterm Delivery, J Clin Endocrinol Metab, 2009, 94: 21-25.
6 Wasserstrum, N. and Anania, C. A., Perinatal consequences of maternal hypothyroidism in early pregnancy and inadequate replacement, Clin Endocrinol (Oxf), 1995, 42: 353-358.
7 Blazer, S., Moreh-Waterman, Y., Miller-Lotan, R., Tamir, A. and Hochberg, Z., Maternal hypothyroidism may affect fetal growth and neonatal thyroid function, Obstet Gynecol, 2003, 102: 232-241.
8 Haddow, J. E., Palomaki, G. E., Allan, W. C., Williams, J. R., Knight, G. J., Gagnon, J., O'Heir, C. E., Mitchell, M. L., Hermos, R. J., Waisbren, S. E., Faix, J. D. and Klein, R. Z., Maternal Thyroid Deficiency during Pregnancy and Subsequent Neuropsychological Development of the Child, N Engl J Med, 1999, 341: 549-555.
9 Pop, V. J., Brouwers, E. P., Vader, H. L., Vulsma, T., van Baar, A. L. and de Vijlder, J. J., Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study, Clin Endocrinol (Oxf), 2003, 59: 282-288.
10 Pop, V. J., Kuijpens, J. L., van Baar, A. L., Verkerk, G., van Son, M. M., de Vijlder, J. J., Vulsma, T., Wiersinga, W. M., Drexhage, H. A. and Vader, H. L., Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy, Clin Endocrinol (Oxf), 1999, 50: 149-155.
11 Gyamfi, C., Wapner, R. J. and D'Alton, M. E., Thyroid dysfunction in pregnancy: the basic science and clinical evidence surrounding the controversy in management, Obstet Gynecol, 2009, 113: 702-707.
12 Casey, B. M., Subclinical hypothyroidism and pregnancy, Obstet Gynecol Surv, 2006, 61: 415-420; quiz 423.
13 Casey, B. M., Dashe, J. S., Wells, C. E., McIntire, D. D., Byrd, W., Leveno, K. J. and Cunningham, F. G., Subclinical hypothyroidism and pregnancy outcomes, Obstet Gynecol, 2005, 105: 239-245.
14 Mannisto, T., Vaarasmaki, M., Pouta, A., Hartikainen, A.-L., Ruokonen, A., Surcel, H.-M., Bloigu, A., Jarvelin, M.-R. and Suvanto-Luukkonen, E., Perinatal Outcome of Children Born to Mothers with Thyroid Dysfunction or Antibodies: A Prospective Population-Based Cohort Study, J Clin Endocrinol Metab, 2009, 94: 772-779.
15 Casey, B. M., Dashe, J. S., Wells, C. E., McIntire, D. D., Leveno, K. J. and Cunningham, F. G., Subclinical hyperthyroidism and pregnancy outcomes, Obstet Gynecol, 2006, 107: 337-341.
16 Negro, R., Formoso, G., Mangieri, T., Pezzarossa, A., Dazzi, D. and Hassan, H., Levothyroxine Treatment in Euthyroid Pregnant Women with Autoimmune Thyroid Disease: Effects on Obstetrical Complications, J Clin Endocrinol Metab, 2006, 91: 2587-2591.
17 Lavado-Autric, R., Auso, E., Garcia-Velasco, J. V., Arufe Mdel, C., Escobar del Rey, F., Berbel, P. and Morreale de Escobar, G., Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny, J Clin Invest, 2003, 111: 1073-1082.
18 Auso, E., Lavado-Autric, R., Cuevas, E., del Rey, F. E., Morreale de Escobar, G. and Berbel, P., A Moderate and Transient Deficiency of Maternal Thyroid Function at the Beginning of Fetal Neocorticogenesis Alters Neuronal Migration, Endocrinology, 2004, 145: 4037-4047.
19 Wasserman, E. E., Nelson, K., Rose, N. R., Eaton, W., Pillion, J. P., Seaberg, E., Talor, M. V., Burek, L., Duggan, A. and Yolken, R. H., Maternal Thyroid Autoantibodies during the Third Trimester and Hearing Deficits in Children: An Epidemiologic Assessment, Am. J. Epidemiol., 2008, 167: 701-710.
