Proposal summaries

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

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- MODELLING THE ECONOMIC IMPACT OF CHILDHOOD ANXIETY PROBLEMS - 2017/16/03

B number: 
Principal applicant name: 
Mara Violato | Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford (United Kingdom)
Co-applicants: 
Professor Alastair Gray, Professor Cathy Creswell
Title of project: 
MODELLING THE ECONOMIC IMPACT OF CHILDHOOD ANXIETY PROBLEMS
Proposal summary: 

This research will adopt a life course approach to the assessment of child mental health outcomes and associated costs. Primary analyses of the Avon Longitudinal Study of Parents and Children (ALSPAC) will be conducted to identify the natural history of child anxiety problems into adulthood, and quantify their lasting effects - over the life cycle - in terms of educational attainments, adult health, employment, and associated health and social care, and productivity costs.

Impact of research: 
To provide evidence-base on the long-term mental health outcomes and economic burden of childhood anxiety in the UK. To develop the modelling scenarios and the relevant parameters that can be used to extrapolate results of short term economic evaluations of treatment of child anxiety beyond the duration of the trial.
Date proposal received: 
Wednesday, 15 March, 2017
Date proposal approved: 
Thursday, 16 March, 2017
Keywords: 
Health Economics, Mental health, Statistical methods, Health economics, Child anxiety

B2844 - The Detection of Pseudo-papilloedema Study - 2017/15/03

B number: 
B2844
Principal applicant name: 
Cathy Williams | CCAH (United Kingdom)
Co-applicants: 
Dr Richard Blanch, Dr Alexandra Creavin, Mr Mike Burdon
Title of project: 
The Detection of Pseudo-papilloedema Study
Proposal summary: 

Papilloedema refers to bilateral swelling of the optic nerve head (where the optic nerve enters the eye to transmit visual information to the brain) caused by raised intracranial pressure and is an important clinical sign that may mean that a patient has a life-threatening condition such as a brain tumour, or that they are at risk of losing vision. An unknown proportion of the population have optic nerve heads that look swollen but are not – termed pseudo-papilloedema. It is not known how many people have pseudo-papilloedema and it is therefore not possible to say how useful papilloedema is as a clinical sign in all cases.

Impact of research: 
This study will provide essential data to: 1) Consider the workload to the NHS engendered by primary screening of fundus photographs in optometry practices 2) Inform the utility of a finding of apparent disc swelling in isolation by: a. Allowing integration of the prevalence of pseudopapilloedema with the known prevalence of conditions causing true papilloedema. b. Providing figures on inter-observer agreement – i.e. how reliable a sign is it?
Date proposal received: 
Wednesday, 15 February, 2017
Date proposal approved: 
Wednesday, 15 March, 2017
Keywords: 
Ophthalmology

B2851 - Parent of Origin Effects and Genetics of Symptom Dimensions in Attention Deficit Hyperactivity Disorder and Related Phenotypes - 2017/15/03

B number: 
B2851
Principal applicant name: 
Tetyana Zayats | University of Bergen and Broad Institute of Harvard and MIT (Norway)
Co-applicants: 
Prof Jan Haavik
Title of project: 
Parent of Origin Effects and Genetics of Symptom Dimensions in Attention Deficit Hyperactivity Disorder and Related Phenotypes
Proposal summary: 

Attention deficit hyperactivity disorder (ADHD) is one of the most common and most heritable childhood onset psychiatric conditions. Children with ADHD are at high risk of developing antisocial behavior, substance abuse and other psychiatric disorders, consequently presenting difficulties in their education and social integration.
ADHD does not obey the classical laws of Mendelian inheritance, making it difficult to pinpoint the genes involved. Despite the early advances of candidate gene approaches, subsequent progress in unraveling genetics of ADHD has been rather slow. So far, association studies of ADHD yielded risk variants that (1) generally tend to have small effect sizes or be rare, (2) often refer to co-occurring conditions and (3) lack consistent replication. Even the most comprehensive genome-wide scans available with thousands of patients still appear to result in variants accounting for a relatively small proportion of disorder expression. Thus, there is a growing need for pursuing approaches alternative to dominating association studies.
This project proposes the examination of epigenetic factors in ADHD. Epigenetics concerns alterations in gene expression caused by mechanisms other than changes in DNA sequence. These modifications have been shown to be dynamic and may be reversible throughout life, even in fully differentiated brain cells. As epigenetic mechanisms contribute to several neuropsychiatric disorders, we suggest the investigation a well-known process: parent-of-origin effect (POE).
POE is an umbrella term for a range of genetic and epigenetic phenomena inflecting the development of complex traits. POE have already been implicated in psychiatric health, with documented evidence in schizophrenia, autism and bipolar disorder. Nonetheless, little is known about POE in ADHD, with conflicting results dominating the field.
The hypothesis of POE in ADHD may be supported by several previous studies. The variability in ADHD phenotype was shown to vary depending on parental ADHD history and syndromes with ADHD symptomatology exhibit clinical evidence of POE. Furthermore, it is well-established that the expression of growth-enhancing genes such as IGF2 (insulin-like growth factor 2) is regulated through imprinting, while suboptimal prenatal environment resulting in low birth weight or preterm birth can increase the risk for adverse neurobehavioral outcomes, including ADHD.
Currently, there is no methodology to properly investigate POE (especially for continuous phenotypes), meaning that all previous studies on POE in ADHD are subject of much debate and little replication. This project will be performed in collaboration with BROAD Institute of Harvard and MIT (Boston, MA, USA), where we will be working on the development of new methodology as well as the analyses of the data.

