Proposal summaries
B680 - Molecular Phenotyping in the Avon Longitudinal Study of Parents and their Children A resource for understanding Molecular genetic pathways underlying phenotypic variation in humans - 30/07/2008
ObThe aim of this application is to develop a world-class resource for systems biology that elucidates the molecular pathways underlying genotype-phenotype associations in the UK's largest, most densely phenotyped, prospective cohort. Specifically, 1000 adolescents from the Avon Longitudinal Study of Parents and their Offspring (ALSPAC) who have been measured repeatedly in a prospective study across a wide range of biological, sociological and behavioural variables, and for whom pre-existing genome-wide SNP data and genome-wide expression levels in transformed lymphoblastoid cell lines are also available, will be assayed on a range of molecular phenotypes including: (a) level of small molecule metabolites, (b) serum protein concentrations, and (c) methylation profiles. This information will then be entered into a database and made available to bona fide researchers, through data sharing systems that already exist within ALSPAC and that facilitate rapid access with clear variable definitions. The database will not only comprise the world's largest collection of molecular phenotypes to date, but also the first publicly available resource for systems biology which allows users to integrate genetic and molecular data with end stage phenotypes.
B684 - Role of Growth Hormone pathway SNPs in childhood obesity - 28/07/2008
Aim:
We intend to analyse genetic variants in genes of the growth hormone pathway for their association with childhood fat mass and measures of obesity in adulthood.
Rationale:
This is a continuation of a project which has already identified an association between a genetic variant in the the growth hormone gene cluster and fat mass in ALSPAC children. We wish to expand this research to include other genes in the same pathway that may have additional effects on fat mass in order to determine (a) the importance of this pathway in childhood obesity and adult cardiovascular risk and (b) whether there is any potential for therapeutic developments. Genetic variants have been selected on the basis of functional candidacy and nominal association (pless than 0.01) with type II diabetes in the WTCCC genome-wide data. This combines the notion of prior biological knowledge with significance values in genome wide data, as typified for example by the appearance of key pharmacogenetically important genes such as PPARG in genome wide data. The growth pathway includes several drugged, druggable or possibly nutritionally modifiable targets and these may be lower down the order of hundreds of genes with modest effects in polygenic disease although potentially of more practical utility as targets..
Methods:
Genetic analyses will be carried out by KBioscience according to the standard ALSPAC arrangements for SNP genotyping. Data analysis will be carried out in STATA using regression to test per allele genetic effects.
Genetic variants and phenotypes are listed below.
Expected value of results:
Understanding the genetic mechanisms underlying obesity is an important component of researching the obesity epidemic. We hope this project will direct us to genetic variants that are both important in childhood obesity and in predisposition to adult cardiovascular disease. This work will help clarify the role of a candidate genetic pathway and provide valuable information for future research.
B679 - Sedentary Behaviour and its Impact on Physical Fitness in Adolescents - 19/07/2008
Purpose:
To examine any potential, independent, association between sedentary behaviour and physical fitness among the ALSPAC adolescents at 13 years old
Background:
Cardiorespiratory fitness (CRF) is an important component of overall physical fitness and low CRF was found to increase the risk of mortality, in adults, independent of fat mass (1). Therefore improving physical fitness should perhaps be a priority, and may have a greater impact upon health outcomes than if weight reduction is solely targeted. Engaging in physical activity is of great benefit to CRF, especially vigorous physical activity (2). However, physical activity does not explain all the variance in CRF (2). Therefore, specifically reducing the time spent sedentary may be of importance. Previous studies involving adults and children have shown sedentary behaviour to be independently associated with various health outcomes (3, 4). However, there is a lack of research concerning the independent effects of sedentary behaviour upon CRF, and this information could potentially help ameliorate morbidity and mortality rates seen in later life (1).