20 Smith, G. C., Stenhouse, E. J., Crossley, J. A., Aitken, D. A., Cameron, A. D. and Connor, J. M., Early-pregnancy origins of low birth weight, Nature, 2002, 417: 916.
21 de Zegher, F., Pernasetti, F., Vanhole, C., Devlieger, H., Van den Berghe, G. and Martial, J. A., The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency, J Clin Endocrinol Metab, 1995, 80: 3127-3130.
22 Duntas, L. H. and Wartofsky, L., Cardiovascular risk and subclinical hypothyroidism: focus on lipids and new emerging risk factors. What is the evidence?, Thyroid, 2007, 17: 1075-1084.
23 Danese, M. D., Ladenson, P. W., Meinert, C. L. and Powe, N. R., Effect of Thyroxine Therapy on Serum Lipoproteins in Patients with Mild Thyroid Failure: A Quantitative Review of the Literature, J Clin Endocrinol Metab, 2000, 85: 2993-3001.
24 Christ-Crain, M., Meier, C., Guglielmetti, M., Huber, P. R., Riesen, W., Staub, J. J. and Muller, B., Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial, Atherosclerosis, 2003, 166: 379-386.
25 Ozcan, O., Cakir, E., Yaman, H., Akgul, E. O., Erturk, K., Beyhan, Z., Bilgi, C. and Erbil, M. K., The effects of thyroxine replacement on the levels of serum asymmetric dimethylarginine (ADMA) and other biochemical cardiovascular risk markers in patients with subclinical hypothyroidism, Clin Endocrinol (Oxf), 2005, 63: 203-206.
26 Perez, A., Cubero, J. M., Sucunza, N., Ortega, E., Arcelus, R., Rodriguez-Espinosa, J., Ordonez-Llanos, J. and Blanco-Vaca, F., Emerging cardiovascular risk factors in subclinical hypothyroidism: lack of change after restoration of euthyroidism, Metabolism, 2004, 53: 1512-1515.
27 Obuobie, K., Smith, J., Evans, L. M., John, R., Davies, J. S. and Lazarus, J. H., Increased Central Arterial Stiffness in Hypothyroidism, J Clin Endocrinol Metab, 2002, 87: 4662-4666.
28 Owen, P. J. D., Rajiv, C., Vinereanu, D., Mathew, T., Fraser, A. G. and Lazarus, J. H., Subclinical Hypothyroidism, Arterial Stiffness, and Myocardial Reserve, J Clin Endocrinol Metab, 2006, 91: 2126-2132.
29 Monzani, F., Caraccio, N., Kozakowa, M., Dardano, A., Vittone, F., Virdis, A., Taddei, S., Palombo, C. and Ferrannini, E., Effect of Levothyroxine Replacement on Lipid Profile and Intima-Media Thickness in Subclinical Hypothyroidism: A Double-Blind, Placebo- Controlled Study, J Clin Endocrinol Metab, 2004, 89: 2099-2106.
30 Dullaart, R. P., de Vries, R., Roozendaal, C., Kobold, A. C. and Sluiter, W. J., Carotid artery intima media thickness is inversely related to serum free thyroxine in euthyroid subjects, Clin Endocrinol (Oxf), 2007, 67: 668-673.
31 Nagasaki, T., Inaba, M., Henmi, Y., Kumeda, Y., Ueda, M., Tahara, H., Sugiguchi, S., Fujiwara, S., Emoto, M., Ishimura, E., Onoda, N., Ishikawa, T. and Nishizawa, Y., Decrease in carotid intima-media thickness in hypothyroid patients after normalization of thyroid function, Clin Endocrinol (Oxf), 2003, 59: 607-612.
32 Misharin, A., Hewison, M., Chen, C.-R., Lagishetty, V., Aliesky, H. A., Mizutori, Y., Rapoport, B. and McLachlan, S. M., Vitamin D Deficiency Modulates Graves' Hyperthyroidism Induced in BALB/c Mice by Thyrotropin Receptor Immunization, Endocrinology, 2009, 150: 1051-1060.