Impact of research: 
We hope to be able to examine a territory of genetics that has not been addressed so far (at least not in human genetics): parent of origin effects. These effects may not only help our understanding of ADHD, but also provide insight into missing heritability. Figuring out if maternal genome plays a role in the development of ADHD will bring us one step closer to efficient treatment and prevention through better understanding of the disease ethology.
Date proposal received: 
Friday, 24 February, 2017
Date proposal approved: 
Wednesday, 15 March, 2017
Keywords: 
Genetics, Mental health, Epigenetics, GWAS, Statistical methods, parent of origin effects, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Nutrition - breast feeding, diet, Statistical methods, mental health

B2852 - Validation analysis of DNA methylation in children related to prenatal particulate matter air pollution exposure - 2017/15/03

B number: 
B2852
Principal applicant name: 
Paul Yousefi | MRC Integrative Epidemiology Unit, University of Bristol (United Kingdom)
Co-applicants: 
Gemma Sharp , Michelle Plusquin, Caroline Relton , Paolo Vineis, John Henderson
Title of project: 
Validation analysis of DNA methylation in children related to prenatal particulate matter air pollution exposure
Proposal summary: 

Prenatal exposure to air pollution is considered to be associated with adverse effects on developmental processes and children’s health. This may partly be mediated by mechanisms related to DNA methylation. The aim of this study is to investigate the relationship between in utero exposure to air pollution (specifically fine particulate matter ≤10μm (PM10)) with DNA methylation at over 480,000 methylation CpG sites across the genome. This project will work in concert with preliminary analysis conducted by the PACE consortium (Pregnancy and childhood epigenetics), a large collection of birth cohort studies, that have identified several putative CpG-air pollution associations that need to be replicated in a separate, independent study. At the time of the initial conception of this project within PACE, ALSPAC did not have the air pollution data required to participate. However, this has since been developed and we will seek to use the ALSPAC consortium as a unique resource to examine association between PM10 and DNA Methylation at birth, verifying the preliminary results of the PACE analysis.

Impact of research: 
The primary academic beneficiaries of this project will be environmental and biological scientists who will gain insight into the role of the epigenome and environmental air pollution exposures. Researchers in the field of lifecourse epidemiology will benefit from a clearer understanding of the role of epigenetic mechanisms in the programming of later health and behaviors. Academics at all career stages, from PhD students to senior academics will have the opportunity to engage with and benefit from the research proposed.
Date proposal received: 
Friday, 24 February, 2017
Date proposal approved: 
Wednesday, 15 March, 2017
Keywords: 
Epidemiology, Epigenetics, Microarrays, Environment - enviromental exposure, pollution, Air Pollution, Particulate Matter

B2853 - Objectively assessed habitual physical activity and future metabolic functioning - 2017/15/03

B number: 
B2853
Principal applicant name: 
Joshua Bell | MRC IEU at the University of Bristol (United Kingdom)
Co-applicants: 
Prof George Davey Smith, Dr David Carslake, Dr Rebecca Richmond, Prof Mark Hamer
Title of project: 
Objectively assessed habitual physical activity and future metabolic functioning
Proposal summary: 

Physical activity is widely linked with better metabolic functioning, but whether these links reflect distinct causal effects is unclear. In the absence of robust genetic instruments for physical activity, we aim to examine habitual levels of physical activity across adolescence in relation to future metabolic profiles in young adulthood. To do this, we aim to use 3 repeated measures of objectively assessed physical activity (total, light, moderate-to-vigorous, and sedentary time), along with 2 repeated measures of objectively assessed fitness and lean body mass, and to relate these to a wide array of blood-based metabolic markers at follow-up (and to change in these from historical assessments) in the form of clinically relevant traits including fasting insulin and over 80 metabolites including branched chain amino acids. The ALSPAC cohort of children is an ideal resource for carrying out this study given availability of repeated objective measures and the young age of participants which allows associations to be estimated with minimal bias due to subclinical disease.