Variables
- Dependent Variable:
? Physical Fitness (PWC 170; 13 year olds; clinical)
- Independent Variable:
? Sedentary Behaviour (hours per day, accelerometry; 13 years old; clinical)
- Covariates:
? Age, pubertal status (chronological and biological maturation; 13 years old; child-response questionnaire)
? Birth length, birth weight, gestation, TV viewing (38mo) and sleep patterns (30mo) (intrauterine factors and early life factors; parental/birth records, 30 and 38 month questionnaire)
? Parental height, parental BMI, social class, maternal smoking during pregnancy, maternal education at time of birth (parental and sociodemographic factors; 32 week questionnaire)
? Adolescents total fat mass (body composition measure; 13 years old; DXA)
? MVPA (physical activity, accelerometer; 13 years old; clinical)
B678 - Childhood negative early life events and pain in adolescence a birth cohort study - 16/07/2008
Aims and purpose of the proposed research
The proposed study will examine whether negative early life events in childhood predict pain in adolescence. To do so the study will examine the following hypotheses:
1) Negative early life events in childhood (pre-natal, birth and early childhood) predict musculoskeletal pain in adolescence
2) Negative early life events in childhood (pre-natal, birth and early childhood) predict chronic widespread pain in adolescence
3) These relationships are moderated by physiological and psychological factors including HPA axis dysfunction, sleep, anxiety and depression.
B677 - Physical activity in pregnancy and offspring neurodevelopment - 14/07/2008
Background
Physical activity has been associated with improvements in cognitive function in both animals and humans. In adult rats and mice, voluntary physical activity has been associated with neurogenesis in the hippocampus (1, 2) and with an increase in long-term potentiation of synaptic efficacy (2). In adult humans, cardiovascular fitness is associated with better performance on cognitive functioning tests (4). In rats and mice, maternal exercise during pregnancy appears beneficial to offspring neurodevelopment. In mice, voluntary wheel running during pregnancy led to differences in offspring's hippocampal cell proliferation (5). In rats, maternal swimming once a day for 10 minutes was associated with offspring having higher levels of neurogenesis in several regions of the hippocampus, higher levels of brain-derived neurotrophic factor, and better short-term memory (6).
The hippocampus may play a key role in the mechanism underlying these beneficial effects of physical activity. Traditionally, the hippocampus has been thought to preserve episodic memories (memories of events) while its role in memorization of facts (semantic memory) is less established. However, recent research has implicated the hippocampus in semantic memory potentially through its role in associative thinking (7, 8). As an example, the hippocampus was recently implicated in acquiring a unique and imaginary lexicon through visual images. Thus, language acquirement through associative learning, as is done in children, may be mediated by the hippocampus (9).
In humans, the effects of physical activity during pregnancy on the neurodevelopment of offspring have been inadequately studied. Three studies of the subject of three slightly different samples of women have been done by JF Clapp. In one study of healthy women with a history of engaging in regular physical activity, women who continued to exercise throughout pregnancy had neonates (N=34) who scored higher in terms of orientation behavior and their ability to regulate state at 5 days after birth as measured by the Brazelton Neonatal Behavioral Assessment Scales when compared to neonates born to women who did not exercise (N=31) (10). In a similar study design, infants of exercising mothers (N=52) at one year of age scored slightly (non-significantly) higher on the mental performance domain of the Bayley Scales of Infant Development when compared to infants of non-exercising mothers (N=52). For psychomotor score, however, infants of exercising mothers scored statistically significantly higher, though the effect was small (11). In the third study, 5 year-old children of women who exercised during pregnancy (N=20) were compared to women who did not exercise (N=20) using the Wechsler Preschool and Primary Scale of Intelligence-Revised, the Peabody Picture Vocabulary Test, the Expressive One Word Picture Vocabulary Test, and the Clinical Evaluation of Language Fundamentals. The children of exercising mothers scored higher in the domains of general intelligence (p=0.01) and oral language skills (p=0.01) (12). The difference in language skills is particularly intriguing given the potential role of the hippocampus in vocabulary acquisition.
Investigation is needed on physical activity during pregnancy in relation to offspring neurodevelopment in humans. Animal evidence supports a biological mechanism for such an effect but the previous human studies suggest a positive association yet are not convincing.
Project Description
We propose an investigation of physical activity during pregnancy in relation to neurodevelopment in offspring using data from ALSPAC. This cohort is ideal for this project for several reasons. We expect that if physical activity influences neurodevelopment the effect may be small and the large sample size in ALSPAC will improve power. Physical activity was assessed by self-administered questionnaire at approximately week 18 of pregnancy for nearly 12,000 women. Of these, we expect over 4,000 will have had IQ measured at age 8 years.