33 Goswami, R., Marwaha, R. K., Gupta, N., Tandon, N., Sreenivas, V., Tomar, N., Ray, D., Kanwar, R. and Agarwal, R., Prevalence of vitamin D deficiency and its relationship with thyroid autoimmunity in Asian Indians: a community-based survey, Br J Nutr, 2009: 1-5.
B835 - Meta-analysis on the interaction of the rs9939609 SNP in the FTO gene with physical activity on the level of obesity - 16/06/2009
The project will investigate the interaction between the rs9939609 SNP in the FTO gene and physical activity on the level of obesity by meta-analysing data from around 30 studies including around 140,000 individuals. The project does not require direct access to the ALSPAC data, but would require summary statistics from the analyses of the ALSPAC data according to an analysis plan which will be sent by us. Alternatively, the required variables could be sent to us, and we will carry out the required analyses.
The summary statistics we require include information on rs9939609 genotypes, physical activity, age, gender, BMI, waist circumference, and body fat percentage among the children in ALSPAC who have data from Actigraph measurements available, as well as information on the interaction between rs9939609 and physical activity on the levels of obesity, BMI, waist circumference, and body fat percentage among these children.
B912 - Maternal alcohol intake in pregnancy and child behavioural problems in two cohorts - 11/06/2009
(No proposal received).
B833 - Cognitive Function and Social Learning - 08/06/2009
Autistic disorders affect an estimated 60 per 10,000 individuals (1, 2). The traits charateristic of autism spectrum disorders (social communication and language delays, restricted and repetitive interests), however, are normally distributed within the general population (3).
There is substantial IQ- and sex-based variability in the prevalence of both clinical and sub-clinical social communication deficit (4, 5). Specifically, there is evidence that IQ is protective against disordered social communication behavior in women, but less so in men. The degree to which this relationship is stable over time is unclear. Studies examining the longitudinal trajectory of social communication behavior are limited; those including members of the general population have been conducted exclusively among males (6). Further, the relationship between IQ and social developmental trajectory has yet to be established. The primary purpose of this project is to investigate the relationship between social/communication behavior and IQ. Specifically, we are interested in determining whether the longitudinal relationship between social behavior and IQ is modified by gender. The primary hypotheses of this study are outlined below:
1. Social and communication skills (assessed via the Social and Communication Disorders Checklist) will improve for some individuals over time. SCDC scores will be tracked at years 7.5, 10, 13/14, and 15/16.
1a. Higher IQ will predict greater improvement in social and communication skills in women but not in men. IQ will be assessed using the WISC-III at 8 and the WASI at 15/16 (scores will be averaged).
1b. Amongst individuals with diagnosed autistic disorder, asperger's disorder, or pervasive developmental disorder not otherwise specified, higher IQ will predict greater improvement in social and communication skills in women but not in men. Autism will be assessed using NHS data linked to ALSPAC by Williams and colleagues (7).
1c. These relationships will hold after controlling for a number of factors potentially related to both IQ and social behavior as measured. Covariates of interest include: language ability (CCC, WOLD); socioeconomic position (family educational background, indices of multiple deprivation, parental employment status, ethnicity, household income); child behavior (1970 birth cohort scales); hyperactiviy (SCQ); literacy and numeracy (WORD) and; prosocial behavior (parent and teacher reports, CHAMP). These covariates will also be assessed for distributional equivalency between sexes and across IQ groups.
Questions regarding phenotypic consistency are implicit within the above analyses. There exists substantial documentation regarding phenotypic heterogeneity in autism (8, 9). Said heterogeneity influences in the maner in which autism research should be conducted and interpreted (10). The variety of measured ASD-correlates in the ALSPAC data set affords a unique opportunity to examine heterogeneity within a representative sample of individuals diagnosed with autism. Specifically, it permits analysis of phenotypic patterning within subgroups. The secondary aim of this project is to assess the phenotypic consistency of autism 1) across the IQ spectrum and 2) between genders. The primary points of comparison will be the following:
2a. The conditional probability of a diagnosis of autism per a given SCDC score.