Impact of research: 
The likely output of this research will be at least 1 publication in a general medical or epidemiology journal, the impact of which may be theoretical advancement in active research fields of basic biology, health behaviour and clinical disease epidemiology, and dissemination to public health practice.
Date proposal received: 
Thursday, 2 March, 2017
Date proposal approved: 
Wednesday, 15 March, 2017
Keywords: 
Epidemiology, Diabetes, Hypertension, Obesity, Metabolic functioning, Metabolomics, NMR, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Blood pressure, BMI, Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Metabolic - metabolism, Physical - activity, fitness, function

B2859 - Use of ALSPAC HRC imputed GWAS data as a reference data set for iBSc project work - 2017/15/03

B number: 
B2859
Principal applicant name: 
Nicholas Timpson | MRC IEU (United Kingdom)
Co-applicants: 
Dr Oliver Davis, Miss Verity Diamond, Miss Abigail Wooden, Miss Jess Tidley
Title of project: 
Use of ALSPAC HRC imputed GWAS data as a reference data set for iBSc project work.
Proposal summary: 

This proposal contains three projects:

These are the research dissertations for three iBSc students who have been given access to their own 23&me genotype data sets. In the analyses of these, they wish to compare to an essentially annonymised and representative population based collection. As a result, we are seeking permission to generate three "cid" linked releases of the HRC imputed YP GWAS data for these students for supervised analysis. No phenotypic data will be required and this will be solely for the analysis of genetic data as a comparator set.

Impact of research: 
Dissemination of the implications of common genetic variation analysis on an individual.
Date proposal received: 
Tuesday, 7 March, 2017
Date proposal approved: 
Wednesday, 15 March, 2017
Keywords: 
Epidemiology

B2861 - Analysis for Global Lipids Genetics / The Genetic Investigation of Anthropometric Traits GLG/GIANT consortia - 2017/15/03

B number: 
B2861
Principal applicant name: 
Nicholas Timpson | MRC Integrative Epidemiology Unit at the University of Bristol
Co-applicants: 
Mr Simon Haworth, Dr Ruth Mitchell
Title of project: 
Analysis for Global Lipids Genetics / The Genetic Investigation of Anthropometric Traits (GLG/GIANT) consortia
Proposal summary: 

Measures of the size and composition of the human body (such as body mass index or waist to hip ratio) are heritable and associated with many diseases. Similarly, measures of the quantity and composition of fats in the bloodstream (such as total cholesterol) are heritable and predispose to disease. Understanding the genetics of these traits would help understand the biology of body composition and blood fat traits, and would help understand how and why these traits relate to disease.
Two large international consortia have been formed to perform studies on the genetics of measures of the human body (the GIANT consortium) and measures of blood fats (GLGC). These consortia successfully identified a large number of genetic variants which influence these traits and published findings between 2013 and 2015.
Since then, newer methods have been developed which have improved our ability to look at rare genetic variants.
GIANT and GLGC have requested new analysis. This will improve the original analysis by
a) including analysis of rarer genetic variants; b) increasing the sample size to approximately one million participants and c) allow better understanding of the genetics of body composition and blood fats in different ethnic groups.
This project aims to undertake analysis in ALSPAC on behalf of GIANT and GLGC, allowing ALSPAC to contribute to this important research.

Impact of research: 
By continuing to contribute to these high-profile consortia ALSPAC has an opportunity to help resolve important research questions. In addition publications arising from this analysis are likely to be widely disseminated and will help maintain the profile and awareness of ALSPAC.
Date proposal received: 
Thursday, 9 March, 2017
Date proposal approved: 
Wednesday, 15 March, 2017
Keywords: 
Genetics, Obesity, GWAS, BMI, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Growth

B2862 - The role of vision in the development of speech - 2017/15/03

B number: 
B2862
Principal applicant name: 
J Margaret Woodhouse OBE, PhD, BSc (hons), FSMC | Cardiff University (Wales)
Co-applicants: 
Miss Rebecca John Bsc (hons) MCOptom, Dr Yvonne Wren BSc (Hons) Speech Pathology, MEd, PhD, CertMRCSLT, Dr Cathy Williams BSc, MBBS, PhD(Bristol), FRCOphth
Title of project: 
The role of vision in the development of speech
Proposal summary: 

Both speech delay and refractive error are common childhood problems. Left untreated both can result in delays in learning, social isolation, poor self-esteem, communication difficulties and problems performing daily living activities.
No literature exists to suggest whether a link exists between these two common childhood problems. However, literature does confirm and reinforce the role of vision in speech perception and auditory visual speech perception, both of which are precursors for speech development. It is therefore hypothesized that children with a vision impairment in early life would be more likely to have speech impairment and/or delay in the development of speech.
This research aims to investigate this hypothesis. This will be done through review of the ALSPAC data relating to speech and vision, assessment of the speech of a cohort of children with known vision impairment and the vision of those children referred to speech and language therapy.
If a link exists between vision impairment and speech then evaluation of the type of speech impairment can be made, thus assisting in understanding the nature of speech development in children with a vision impairment.
Identifying the presence of a link between vision impairment and speech impairment would enable practitioners to more readily identify each. By understanding the relationship, the therapies and guidelines used for children with vision impairment who are undergoing speech and language therapy can be developed.