Several questions in section G of the 18 week pregnancy questionnaire have questions on physical activity. Most importantly, question G19 ascertains the number of hours per week, at present, that the woman participated in any of 11 specific exercise-intensive activities.
With respect to outcome, ascertainment was of especially high quality at age 8 compared with other large cohorts that rely on parent-completed questionnaires only. We will follow the analytical plan as presented by Hibbeln et al. (13), in their recent paper on pregnancy seafood consumption in relation to neurodevelopmental outcomes in childhood (except with physical activity scale(s) as the main exposure variable). Their results were adjusted for 26 potentially confounding factors; we might also want to adjust for pregnancy seafood intake.
B676 - Long-term consequences of feeding problems in infancy and early childhood - 11/07/2008
Young infants spend between a half and a third of their waking time feeding, making the outcome of the feeding situation important, not just in terms of nutrition, but also in the establishment of the relationship between the caregiver and the child (Wolke, Skuse and Reilly, 2006). Feeding problems are common amongst infants and young children. The reported prevalence of feeding disorders is 5-10% (Lindberg et al, 2006), with 20-25% of parents reporting feeding problems at some time in the first two years (Wolke, 2003). Considering that there were 669,601 live births inEnglandandWalesin 2006 (Office of National Statistics) up to 167,000 will experience some form of feeding problem in their first two years of life. The most prevalent feeding problem is refusal to eat, with only 14% of cases being linked to some form of physicaldisorder (Wolke, 1994).
One serious consequence of feeding problems in young children can be failure to thrive, or growth faltering, as it is coming to be known. Failure to thrive has been defined as the rate of weight gain being significantly below the weight gain on population standards and persisting for more than three months (Wolke, Skuse and Reilly, 2006). The prevalence of failure to thrive is 3-5 % of the population in Western countries (Corbett and Drewett, 2004). A conditional weight gain criterion has been used to define growth faltering, which takes weight and gestational age at birth into account to identify the slowest 5% of infants to gain weight ( Drewett et al, 2004; Blair et al, 2004; Emond et al, 2007). Corbett and Drewett (2004) conducted a review and meta-analysis and concluded that "failure to thrive in infancy is associated with adverse intellectual outcomes sufficiently large to be of importance at a population level".
However, the majority of those with feeding disorders do not fail to thrive (Lindberg et al, 2006), and feeding problems and failure to thrive are separate phenomena (Rydell and Dahl, 2005). It is necessary to look at the long-term consequences of feeding problems where there is no failure to thrive as distinguished from any consequences that are the result of the severity of the effects on growth. There are a few studies that have looked at the long-term outcome of feeding problems with and without growth faltering (e.g. Lindberg et al, 2006; Dahl et al, 1994; Rydell and Dahl, 2005; Marchi and Cohen, 1990; Kotler et al, 2001). However, the community samples have been usually small and most studies are based on clinically referred populations more likely to suffer multiple regulatory problems (Wolke, 2003; Papousek et al, 2008).
Previous work using ALSPAC
Motion et al (2001) reported on persistent early feeding difficulties and subsequent growth and early development outcomes using the ALSPAC data. Persistent difficulties were defined by reference to weak sucking at 4 weeks and great difficulties feeding at 4 weeks, 6 months and 15 months of age. Persistent feeding difficulties were associated with significant developmental impairments in motor, language and behaviour at 18 months, with weight gain being a continuing problem. Behavioural outcomes were temper tantrums and frequent meal refusal at 18 months.
Emond et al (2005) investigated the relationship between feeding symptoms and early growth faltering in ALSPAC. They reported that growth faltering between birth and 8 weeks was associated with infant sucking problems regardless of the type of milk, and after 8 weeks of age the most significant post-natal influences on growth were the efficiency of feeding, the ability to successfully take solids, and the duration of breastfeeding. A subsequent study (Emond et al 2007) found that growth faltering in infancy was associated with persisting deficits in IQ at 8 years. Multivariate analysis showed that reduction in IQ was linked with growth faltering before 8 weeks and associated feeding problems.