2b. Evidence of early childhood social/communication delay relative to overall development. Communication delay will be assessed via the communication and social subscales of the Denver at 6, 18, and 30 months and the MacArthur at 15, 24, and 36 months. Overall development in early childhood will be assessed through the remainder of the Denver at 6, 18, and 30 months and the Griffiths (18 months).
2c. The prevalence of associated phenotypes (Theory of Mind, Non-verbal information)
All longitudinal analyses will be conducted using generalized linear mixed effects models (11). The hypotheses of this project are in line with GLMM as, using this method, population averages are interpreted as conditional upon a system of random effects (individual trajectories). Using a mixed (random) effects technique, we will be able to a) control for within-individual clustering of social communication scores across time and b) evaluate between-individual heterogeneity in trajectories. We will use time-variant predictors when available. Accordingly, many covariates (e.g. verbal ability) have been requested at multiple time points. The comparisons involved in questions 2a-c involve basic statistical associations (probabilities, percents). All analyses will be conducted in SAS v. 9.2.
References
1. Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C. Prevalence of Autism in a US Metropolitan Area. Journal of the American Medical Association. 2003;289:49-55.
2. Bertrand J, Mars A, Boyle C, Bove F, Yeargin-Allsopp M, Decoufle P. Prevalence of Autism in a United States Populations: The Brick Township, New Jersey, Investigation. Pediatrics. 2001;108:1155-1161.
3. Constantino J, Todd R. Autistic traits in the general population. Archives of General Psychiatry. 2003;60:524-530.
4. Fombonne E. Epidemiological Surveys of Autism and Other Pervasive Developmental Disorders: An Update. Journal of Autism and Developmental Disorders. 2003;33(4):365-382.
5. Skuse D, Mandy W, Steer C, et al. Social Communication Competence and Functional Adaptation in a General Population of Children: Preliminary Evidence for Sex-by-Verbal IQ Differential Risk. Journal of the American Academy of Child and Adolescent Psychiatry. 2009;48(2):128-137.
6. Constantino J, Abbacchi A, Lavesser P, et al. Developmental course of autistic social impairment in males. Development and Psychopathology. 2009;21:127-138.
7. Williams E, Thomas K, Sidebotham H, Emond A. Prevalence and characteristics of autism spectrum disorders in the ALSPAC cohort. Developmental Medicine and Child Neurology. 2008;50:672-677.
8. Spence S, Cantor R, Chung L, Kim S, Geschwind D, Alarcon M. Stratification Based on Language-Related Endophenotypes in Autism: Attempt to Replicate Reported Linkage. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2006; 141B: 591-598.
9. Spiker D, Lotspeich L, Dimicell S, Myers R, Risch N. Behavioral phenotypic variation in autism multiplex families: Evidence for a continuous severity gradient. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2002; 114: 129-136.
10. Happe F, Ronald A, Plomin R. Time to give up on a single explanation for autism. Nature Neuroscience. 2006;9:1218-1220.
11. Fitzmaurice G, Laird N, Ware J. Applied Longitudinal Analysis. Hoboken, NJ: Wiley; 2004.
B830 - Attention Deficit Hyperactivity Disorder in Children with Learning Disability - 05/06/2009
Attention Deficit Hyperactivity Disorder (ADHD) otherwise known as Hyperkinetic disorder (ICD 10) is an extremely disabling condition, affecting 1.4-6% of children. It is now the commonest reason for follow-up in Child and Adolescent Mental Health Services as well as being seen in Community Child Health Services. Behavioural, social and educational problems as well as increased rates of adult difficulties including criminality and drug misuse are associated with ADHD in children with normal intelligence. In contrast, virtually nothing is known about ADHD in children with learning disability (LD/mental retardation) as sub average intelligence (IQless than 70) has traditionally been used as an exclusion criterion in studies of ADHD. Neither the DSM-IV nor the ICD-10 gives detailed consideration to the diagnosis of ADHD/Hyperkinetic disorder among children with LD.