Impact of research: 
Currently, all children who are identified as having speech and language delay are required to routinely undergo a hearing test prior to the onset of speech and language therapy. If a relationship is found between vision impairment and the development of speech, it may be recommended that children should also undergo a full sight test prior to the onset of speech and language therapy. This would act to increase the identification of vision impairment in children and increase the effectiveness of current speech and language therapy techniques. Left untreated both speech delay and vision impairment can result in delays in learning, social isolation, poor self-esteem, communication difficulties and problems performing daily living activities. Timely identification and effective intervention is essential for children to fulfill their potential.
Date proposal received: 
Thursday, 9 March, 2017
Date proposal approved: 
Wednesday, 15 March, 2017
Keywords: 
Clinical research/clinical practice, Developmental disorders - autism, Speech/language problem, Vision impairment, Statistical methods, Childhood - childcare, childhood adversity, Communication (including non-verbal), Development, Speech and language, Vision

B2864 - The association of maternal dietary intakes during gestational with maternal characteristics - 2017/15/03

B number: 
B2864
Principal applicant name: 
Sumaiya Patel | Manchester Metropolitan University (United Kingdom)
Co-applicants: 
Dr Abigail Fraser , Dr Carolina Bonilla
Title of project: 
The association of maternal dietary intakes during gestational with maternal characteristics,
Proposal summary: 

A woman’s health during pregnancy is of vital importance, not only for the mother’s short and long-term health but also for the children born of the pregnancy. Research has shown that women who develop gestational diabetes are more likely to have type 2 diabetes in later life, and greater weight gain during pregnancy is related to higher BMI. In addition to this. Women who gestational diabetes or greater weight gain during pregnancy also have more complications during birth.
Presently, there is very little information on how mothers’ dietary intake is related to the risk of developing gestational diabetes (or poor glucose control) and weight gain during pregnancy.

Impact of research: 
It is likely that the project will lead to an understanding of the dietary factors associated with crucial maternal characteristics that influence both maternal and offspring outcomes.
Date proposal received: 
Tuesday, 14 March, 2017
Date proposal approved: 
Wednesday, 15 March, 2017
Keywords: 
Epidemiology, Diabetes, Obesity, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, BMI, Mothers - maternal age, menopause, obstetrics, Nutrition - breast feeding, diet

B2865 - Life course factors and sexual orientation - 2017/15/03

B number: 
B2865
Principal applicant name: 
Qazi Rahman | King's College London (UK)
Co-applicants: 
Mr Yin Xu, Dr Sam Norton
Title of project: 
Life course factors and sexual orientation
Proposal summary: 

The overall aim of this project is to investigate the contribution of biological and psychosocial factors early in life to sexual orientation later in life. Scholars from across the natural sciences, social sciences, and humanities have argued that differences in human sexuality and gender behaviour are shaped by a rich complexity of biopsychosocial factors including genetics, environment, and culture. However, no studies have robustly tested this “biopsychosocial approach”. For example, previous studies are limited by relying on peoples' reports of their past or on “snap shots” of groups of people at one time point which may produce biases in the data. This study aims to avoid these limitations by exploring how early life factors (including factors such as birth weight, number of siblings, home life, demographic variables) are related to later sexual orientation. We will use longitudinal statistical analysis to quantify how early life factors influence later sexual orientation, as well as changes within-individuals over time. We also want to see if any relationships we find are influenced by the levels of gender behaviour early in childhood, because gender behaviour is strongly associated with sexual orientation. For example, individuals who are more gender nonconforming in their behaviour might have a different pattern of early life factors compared to gender conforming individuals regardless of sexual orientation. We hope our results will provide greater social and cultural understanding of the diversity in human sexuality and gender.

Impact of research: 
The main impacts of our research will be academic, including academic publications and conference presentations. The research is also part of a PhD thesis by Mr Yin Xu. However, we also anticipate that our findings will be of interest to scholars from across the natural sciences, social sciences, and humanities who are interested in questions related to the origins of diversity in human sexuality and gender behaviour. This includes scholars who take a biopsychosocial or interactionist perspective on understanding human behaviour and psychology. Due to this broad relevance, we anticipate the findings to be published in high profile, interdisciplinary scientific outlets. Dr Rahman also has wide-ranging experience in public engagement regarding the science of sexuality and gender diversity. This includes regular features at interactive public events including the Science Museum, Natural History Museum, The Wellcome Trust, British Film Institute, World of Women Festival, and Pint of Science. Dr Rahman also has specific expertise engaging directly with LGBT communities via established contacts with community partners. Thus we anticipate the results of the research will be disseminated widely and to help promote greater societal understanding of diversity in both sexuality and gender.
Date proposal received: 
Wednesday, 15 March, 2017
Date proposal approved: 
Wednesday, 15 March, 2017
Keywords: 
Social Science, Statistical methods, Birth outcomes, Childhood - childcare, childhood adversity, Social science, Statistical methods, Handedness, Fathers, Mothers - maternal age, menopause, obstetrics, Offspring, Parenting, Psychology - personality, Sex differences, Siblings, Sexuality; gender behaviour