There is a surprising paucity of investigations of the long-term consequences of feeding problems on behavioural outcome and continued eating disorder in childhood (Micali, 2005). Little is known about whether the chronicity of feeding problems increases the risk for other behavioural maladaptations. No previous study has taken into account whether any long-term consequences of feeding difficulties may be impacted by co-morbidity with other infant problems such as crying or sleeping problems (Wolke et al. 1995; Wolke et al., 2002;Von Hofacker & Papousek, 1998). ALSPAC provides an excellent dataset for investigating the longitudinal trajectories of feeding problems, and the interaction with other problems, both those intrinsic to the infant and factors in the family and wider environment.
The research questions to be addressed by the proposed project are:
- What is the impact of feeding problems in infancy and the toddler years on the development of behavioural and psychiatric problems in childhood? Do early feeding problems predict later eating disorder?
- Are the long-term consequences due to feeding problem behaviour, or are these a consequence of multiple regulatory problems in infancy (i.e. crying, sleeping problems) or social and family problems?
B675 - Cardiovascular Health During Growth Hormone Therapy in Transition - 10/07/2008
No outline received
B258 - The functional study of preterm birth - 06/07/2008
We wish to investigate the associations between birth outcomes, (primarily gestational age and birth weight) and SNPs with proven roles in biochemical phenotypes. Key pathways include the inflammatory response and vascular function, which has important implications for utero-placental function. We have recently performed a genome wide assocaition study of mulitple biochemistry phenotypes in the InCHIANTI study (Melzer et al PloS Genetics, May 08), that has identified, or taken to GWAS significance, many variants altering biochemical traits. This study and other recent genome-wide and large-scale association studies have provided robust evidence (P values less than 5 x 10-8) that common genetic variants, marked by key SNPs, influence the levels of various inflammatory cytokines, clotting factors, and susceptibility to aneurysm. This makes them excellent candidates for altering fetal growth and or gestational age and greatly increases the prior odds that they will influence genetic susceptibility to preterm birth through these pathways. In addition, SNPs have been identified which alter the circulating serum levels of various nutrients, hormones and growth factors, including Vitamin A, each of which is also a potential candidate for influencing susceptibility to preterm birth. In the case of Vitamin A , a known teratogen, the SNP that alters Vitamin A may alter risk of miscarriages or fetal abnormalities.
In this study we propose to test the hypothesis that each selected "functional" SNP is associated with fetal growth and or gestational age.
We wish to genotype the selected SNPs in all ALSPAC mothers and children in order to assess associations between fetal growth gestational age and both maternal and fetal genotypes.
ALSPAC is the largest and best UK study for investigating the genetics of fetal growth and perinatal outcomes as it is well-powered to detect small genetic effects, it has the availability of both maternal and fetal DNA and has detailed clinical data on birth size and pregnancy outcomes as well as other relevant maternal phenotypes. RAINE in collaboration with Lyle Palmer, and NFBC with Mark McCarthy, Leena Peltonen and Marjo-Riita Jarvelin are other potential sources of replication/meta-analysis for fetal effects.
B674 - Biobank methods proposal - 30/06/2008
No outline received
B673 - Provision of demographic variables from ALSPAC cohort to link with CDR gathered variables during TF2 - 27/06/2008
The collaboration between Cognitive Drug Research (CDR) Ltd and the Avon Longitudinal Study of Parents And Children (ALSPAC) involved the measurement of attention in ALSPAC participants using the laptop-based CDR computerised assessment system. This collaboration was to be based around our generic collaboration agreement, a copy of which is attached, but owing to oversights, was not signed for this particular data gathering exercise.
The central dataset we use at CDR will include the CDR variables collected, and require demographic information from the ALSPAC study (gender and age required; handedness and race if available).
In keeping with the spirit of the standard CDR Collaborative Research Programme agreement (example attached), it is proposed that both parties have shared access to the data by holding identical copies.
Intended use
CDR hold a large in-house normative database of cognitive data. We propose to add the ALSPAC data to this database. Data will be anonymised, and reference to the source of the data in relation to our norms will not be made. The CDR normative database is used internally for reference and not published or sold externally.