At one time, clinical lore suggested that ADHD did not occur in children with LD, and any inappropriate behaviour children with LD showed was secondary to mental impairment. That view is not supported by current evidence. More recent studies have shown that ADHD occurs more commonly in these children but may be underdiagnosed due to issues such as '' diagnostic overshadowing'', the tendency by which clinicians tend to overlook additional psychiatric diagnosis once a diagnosis of learning disability is made; or ''masking'' in which the clinical characteristics of a mental disorder are masked by a cognitive, language or speech deficit.While available evidence suggests that ADHD may be more common among children with learning disability, research has been hindered as most studies of ADHD in children with LD do not use standardised diagnostic interviews and criteria. Also this sub-group of children with ADHD and learning disability are excluded from virtually all aetiological and treatment studies. Thus it is not known whether the clinical presentation, pattern of correlates and aetiology of ADHD differs in children with learning disability. This may have ethical implications as not much is known about the diagnosis and treatment in this group of children and hence they are frequently undiagnosed and untreated.
Although there is evidence that ADHD does occur in those with LD a crucial clinical issue is whether or not ADHD in this group is the same entity as that found in those without learning disability; that is can those with both ADHD and LD be viewed as having "true" ADHD. As this sub-group is almost always excluded from research, it remains unknown whether they are similar to children with ADHD and normal IQ in terms of clinical and aetiological correlates. Our preliminary pilot study analyses using a sample of children with ADHD with low IQ test scores showed that lower IQ, is associated with increased ADHD symptom severity and conduct disorder symptoms. This suggests that ADHD and LD may represent a clinically more severe variant of ADHD.On the basis of pilot data, we hypothesise that children with ADHD and LD will show a similar clinical presentation and pattern of genetic and psychosocial correlates to those found in children with ADHD and IQ within the normal range. If our hypothesis is correct, then children with ADHD and LD are likely to benefit from stimulant and other treatments that are known to be effective in those with ADHD without LD and our work will provide impetus for therapeutic trials in this important and disadvantaged group. Moreover, the findings will further highlight that children with ADHD and learning disability should not necessarily be excluded from aetiological and other clinical studies.
AIMS OF THE STUDY:
The aim of this study is to
1) Collect and comprehensively assess a sample of 100 children with ADHD and learning disability.
2) Compare this group with two other groups-a well-characterised sample of children with ADHD who have normal intelligence (IQgreater than 70) that has already been collected and a control group of children with low IQ alone on a) clinical characteristics b) genetic and psychosocial correlates that are known to be associated with ADHD.
The control group of children with low IQ and no clinical comordity have been difficult to recruit from a clinical setting and the ALSPAC would be ideally placed to provide the clinical and cognitive data required for this group of children.
Current data requested:
ADHD -
DAWBA data on Attention & Activity from parent questionnaires at ages 91mths and 128 months
DAWBA data on Attention, Activity and Impulsiveness from teacher questionnaires at Yr 3 & Yr 6
Antisocial Behaviour -
DAWBA data on Awkward & Troublesome Behaviour from parent questionnaires at ages 91mths and 128 mths
DAWBA data on Awkwardness & Troublesome Behaviour from teacher questionnaires at Yr 3 & Yr 6
Antisocial Behaviour questions from Focus@8 and Focus@10 from the child
Cognitive measures -
WISC IQ measure from Focus@8, including digit span subtest, full scale IQ, pe rformance IQ and verbal IQ measure
Other Measures:
Demographic measures -
Sex,
Age at each assessment,
whether from a multiple birth
Social class (maternal education and housing type),
Ethnicity.
B829 - Testing for shared genetic liability between maternal smoking during pregnancy and ADHD - 05/06/2009
Attention deficit hyperactivity disorder (ADHD) is a common, extremely disabling disorder which has major adverse squalae in childhood and later life. Despite being such an important clinical problem, the aetiology and pathogenesis of ADHD is poorly understood. Available evidence suggests that both genetic and environmental risk factors are important.
Association studies have suggested that maternal smoking during pregnancy may be an environmental risk factor for ADHD. However, there is a growing body of evidence to suggest that these associations are due to shared genetic liability between smoking and ADHD, rather than there being a causal environmental effect.