B2845 - Maternally inherited genetic variants and breast cancer risk factors - 2017/08/03

B number: 
B2845
Principal applicant name: 
Carolina Bonilla | School of Social and Community Medicine (United Kingdom)
Co-applicants: 
Dr. Santiago Rodriguez, Vivienne Riley
Title of project: 
Maternally inherited genetic variants and breast cancer risk factors
Proposal summary: 

Reactive oxygen species (ROS), generated predominantly by the electron transport chain that takes place in the mitochondria, have been associated with a number of human diseases, including cancer[1]. It has also been observed that mitochondrial genetic variation is associated with oxidative stress markers, the inhibition of oxidative phosphorylation, the promotion of tumour development and the ability of cancer cells to metastasize[2].
Because of the increased exposure to high ROS levels produced during respiration, lack of protective histones, and limited capacity for DNA repair[3,4] human mtDNA carries a large number of mutations that have segregated during evolution. Some of these genetic variants are used to define mtDNA haplogroups, and a few of them slightly modify metabolic performance and energy production; thus not all haplogroups have identical metabolic capacities[1]. It has been hypothesized that the geographic distribution of mtDNA haplogroups is the result of the selection of metabolic properties driven mainly by adaptation to climate and nutrition[1].
Nine mtDNA haplogroups have been identified in Europeans (namely H, I, J, K, T, U, V, W, X) which show varying frequencies by population. Particular haplogroups have been associated with breast cancer risk but no strong evidence of an effect has been found yet, inconsistencies being attributed to population stratification, genotyping error and inadequate design or statistical analysis[5].

Impact of research: 
Findings from this project will contribute to elucidate whether mtDNA variation is likely to be a causal factor for breast cancer.
Date proposal received: 
Thursday, 16 February, 2017
Date proposal approved: 
Wednesday, 8 March, 2017
Keywords: 
Genetics, Cancer, Genomics - structural variants, BMI, Breast feeding, Contraception, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Hormones - cortisol, IGF, thyroid, Mothers - maternal age, menopause, obstetrics, Physical - activity, fitness, function, Puberty, breast cancer, mitochondrial DNA

B2847 - Assessing the impact of parental smoking on genetic variation in offspring Y chromosome - 2017/08/03

B number: 
B2847
Principal applicant name: 
Srikant Ambatipudi | IEU, University of Bristol (UK)
Co-applicants: 
Prof. Caroline Relton, Dr. RC Richmond, Dr. E Stergiakouli
Title of project: 
Assessing the impact of parental smoking on genetic variation in offspring Y chromosome
Proposal summary: 

Tobacco smoke is a complex mixture of chemicals, known to cause genetic and epigenetic aberrations (1). The genetic aberrations caused by tobacco smoke are detected in both the directly exposed (e.g. lung) and unexposed tissues (e.g. blood) (2). Most of the previous studies have looked at the germline mutation with a rationale that a vast majority of cells in the human soma are genetically identical and is stable across the human lifespan. However, the field of human genetics is increasingly recognising that genetic variation acquired during life (i.e., post-zygotic changes) (3). A recent study by Dumanski et al. found that men who smoke are thrice more likely to show post-zygotic loss of Y chromosome (LOY) in their blood cells suggesting that LOY was by far the most common postzygotic mutation (4). However, the differential impact of parental smoking on LOY in male offspring remains unexplored.
The Avon Longitudinal Study of Parents and Children provides a unique opportunity to delineate the genetic impact of parental smoking on offspring sex chromosomes at birth and to study the persistence of these events longitudinally.

References:
1. Humans IWGotEoCRt. Personal habits and indoor combustions. Volume 100 E. A review of human carcinogens. IARC Monogr Eval Carcinog Risks Hum 2012;100(Pt E):1-538.
2. Lee KW, Pausova Z. Cigarette smoking and DNA methylation. Front Genet 2013;4:132.
3. Dumanski JP, Lambert JC, Rasi C, Giedraitis V, Davies H, Grenier-Boley B, et al. Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease. Am J Hum Genet 2016;98(6):1208-19.
4. Dumanski JP, Rasi C, Lonn M, Davies H, Ingelsson M, Giedraitis V, et al. Mutagenesis. Smoking is associated with mosaic loss of chromosome Y. Science 2015;347(6217):81-3.