Publication
If publication or presentation of the work occurs, both CDR and the Collaborating Group must agree the content of the publication or presentation. The 'Cognitive Drug Research computerised assessment system' must be mentioned in any publication or presentation. Representatives from both CDR and the Collaborating Group must be on the author list of any publication or presentation.
The publication policy of the ALSPAC study will be adhered to.
Generally, with any publications or conference presentations, the ALSPAC will take senior authorship, and one or more members of the CDR team who has been involved in the research will receive junior authorship.
If there are any questions relating to this proposal, Paul Snell would be happy to address them in the first instance.
B668 - Adiponectin as a biomarker in pharmacoepidemiology and as a biomarker in the wide human clinical phenome - 26/06/2008
Adiponectin is the most highly expressed adipocyte protein and is readily measurable in serum. It
has been extensively studied in the context of obesity, diabetes and metabolic syndrome and has
been clearly shown to have a direct role in the pathogenesis of diabetes. Being negatively
correlated with fat mass and acting as an insulin sensitizer, it represents one critical link between
fat mass and diabetes. It also has directly anti-inflammatory actions. Vascular disease and other
consequences of diabetes are among the most major diseases of our era in the developed and
developing worlds. This then states the general prominence of the protein. This proposal concerns
the biomarker potentials of adiponectin ranging beyond its pathogenic role in diabetes. We focus
on its potential as a pharmacoepidemiological marker and on its relationships to many other
facets of the clinical phenome.
B665 - The Epidemiology of Balance Problems in Childhood the affect of alcohol consumption during pregnancy - 26/06/2008
05.07.2010
E-mail from Rachel - 5/7/10
I'm doing this project for my PhD - have done nearly three years, another 12 - 18 months to go I think. I've had one paper rejected, and am about to send the exec a new version. Another paper is also nearly ready for the exec.
B667 - Long-Term Outcomes of Information Processing in Infancy - 25/06/2008
Long-Term Outcomes of Information Processing in Infancy
(From data on "Children in Focus")
From data on "Children in Focus" collected from 4 months to 11 years, we aim to investigate the following research questions:
Prediction from habituation to later information processing/memory as well as to attention measures.
Prediction from habituation to later cognitive tests and language /speech.
Stability of information processing and short term memory tasks.
Stability of IQ/cognitive tests.
Stability of Language/Speech.
Stability of individual differences in children's performance across age will be evaluated by Pearson correlation coefficients. To assess the predictive validity of habituation on later child outcomes, structural equation modeling will be conducted to obtain both direct and indirect effects as well as take into consideration a variety of control variables. To increase the precision of the within-child cognitive stability findings and to obtain the unique predictve validity of infant habituation on childhood outcomes, we will take into consideration (as we have done previously) child temperament, gender, birth-order, maternal education, and home environment.
B666 - Using Lifecourse analyses to predict axial length changes and myopia in the ALSPAC cohort - 25/06/2008
Study Plan
In this 3-year study, the named applicant (SS) will spend 2 years working on life course models to develop and test causal pathways for myopia using the 15-year data. At the same time, data on myopic progression will be collected from cohort members who attend the 17+ clinic (estimated as 4,500?). In the third and final year, the most robust models derived from years 1 and 2 will be used to analyze the newly acquired myopia progression data (i.e. change in axial length). Outputs will include papers on both the methodologies employed, with recommendations for use in other contexts and on the predictive power of eye growth over the lifecourse analyses to predict myopia.
B669 - A replication of Jacobusse et als Rasch model for child development - 23/06/2008
No outlined received
B670 - A combinatorial approach using steroidogenic factor 1 SF-1 NR5A1 to elucidate novel mechanisms in human biology - 16/06/2008
BACKGROUND
Steroidogenic factor-1 (SF1, NR5A1) is a nuclear receptor that plays a central role in many aspects of adrenal, reproductive and metabolic function. Deletion of Sf1 (FtzF1) in mice causes adrenal and gonadal agenesis, and several loss of function mutations in SF1 have now been reported in humans with adrenal dysfunction and/or disorders of sex development. In addition to these well-established effects, Sf1 is also emerging as an important regulator of ventromedial hypothalamic development and programming, and post-natal obesity has been reported in Sf1 knock-out mice rescued by adrenal transplantation (1, 2). Although incidental reports of weight changes in patients with SF1 mutations exist, corticosteroid administration may have influenced growth in some cases, so the true role of SF1 in humans is still poorly understood.