Using a novel design looking at children born through IVF, we have shown that where mothers are not genetically related to the child they carry in pregnancy (e.g. children conceived following egg donation) no significant association is observed between maternal smoking during pregnancy and ADHD symptoms. Conversely when the mother is genetically related to the child she carries (e.g. children conceived following sperm donation) a significant association between smoking during pregnancy and ADHD is observed. This suggests that the association may arise because of shared genetic liability for maternal smoking and child ADHD. Similarly, studies looking at the children of twins and discordant sibling pairs where the mother smokes during one pregnancy but not the other, also indicate that there is a genetic or familial influence on the links between maternal smoking during pregnancy and child behaviour.
Although these studies are suggestive of shared genetic liability, the evidence is still incomplete.
The aim of this proposal is to further explore the causal pathways for association between maternal smoking during pregnancy and childhood ADHD and the possibility that this is due to shared genetic liability.
1). Firstly, we propose to compare the risk for child ADHD when mothers and fathers smoked during the pregnancy; any true environmental effect (taking into account passive smoking effects) would be observed only in those who are exposed to smoke in utero via their mother whilst an equal risk from the father would be indicative of shared genetic liability.
2). We also propose to look at a specific gene variant in the CHRNA3 gene (rs1051730) which has been shown across a number of studies to be associated with increased risk of cigarette smoking and in the ALSPAC sample with smoking during pregnancy, again comparing differential risk passed from the mother and father.
3). Using this genetic information, we aim to look at the child's genotype: If there is shared genetic liability for this particular variant-then we would expect to find association between this SNP and childhood ADHD symptoms. In the future this pilot work could lead to applying for funding to test other variants in relation to the shared genetic liability between smoking and ADHD.
4). Stan Zammit to lead:
Although there have been fewer studies that have examined the relationship between maternal substance use and psychosis, effects on psychosis are equally plausible given the diverse detrimental effects of in-utero exposure to tobacco on cerebral development and function, and also given the evidence that such exposure can lead to cognitive deficits that are an established risk factor for psychosis. In fact, within ALSPAC, we observed that maternal smoking during pregnancy was associated with increased risk of child psychotic experiences, whereas paternal smoking during pregnancy was not associated (although confidence intervals for maternal and paternal smoking overlapped). High levels of maternal alcohol use during pregnancy were also associated with child psychotic symptoms. We would therefore like to examine whether maternal and child genetic variants associated with smoking behaviour are associated with risk of child psychotic experiences.
B825 - Replication of associations seen in Duke Genetics of Memory and Epilepsy Studies - 03/06/2009
We will provide a list of 235 SNPs that have been found to be associated with performance in our cohort. We genotyped our samples using the Illumina HumanHap550 or 610 and will pick the top 10 (approximately) associations from each of the 23 phenotypes examined in our cohort for followup in the ALSPAC cohort. We would like the p-values, betas, standard errors, and direction of effect by allele for a linear regression between each of these SNPs and each of the cognition phenotypes available in the ALSPAC cohort (with covariates such as age and gender included in the model). Since our cohort is composed of individuals over the age of 18, we would prefer the cognition data to be from a timepoint past childhood.
Our analysis was done in a sample of 291 Caucasians for the following tests: Green Story Recall Immediate and Delayed, TrailsA, TrailsB, WAIS Digit Span Forward, WAIS Digit Span Backward, Controlled Oral Word Association, Animals, WAIS Digit Symbol, WAIS Symbol Search, Stroop Color-Word, and the first principal component of these 11 phenotypes. Analysis was performend in a partially overlapping sample of 656 Caucasians and Asians for the following tests from Cantab: paired associates learning (PAL) (2 phenotypes from test), spatial working memory (SWM) (2 phenotypes from test), verbal recognition memory - immediate recall (VRM), pattern recognition memory (PRM), intra-extradimensional set shifting (IED), rapid visual processing (RVP), spatial span (SSP), spatial recognition memory (SRM), and the first principal component from these 10 phenotypes. Cognition phenotypes that are most similar to these measures would be ideal for comparison.