Impact of research: 
The present study tries to assess the previously unexplored role of parental smoking on Y chromosome-specific genetic aberrations. The results generated through the study would bridge the knowledge gap in the field of intergenerational impact of tobacco smoking on Y chromosome. We aim to publish the findings of the study in a peer-reviewed journal in the near future.
Date proposal received: 
Monday, 20 February, 2017
Date proposal approved: 
Wednesday, 8 March, 2017
Keywords: 
Epidemiology

B2848 - Maternal depression antidepressant use during pregnancy and autism/autistic traits - 2017/23/02

B number: 
B2848
Principal applicant name: 
Dheeraj Rai | School of Social and Community Medicine (UK)
Co-applicants: 
Dr Katy Franklin, Prof George Davey Smith, Dr Hein Heuvelman , Dr Alexandra Havdahl, Hannah Jones, Prof Jean Golding
Title of project: 
Maternal depression, antidepressant use during pregnancy and autism/autistic traits
Proposal summary: 

Depression is common in women of childbearing age and pregnancy. Antidepressants are some of the most common medications prescribed by the NHS. Recent studies have estimated that up to 10% of women in some western countries take antidepressants during pregnancy. Recent studies have raised the possibility of an association between antidepressant use during pregnancy with longer term neurodevelopmental problems such as autism. However, maternal depression may independently be associated with adverse neurodevelopment- potentially confounding the association between antidepressant use and autism.
This study aims to investigate the association of maternal depression or taking antidepressants during pregnancy with offspring risk of autism or autistic traits in ALSPAC.

Impact of research: 
The project is likely to lead to a significant advance in the understanding of the relationship between antidepressant use during pregnancy and autism related outcomes.
Date proposal received: 
Tuesday, 21 February, 2017
Date proposal approved: 
Thursday, 23 February, 2017
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Developmental disorders - autism, Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Birth outcomes, Communication (including non-verbal), Development, Offspring, Social science

B2838 - The developmental role of metabolism appetite and growth in eating disorders exploring novel longitudinal risk pathways - 2017/15/02

B number: 
B2838
Principal applicant name: 
Nadia Micali | UCL Institute of Child Health (Uk)
Co-applicants: 
Cynthia Bulik, Bianca De Stavola, Debbie Lawlor, Diana Santos Ferreira, Ruth Loos, Gerome Breen
Title of project: 
The developmental role of metabolism, appetite and growth in eating disorders: exploring novel longitudinal risk pathways
Proposal summary: 

The Eating Disorders (full and partial syndrome anorexia nervosa and bulimia nervosa and binge eating disorder) are life-threatening illnesses that start in adolescence and affect between one and two in ten adolescents and young adults. There is a lack in our understanding of why eating disorders develop, which affects our ability to develop treatment and adequately prevent eating disorders. This project builds on our preliminary data showing that metabolism and growth might play a role in the development of eating disorders; and aims to test the hypothesis that metabolic function, appetite and growth factors might precede onset of eating disorders. We also aim to explore whether these factors might be related to individuals’ genetic make up, using novel methodologies and based on novel genetic findings. This study will be fundamental in starting to understand new risk mechanisms for adolescent and young adult eating disorders that can be further investigated in larger and more detailed studies following this project.

Impact of research: 
large, given hat this is the first study of its kind
Date proposal received: 
Wednesday, 8 February, 2017
Date proposal approved: 
Wednesday, 15 February, 2017
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Eating disorders - anorexia, bulimia, GWAS, Metabolomics

B2840 - Depot specific effect of pre-pubertal IGF-II on post pubertal fat distribution in ALSPAC cohort - 2017/15/02

B number: 
B2840
Principal applicant name: 
Andy Ness | University of Bristol (Avon )
Co-applicants: 
Dr.Maiadah ALfares, Dr Sam Leary
Title of project: 
Depot specific effect of pre-pubertal IGF-II on post pubertal fat distribution in ALSPAC cohort
Proposal summary: 

Insulin like growth factor II (IGF-II) is a hormone. IGF-II levels in the human circulation are maintained at high levels throughout life unlike those of rodents. IGF-II has been strongly linked to obesity in genetic studies but its metabolic role is still far from understood. We were able to confirm using fat biopsies from children that IGF-II is a key regulator of fat cell biology. Our results suggest it acts as a buffer to excess visceral fat accumulation in children.

Impact of research: 
IGF-II may prove useful as a prognostic biomarker that predicts future weight gain, visceral adiposity and metabolic risk in children. It is theoretically possible that this biological system could be manipulated by diet or pharmacology in the future to prevent excess visceral adiposity.
Date proposal received: 
Monday, 13 February, 2017
Date proposal approved: 
Wednesday, 15 February, 2017
Keywords: 
Epidemiology, Obesity, Statistical methods, BMI, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Metabolic - metabolism

B2841 - The role of X chromosome polymorphisms in cardiovascular disease - 2017/15/02

B number: 
B2841
Principal applicant name: 
JIE ZHENG | MRC Integrative Epidemiology Unit (United Kingdom)
Co-applicants: 
Dr. Evie Stergiakouli, Dr. Linda OKeeffe, Ms. Ellie Clements
Title of project: 
The role of X chromosome polymorphisms in cardiovascular disease
Proposal summary: 

We are aiming to identify the role of X chromosome on cardiovascular diseases in ALSPAC (including presence of disease, blood pressure, anthropometric traits including BMI, lipid levels and glycemic traits). X chromosome association analysis will be conducted using ALSPAC genotype data. The Variance explained by the X chromosome will be estimated.