Recent work has shown that a non-synonymous polymorphism exists in the coding sequence of SF1 (p.G146A, rs1110061) (3, 4). Studies in our laboratory have shown that this change does not affect nuclear localization or cellular dynamics, but does result in a mild but potentially significant effect on SF1 function in the transcriptional regulation of a range of target genes. In additional limited studies published recently, this polymorphim has been shown to be associated with undescended testes or micropenis in two small cohort studies in Japan (5, 6), and with an increased incidence of type 2 diabetes mellitus in the Chinese (7).
We have now undertaken analysis of this p.G146A polymorphism in SF1 in a UK-based cohort of mothers and children in the UCL Fetal Growth Study (Professor Peter Hindmarsh). This polymorphism is present in heterozygous state in approximately 8% of the 460 children studied and is in Hardy-Weinberg equilibrium. Heterozygosity for p.G146A was associated with a reduction in placental weight (643g vs 678g, pless than 0.05) and preterm delivery (15.3% vs 4.3%; Chi-square, 7.4; p=0.02; OR 0.25, 95% CI 0.09-0.77). Although there was no significant difference in birth weight between groups, analysis of post-natal growth data in a subset of children showed that a heterozygous p.G146A polymorphism was associated with higher BMI at three years of age (17.8 kg/m2 vs 16.3 kg/m2, pless than 0.001) and a significant elevation in both systolic and diastolic blood pressure.
We are therefore interested in establishing whether these findings can be reproduced in an independent population based cohort of children in the UK. It would also be of great interest to see if an association with undescended testes or hypospadias could be seen in the UK population, although it is possible that this would be underpowered and a case-control approach would be better.
AIM
We would aim to collaborate with K biosciences to establish the SF1 polymorphism (p.G146A, G/C, rs1110061) genotype status in the ALSPAC cohort. We would agree that genetyping the entire cohort would have potential added value in the long term, and would support this approach depending on cost implications. Taqman SNP genotyping probes for this change have been obtained from ABI and validated by Professor Steve Humphries at UCL for the study of an adult cohort, thus I would assume that K biosciences would be able proceed with this project without unexpected difficulties.
B663 - Does a variant in the ADH1B gene predict alcohol intake - 12/06/2008
To date, no common genetic variant is known to be associated with levels of alcohol intake in populations of European ancestry. We have identified one genetic variant in one of the genes involved in alcohol metabolism (ADH1B), which predicts alcohol intake in a cohort of 50-70 year old British men of white ethnic origin (N=4000). The minor allele frequency in Europeans ranges between 1% and 3%. This variant has recently been reported to be highly protective of aerodigestive tract cancers in a pooled analysis of 5 cohorts, with a more marked effect among heavy drinkers compared to moderate drinkers, and no evidence of an effect in lifelong teetotallers, suggesting the effect is purely due to a gene-environment interaction (1). In laboratory experiments, individuals with at least one copy of the variant have been shown to metabolise ethanol 100 times faster than those with two copies of the common allele (2).
ADH1B has three alleles - ADH1B*1 is 47Arg and 369Arg (common allele, common SNPs at both sites), ADH1B*2 is 47His and 369Arg (variant at site rs1229984 and common at site rs2066702), ADH1B*3 is 47Arg and 369Cys (common and variant, respectively, not found among Europeans). According to Osier (3), the double variant is in theory possible but has not been observed. The ADH1B*2 (almost fully captured by the SNP rs1229984) is the variant associated with protective effect for alcoholism (the His variant is the fast metabolizer, resulting in much higher levels of acetaldehyde). Although this has been observed e.g. among Jewish university students in the US who exhibited higher alcohol elimination rates (His/His greater than Arg/His greater than Arg/Arg) (4), environmental factors (e.g. social setting) have been shown to account for more marked differences in frequency and amount of drinking than ADH1B genotypes (5), with students drinking considerably more than other adults from the Jewish community.