B828 - Investigation of BMI T2D alleles and cognition - 02/06/2009
It is widely accepted that there is an increased prevalence of cardiovascular risk factors in the schizophrenic population. There is also increasing evidence that some of the second generation antipsychotics may contribute additionally to a number of cardiovascular risk factors, particularly type 2 diabetes, obesity, and dyslipidemias. There is also some evidence that many of these factors may contribute risk to cognitive impairment, including dementia (Biessels et al 2006;Qiu et al 2005;Kivipeklto et al 2005) and more subtle cognitive decrements in non-psychiatric populations (reviewed by van den Berg et al 2008). Whether these factors are causal is less clear, but is a question that has obvious importance for public health.
We have become interested in this issue from the perspective of schizophrenia patients given their already impaired cognitive function and the greater prevalence of obesity and type 2 diabetes. Pilot data generated from subjects recruited for projects conducted by the Conte Center for the Neuroscience of Mental Disorders (CCNMD) at the Mount Sinai School of Medicine (a subset of which has been reported on previously, Friedman et al 2008) provides some evidence for association between increased weight and poor cognitive function. Analyses were conducted on 153 subjects (100 with schizophrenia, 53 non-psychiatric) with complete medical and cognitive data. Our analyses provided evidence for an inverse correlation between increased BMI and performance on delayed and immediate memory tasks. There was no evidence for caseness as an interaction term, suggesting the findings might generalize to the population. These pilot data provide some support for the hypothesis for a relationship between BMI and cognitive impairment. While the findings are preliminary, if correct may not reflect causality, and if they do, they may result from pathological changes that are not likely to occur to any appreciable extent, we are interested in exploring an alternative possibility of more direct causal links. Thus, we wish to use the ALSPAC data a) to explore relationships between BMI in childhood and cognition and b) to explore relationships between cognition and alleles that are known to be associated with increased BMI and T2D using the Mendelian randomization approach to test for possible causality.
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Friedman JI, Tang C, Carpenter D, Buchsbaum M, Schmeidler J, Flanagan L, Golembo S, Kanellopoulou I, Ng J, Hof PR, Harvey PD, Tsopelas ND, Stewart D, Davis KL. Diffusion tensor imaging findings in first-episode and chronic schizophrenia patients. Am J Psychiatry. 2008 Aug;165(8):1024-32.
B827 - Genes and intelligence Do genes make us smarter - 02/06/2009
Multiple genome wide and candidate gene analysis have been performed in order to identify genetic varaints that explain the inter-individual differences in intelligence(Butcher, L. M. et al., 2005; Butcher, L. M., Davis, O. S., Craig, I. W., & Plomin, R., 2008; Plomin, R., 1999; Plomin, R. et al., 2004; Plomin, R. et al., 2001; Buyske, S. et al., 2006; Dick, D. M. et al., 2006; Luciano, M. et al., 2006; Posthuma, D. et al., 2005, for a review see Posthuma and de Geus (Posthuma, D. & de Geus, E. J. C., 2006)) but so far results are far from clear. Of all reported genetic association studies in the literature, only 4% have shown replicable association according to a 2002 search (Hirschhorn, J. N., Lohmueller, K., Byrne, E., & Hirschhorn, K., 2002). Using data from the IMAGE project, we performed a GWAS on IQ using data from 947 European Caucasian nuclear families (2844 individuals) from eight countries (Belgium, England, Germany, Holland, Ireland, Israel, Spain, and Switzerland) that were included in the analysis. Families were recruited based on having one child with ADHD (Attention-Deficit/Hyperactivity Disorder) and another who would provide DNA and quantitative trait data. In addition, both parents had to be available for DNA-sampling. IQ scores were available for 634 probands (for which we also had genotyping data), of which 554 are males, with a mean age of 10.99 (SD 2.74). IQ was measured with WISC-III-R (Wechsler Intelligence scales for children) (Wechsler, D, 1991) or the WAIS-III-R (Wechsler Adult Intelligence Scale) (Wechsler, D, 1997) when appropriate (for children aged 17 and older). The vocabulary, similarities, picture completion and block design subtests from the WISC were used to obtain an estimate of child's IQ (prorated following procedures described by Sattler) (Sattler, J. M., 1992). Age-appropriate national population norms were available for each participating site and these were used to derive standardized estimates of intelligence (Sonuga-Barke, E. J. et al., 2008). Standardized Full Scale IQ scores ranged from 56 to 154, with a mean of 100.7 (SD 15.6).