Impact of research: 
This study will support the genome research project for a iBSc student. Based on the findings, it can turn up become a publication for ALSPAC and MRC-IEU
Date proposal received: 
Monday, 13 February, 2017
Date proposal approved: 
Wednesday, 15 February, 2017
Keywords: 
Genetics

B2842 - Causes and consequences of urinary incontinence in women - 2017/15/02

B number: 
B2842
Principal applicant name: 
Abigail Fraser | MRC IEU (United Kingdom)
Co-applicants: 
Nour Alhababi
Title of project: 
Causes and consequences of urinary incontinence in women
Proposal summary: 

Urinary incontinence (UI) in women is a form of involuntary leakage of urine that affects between 25-45% globally. Several possible UI determinants that have been suggested in the literature include number of children, how they were delivered (vaginally or by C-section), body mass index (BMI), age, hysterectomy, smoking, recurrent urinary tract infection and family history but the reasons for UI remain understudied and poorly understood.

It has been estimated that stress urinary incontinence (SUI) which is an involuntary leakage of urine due to physical efforts ranges from 3% to 25% of elderly women. Quality of life and sexual function are often affected by SUI. The ability to perform activity of daily living may be severely affected by SUI, resulting in embarrassment, social isolation and decrease in health-related quality of life. Women suffering from SUI may avoid participating in physical activity, which in turn impacts on the overall health. Finally, some evidence has shown that up to 50% of women with UI will avoid sexual intimacy with their spouse.

Impact of research: 
Better understanding of the aetiology and consequences of urinary incontinence causes and consequences; improved risk stratification; greater awareness of the condition. Nour works in a women's health clinic and through this project she will gain important research skills that she will apply in her future work.
Date proposal received: 
Monday, 13 February, 2017
Date proposal approved: 
Wednesday, 15 February, 2017
Keywords: 
Epidemiology, Incontinence, Mental health, Statistical methods, Mothers - maternal age, menopause, obstetrics, Statistical methods

B2843 - Investigating putative risk factors for neurodevelopmental disorders using Mendelian Randomization 14-02-2017 - 125156 - 2017/15/02

B number: 
B2843
Principal applicant name: 
Alexandra Havdahl | MRC Integrative Epidemiology Unit, University of Bristol (United Kingdom)
Co-applicants: 
Prof George Davey Smith , Dr Evie Stergiakouli , Dr Neil Davies, Dr Ruth Mitchell
Title of project: 
Investigating putative risk factors for neurodevelopmental disorders using Mendelian Randomization (14-02-2017 - 12:51:56)
Proposal summary: 

Neurodevelopmental disorders (NDDs) are conditions involving perturbed brain development with manifestations ranging from specific to global impairment of developmental domains such as communication, social interaction, motor skills, cognition, activity and emotion. This includes autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), disorders of language, learning and motor functions, intellectual disabilities, schizophrenia and bipolar disorder. NDDs are highly prevalent in the population (~5% of children), typically emerge early in life, and are associated with substantial and long term disability.

The aim of this study to investigate the role of potentially modifiable risk factors for NDDs, using Mendelian Randomization (MR). Multiple pre-/perinatal risk factors are associated with NDDs, including nutritional deficiency (vitamin D deficiency, fatty acids), thyroid dysfunction, inflammation and autoimmune conditions, metabolic conditions, stress, smoking and low birth weight. However, results from epidemiological studies have been inconclusive and the causal role of these risk factors has not been established for most NDDs. Studies using methods that strengthen causal inference are important so that the role of these potentially modifiable risk factors can be determined.

In this project we plan to use MR analysis, whereby genetic variants robustly associated with the risk factors above are used as instrumental variables (IV) to examine whether they have a causal effect on NDDs (categorical disorders and dimensional traits). We will use two-sample MR in which the IV-risk factor and IV-outcome associations are obtained from non-overlapping samples (Burgess et al., 2015). First, published GWAS studies will be used to identify genetic variants robustly associated with the risk factors. Second, these genetic variants will be used to calculate a genetic score for each risk factor in an independent target sample (ALSPAC). Standard linear and logistic regression models will be used to estimate the effect of each risk factor on the NDD trait of interest in the ALSPAC target sample, using the genetic scores as an instrument.

We will also employ additional methods such as positive and negative control designs to strengthen causal inference (Lawlor, Tilling & Davey Smith, 2017).

References

Burgess S, Scott RA, Timpson NJ, Davey Smith G, Thompson SG, Consortium E-I (2015). Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. European Journal of Epidemiology 30, 543–552.