There have been many speculations about selection operating on ADH1B*47His allele in East Asia (see, for example, (6)), Han conducted a comprehensive study of 54 SNPs in 42 populations on the ADH cluster, finding the first evidence of selection for the locus but doubting its link to the 'modern' phenotype of alcoholism (7). However, among Irish and Danish, no variation was observed at site ADH1B Arg47His (rs1229984), nor at rs28626993 (intron3) (see Han et al (7)).
There are inconsistencies in the literature that cannot confirm a clear effect of the rare variant of this SNP on alcohol intake in Caucasian populations, mainly due to lack of power. We have recently investigated the association between the ADH1B variant rs1229984 and alcohol consumption in approximately 4000 middle-aged British men who attended prostate cancer screening. This is a case-control study nested in cohort from the ProtecT study, and alcohol consumption in these men is significantly varied, with many classified as heavy drinkers. Excluding men of ethnicity different from 'white', we noted that the presence of the rare allele for this SNP was associated with lower alcohol consumption. Notably our results would be consistent with the gene-environment interaction effect reported by Hashibe and colleagues (1), however no direct data on alcohol intake are available for a formal comparison.
Given the initial evidence that this SNP is associated with alcohol drinking in men with such high levels of the phenotype (alcohol drinking), we aim at replicating such findings in ALSPAC using genotype and alcohol data collected from the mothers during several times in their life, which we expect to be reflecting on average lower intakes, and to be of better quality (smaller measurement error).
Concept * Specific Measure * Person * Source * Time
Alcohol intake * self-reported alcohol intake * Mother * Questionnaire * ALL
(markers) * smoking * Mother * " * ALL
* socio-economic status variables * " * " * "
* height, weight * " * " * "
B664 - Comparison of dietary patterns in under-reporters vs valid reporters and 24h recall vs diet diaries - 09/06/2008
We have recently shown in the ALSPAC cohort that differences are evident in food and nutrient intakes at 10 and 13 years in those young people classified as under-reporters compared to those with valid reports. Similarly, differences are evident in those completing 2/3 dietary diaries compared to 24 hour recall (papers in progress).
Following on from my PhD work, I would like to investigate any differences in dietary patterns obtained using Principal Components Analysis (PCA) and cluster analysis in these groups. To my knowledge this has not been investigated by any other studies and will therefore make a significant contribution to the literature on dietary patterns. This work will also feed into the analyses that we hope to carry out should our NIH application (dietary patterns and changes in body fat) be successful.
B661 - Does a common variant in the Per2 gene predict alcohol intake and sleeping patterns - 05/06/2008
Daily and seasonal rhythms in the endocrine system are co-ordinated by a hypothalamic pacemaker, the suprachiasmatic nuclei (SCN) that is synchronised to solar time by inputs from the eyes. The SCN neurons act as circadian clocks and incorporate Period (Per) and Cryptochrome (Cry) genes. Mutations that alter the rate of transcription of Per and Cry genes or the stability of Per and Cry proteins affect clock speed 1. In Framingham off-spring study, clock variants have been associated with time of going to bed, sleepiness and sleep duration 2. There is also evidence of a role for clock variants in major depressive illness (where sleep disturbance is a feature), seasonal affective disorder (winter depression) 3, bipolar mental illness but little evidence for anxiety states 4.
Alcohol consumption has been shown to be linked to altered circadian rhythmicity in a complex bidirectional way. On one hand, animal studies suggest that "fetal exposure to ethanol significantly alters the clock mechanism governing the circadian function of beta-endorphin neurons"5, and increased drinking in adulthood has been suggested as a consequence of night-shift work 6 or severe jet lag 7. On the other hand, Spanagel et al published evidence on mPer2 mutant mice presenting increased consumption of self-administered ethanol, which was supported by a study among 215 patients with confirmed alcohol dependence 8. The effect seems to be specific to Per2, as no evidence was found for a differential ethanol reinforcement, seeking, or relapse behaviour in mPer1-mutant mice, compared to the wild type 9. Moreover, alterations of glutamatergic components resulted from deletion of mPer2 8 but not mPer1 9. The evidence on efficacy of acamprosate for relapse prevention in alcoholics 10, 11 and mPer2 mutant mice 8 supports a direct effect of hyperglutamatergic states in the brain on alcohol addiction. A haplotype composed of 4 SNPs (including the rare allele of the proposed SNP rs2304674) was found to be associated with lower alcohol consumption among Western European alcoholics (less than 300 g/d compared to (cubed)300 g/d), with one SNP in the haplotype possibly regulating transcriptional activation of Per2 8. However it is not clear whether the differential ethanol intake in mPer2 mutant mice and in the patients with the lower alcohol consumption haplotype was specifically due to altered circadian rhythmicity 12.