The IMAGE consotium makes part o the Genetic Association Information Network (GAIN) a public-private partnership of FNIH (Foundation for the National Institutes of Health, Inc.) that currently involves NIH, Pfizer, Affymetrix, Perlegen Sciences, Abbott, and the Eli and the Edythe Broad Institute (of MIT and Harvard University (http,//www.fnih.org)). Genotyping was conducted at Perlegen Sciences using their genotyping platform, which comprises approximately 600,000 tagging SNPs designed to be in high linkage disequilibrium with untyped SNPs for the HapMap populations. Genotype data were cleaned by NCBI (The National Center for Biotechnology Information). Quality Control analyses were processed using the GAIN QA/QC Software Package (version 0.7.4) developed by Goncalo Abecasis and Shyam Gopalakrishnan at the University of Michigan. Details of the genotyping and data cleaning process for the ADHD GAIN study (Study Accession, phs000016.v1.p1) have been reported elsewhere (Neale, B. M. et al., 2008a). Briefly, we selected only SNPs with minor allele frequency (MAF) >= 0.05 and Hardy-Weinberg equilibrium (HWE) (P >= 1x10-6). Genotypes causing Mendelian inconsistencies were identified by PLINK and removed (http,//pngu.mgh.harvard.edu/purcell/plink/) (Purcell, S. et al., 2007a). We additionally removed SNPs that failed the quality control metrics for the other two GAIN Perlegen studies (for Major Depression Disorder (dbGAP Study Accession, phs000020.v1.p1) and Psoriasis (dbGAP Study Accession, phs000019.v1.p1). With this filtering, 384.401 SNPs were retained in the final dataset. To increase coverage in the targeted genomic areas, we used the imputation approach implemented in PLINK (v1.04), which imputes genotypes of SNPs that are not directly genotyped in the dataset, but that are present on a reference panel. The PLINK algorithm is an extension of multimarker tagging. The reference panel used consisted of 2,543,285 polymorphic autosomal SNPs genotyped on the 60 HapMap CEU founders which are publicly available for download from the HapMap website (http://www.hapmap.org). A threshold of 0.80 confidence level was set for a hard call to be included in further association testing. Most likely genotypes on imputed SNPs were then included in association analyses. Gene coverage was determined by the sum of the typed and imputed SNPs as well as the tagged SNPs divided by the total known common SNPs within a gene, using WGAviewer (Ge, D. et al., 2008). Association analysis of 634 ADHD probands was conducted using the linear procedure implemented in PLINK using the prorated IQ score as quantitative outcome and adjusting for the language in which the IQ tests were done. Initial findings show several SNPs with interesting (non geneome wide significant) association p values (p less than 10E-06) including a haplotype block on chromosome 3 (rs7643566, rs6800161, rs9860985, rs7642425, rs1602, rs480668, rs6583190 and rs553783 (uncorrected p values = 5.32E-6)) also SNP rs11594325 (uncorrected p value = 6.43 E-6) in the PRKG1 gene on chromosome 10 and SNP rs2134947 (uncorrected p value=9.47E-7) in the CNTN5 genme on chromosme 11. In order to validate these findings, an independent replication sample is needed. We propose to use the genetic and IQ information available from the ALSPAC study in order to replicate these association findings. ALSPAC, as a birth cohort is comparable to an ADHD sample as IMAGE in terms og IQ because the selection criteria applied for the IMAGE participants only required that the IQ was equal or higher than 70, meaning that the distribution of the trait in our ADHD sample is perfectly normal (overall mean IQ [all probands] = 100.0, SD=15.4). Also, the proportion of IQ values lower that this threshold is low, skewing our IQ distribution only slightly, skewness 0.103, SE=0.070), this will not influence our comparison with cohort such as ALSPAC.