Lawlor DA, Tilling K, Davey Smith G (2017). Triangulation in aetiological epidemiology. International journal of epidemiology. [Epub ahead of print]

Impact of research: 
This research will contribute to determining the causal effect of the above potentially modifiable risk factors for neurodevelopmental disorders. The direct output from the research will be articles published in international high-ranking journals, targeted to the scientific community.
Date proposal received: 
Tuesday, 14 February, 2017
Date proposal approved: 
Wednesday, 15 February, 2017
Keywords: 
Epidemiology, Allergy, Developmental disorders - autism, Respiratory - asthma, Speech/language problem, Cognitive impairment, Diabetes, Eczema, Gastrointestinal, Infection, Mental health, Obesity, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., GWAS, Metabolomics, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., BMI, Development, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Immunity, Mothers - maternal age, menopause, obstetrics, Metabolic - metabolism, Nutrition - breast feeding, diet

B2833 - Assessing the impact of parental smoking on DNA methylation in offspring sex chromosomes - 2017/08/02

B number: 
B2833
Principal applicant name: 
Srikant Ambatipudi | IEU, University of Bristol (UK)
Co-applicants: 
Prof. Caroline Relton, Dr. RC Richmond, Dr. MJ Suderman
Title of project: 
Assessing the impact of parental smoking on DNA methylation in offspring sex chromosomes
Proposal summary: 

Tobacco smoke has been shown to cause highly reproducible changes to the methylome. This has been observed in response to own smoking but also in offspring exposed to maternal smoking in utero. Sustained maternal smoking during pregnancy is associated with aberrant DNA methylation reported in large-scale epigenome-wide association studies (EWAS) of cord blood (1,2). Associations are also seen with paternal smoking, although these largely attenuate when adjusted for maternal smoking (explained by the correlation of maternal and paternal smoking habits). However, all the EWAS for prenatal smoking exposure performed in cord blood to date have focused on autosomes and sex chromosomes have been previously excluded from the analysis. We propose that methylation changes induced in sex chromosomes may have biological importance and we seek to specifically analyse these in the Accessible Resource for Integrated Epigenomic Studies (ARIES).
We hypothesise that paternal and maternal exposure to cigarette smoke may lead to DNA methylation variation in the offspring sex chromosomes and these aberrations may increase the susceptibility of exposed offspring to adverse perinatal outcomes.

References:
1. Joubert BR, Felix JF, Yousefi P, Bakulski KM, Just AC, Breton C, et al. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis. Am J Hum Genet 2016;98(4):680-96.
2. Richmond RC, Simpkin AJ, Woodward G, Gaunt TR, Lyttleton O, McArdle WL, et al. Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC). Hum Mol Genet 2015;24(8):2201-17.

Impact of research: 
The present study tries to assess the previously unexplored role of smoking on sex chromosome-specific epigenetic aberrations. The results generated through the study would bridge the knowledge gap in the field of intergenerational impact of tobacco smoking on sex chromosomes. We aim to publish the findings of the study in a peer-reviewed journal.
Date proposal received: 
Friday, 3 February, 2017
Date proposal approved: 
Wednesday, 8 February, 2017
Keywords: 
Epidemiology, Respiratory - asthma, Birth Weight, Epigenetics, Statistical methods, Environment - enviromental exposure, pollution, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Smoking, Sex chromosomes, Cord blood

B2834 - Understanding the Relationship between Adolescent Biopsychological Development and their Behaviour in the School Context - 2017/08/02

B number: 
B2834
Principal applicant name: 
Ros McLellan | University of Cambridge (UK)
Co-applicants: 
Mr Simon Butler
Title of project: 
Understanding the Relationship between Adolescent Biopsychological Development and their Behaviour in the School Context
Proposal summary: 

The inclusion and achievement of boys in the school setting is of significant concern, especially for those whose challenging behaviour is so severe that it disrupts the learning and wellbeing of others. With a reduction in specialist places for boys with behavioural, emotional and social difficulties (BESD), schools are expected to use devolved funding to establish support mechanisms ‘in-house’. If this includes exclusion to a behavioural unit, the socio-economic outcomes for individuals is often dire involving educational underachievement, youth unemployment, crime and substance dependence. My proposed study aims to explore factors associated with the challenging behaviour of boys with BESD in the school setting with the aim of informing possible interventions and strategies to positively support their behaviour and inclusion. These include biological factors associated with puberty and psychological factors such as social skills and cognition.

Impact of research: 
To present to teachers and school leaders possible bio-psychological factors associated with the adverse behaviour exhibited by some boys as they pass through adolescence. Such knowledge may improve the support and inclusion of such boys in mainstream education.
Date proposal received: 
Sunday, 5 February, 2017
Date proposal approved: 
Wednesday, 8 February, 2017
Keywords: 
Educational and developmental psychology., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Cognitive impairment, Learning difficulty, Statistical methods, BMI, Cognition - cognitive function, Hormones - cortisol, IGF, thyroid, Intelligence - memory, Psychology - personality, Puberty, Social science, Statistical methods

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