No further published evidence is available to date to confirm these findings in humans. We have recently investigated the association between Per2 variants rs56013895 and rs2304674 (two of those in Spanagel's paper 8) and alcohol consumption in the British Women Heart and Health Study (BWHHS). This is a cohort of British women aged 60-80 years, whose alcohol consumption is remarkably low. Excluding women of ethnicity different from 'white', we noted that the presence of the rare allele for the latter SNP was associated with lower alcohol consumption, and the effect was more pronounced for rare allele homozygotes Vs heterozygotes. Notably our results are in the same direction as those reported in 8, but are based on a population sample characterised by extremely different phenotype (moderate drinkers Vs alcoholics). This variant is common among Europeans (HapMap CEU minor allele frequency: 0.233). The other SNP (rs56013895) showed similar results, but is much more rare.
Given the initial evidence that this SNP is associated with alcohol drinking in groups with such different levels of the phenotype, we aim at replicating such findings in ALSPAC using genotype and alcohol data collected from the mothers. Moreover, since variations in hPer2 gene have been linked to morning preference and/or sleeping patterns, we will analyse independently offspring genotype in relation to detailed sleep data in the children.
B660 - Genes and mediating mechanisms in childhood ADHD - 03/06/2008
Attention Deficit Hyperactivity Disorder (ADHD) is a common, extremely disabling disorder that has major adverse sequelae in childhood and later life. Despite being such an important clinical problem, the aetiology and pathogenesis of ADHD is poorly understood. The available evidence shows that genetic factors are of major importance and that genes co-act and interact with environmental risk factors. The presence of antisocial behaviour in children with ADHD is an important marker of heterogeneity, indexing greater clinical severity, poorer outcome, persistent problems in adult life, a stronger association with neurocognitive deficits, especially affecting prefrontal cortical functioning and higher genetic loading.
Previous evidence had suggested that prefrontal cortical function is influenced by a valine/methionine variant in the catechol-O-methyltransferase (COMT) gene and indeed this was recently found in the ALSPAC sample (Barnett et al., 2007). We tested for association between this functional COMT gene variant and antisocial behaviour in ADHD in our well characterised sample of 240 clinic children with ADHD. We found evidence of association with the same COMT val/val genotype (Thapar et al, 2005). Since this publication, the finding has been replicated in two independent population-based samples (Caspi et al, 2008). There was significant evidence of association between the COMT val/val genotype and 1) childhood antisocial behaviour in those with ADHD in one sample, and 2) adult criminality in those with ADHD in the other. A pooled analysis of 4 published studies, showed significant association (Caspi et al, 2008).
The aim of this first stage proposal is to identify a potential mediating mechanism. Specifically we wish to test the hypothesis that
1). the COMT val/val genotype is associatied with antisocial behaviour in ADHD and
2). these effects are mediated through prefrontal cortical functioning.
The aim at this stage is to undertake analysis on existing data, develop research links with Bristol under the auspices of the Neurosciences Centres, publish findings and provide the basis for a subsequent grant /fellowship application.
The future application would aim to integrate the research we are undertaking on a clinical sample through Wellcome Trust programme funding on the genetics of ADHD with ALSPAC data. The key aims would be to test associated gene variants (gene discovery in other samples-notably our own clinical study and collaborative whole genome association studies) in a population-based sample a)for links with ADHD and antisocial behaviour in ADHD and b)investigate potential mediating mechanisms-specifically cognitive vs. emotion-based pathways.