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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B3008 - Epigenome-wide association study of seizures - 06/12/2017

B number: 
B3008
Principal applicant name: 
Doretta Caramaschi | MRC IEU -- University of Bristol (United Kingdom)
Co-applicants: 
Dr Esther Walton, Ms Charlie Hatcher
Title of project: 
Epigenome-wide association study of seizures
Proposal summary: 

Epilepsy is a common disorder that presents with recurrent seizures often from early childhood. It can affect children’s learning and school achievement and it is often related to other conditions such as autism, while significantly inflicting a burden on the affected children and their families. Amongst the known causes are genetic factors and birth complications. However, the mechanism by which epilepsy develops is unclear. Recent studies have found epigenetic alterations being linked with several neurological and psychiatric diseases, including scarce evidence of a link with epilepsy. Epigenetic modifications are chemical changes in the DNA molecule that maintain intact the inherited genetic information while altering, sometimes permanently, the functionality of the interested genes. Investigating these changes in the peripheral blood of children that experience seizures might help develop early biomarkers and understand the biological mechanisms behind epilepsy. In this project we aim to investigate the link between the epigenome at birth, during childhood and adolescence with the experience of seizures and we will investigate its potential consequences for neurodevelopment and mental health.

Impact of research: 
This project will allow us explore an area that is currently under-investigated and will give us new insights into the area of epilepsy and child development. If the results are confirmed by replication in other cohorts, the results will be published in a peer-reviewed journal and communicated to health professionals and to the public where they will be particularly of interest to the families whose children have experienced seizures.
Date proposal received: 
Monday, 4 December, 2017
Date proposal approved: 
Wednesday, 6 December, 2017
Keywords: 
Epidemiology, Epilepsy, Epigenetics, Development

B3011 - Investigating the performance of multiple imputation with increasing proportions of missingness - 06/12/2017

B number: 
B3011
Principal applicant name: 
Jon Heron | Bristol Medical School (PHS) (United Kingdom)
Co-applicants: 
Mr Paul Madley-Dowd, Dr Rachael Hughes, Professor Kate Tilling
Title of project: 
Investigating the performance of multiple imputation with increasing proportions of missingness
Proposal summary: 

Missing data is a common problem in epidemiology where participant drop out can substantially reduce the sample size of initially large cohorts. One method of dealing with missing data is to use multiple imputation (MI) in which copies of the dataset are created and missing values are replaced in each dataset using an imputation model. An analysis model is then fitted to each imputed dataset and the point estimates of model parameters are combined using Rubin’s Rules. Variables included in the imputation model but not the analysis model are known as auxiliary variables.

A common question among researchers and reviewers is what proportion of missing data warrants the use of MI. A lower threshold of 5% missingness has been suggested as a point below which MI provides negligible benefit. At the opposite end some reviewers suggest an upper threshold of 50% missingness above which MI should not be attempted.

The fraction of missing information (FMI) is a measure able to quantify the loss of information to missingness while accounting for the amount of information retained by other variables within the dataset. It can be thought of as the fraction of the total variance of a MI model that is attributable to the between imputation variance. The FMI can take values between 0 and 1 with low values being preferable.

In a simulation study proportions of missing data in a multivariate normal dataset were increased using a missing completely at random pattern. Multiple imputation was then used and its performance compared to complete case analysis. Imputation models with varying amounts of auxiliary information were investigated in terms of the bias and precision of parameter estimates, confidence interval coverage and FMI.

An empirical example, using ALSPAC data, will now be used to support the findings of the simulation study.

Impact of research: 
This research will advise epidemiologists and reviewers as to the limits of the proportions of missing data in an outcome variable that multiple imputation can be used. It will also advise on the importance of auxiliary variables to multiple imputation.
Date proposal received: 
Tuesday, 5 December, 2017
Date proposal approved: 
Wednesday, 6 December, 2017
Keywords: 
Statistics/methodology, Cognitive impairment, Statistical methods, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3012 - Using modern causal inference methods to investigate the role of inflammation in the aetiology of eating disorders - 06/12/2017

B number: 
B3012
Principal applicant name: 
Francesca Solmi | UCL (United Kingdom)
Co-applicants: 
Prof Glyn Lewis, Prof Cynthia Bulik, Prof Bianca De Stavola, Dr Golam Khandaker, Professor Christina Dalman, Dr Karoline Kuchenbaecker
Title of project: 
Using modern causal inference methods to investigate the role of inflammation in the aetiology of eating disorders
Proposal summary: 

Eating disorders are severe psychiatric conditions usually starting in adolescence. Their cause is
poorly understood.

Research has shown that infections in pregnancy and childhood, autoimmune disorders (e.g. type-1
diabetes), and inflammation (i.e. the body’s response to infection or injury) could increase a
person’s risk of developing mental health problems, including depression and psychosis. However,
little research has investigated the relationship between inflammation and eating disorders.
To address this question I will study whether: 1) exposure to infection during pregnancy or
childhood; 2) having high levels of inflammation in childhood; 3) carrying high genetic risk for
autoimmunity increase a person’s risk of developing an eating disorder.

The studies I will carry out use new approaches bringing together eating disorder data, biological markers of inflammation, and genes. This research will help to understand more about what causes eating disorders so that we can develop interventions to reduce the risk.

Impact of research: 
If my hypothesis of an association between inflammation and eating disorders is confirmed, it would justify: further research into anti-inflammatory treatments for EDs; studies linking inflammatory mechanisms to ED treatments; preventative strategies targeting ‘at-risk’ groups (e.g. those with autoimmune disorders).
Date proposal received: 
Wednesday, 6 December, 2017
Date proposal approved: 
Wednesday, 6 December, 2017
Keywords: 
Epidemiology, Diabetes, Eating disorders - anorexia, bulimia, Eczema, Infection, Mental health, Respiratory - asthma, Genomics - structural variants, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Statistical methods, BMI, Cognition - cognitive function, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Hormones - cortisol, IGF, thyroid, Immunity, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Nutrition - breast feeding, diet, Offspring

B3013 - Intrauterine effects of maternal sex hormones on offspring DNA methylation and health outcomes - 06/12/2017

B number: 
B3013
Principal applicant name: 
Ryan Arathimos | MRC Integrative Epidemiology Unit (United Kingdom)
Co-applicants: 
Prof Caroline Relton, Dr Matthew Suderman
Title of project: 
Intrauterine effects of maternal sex hormones on offspring DNA methylation and health outcomes.
Proposal summary: 

Associations between circulating sex hormones in blood serum and DNA methylation have previously been found in ALSPAC children in both childhood and adolescence. Such associations may tag biological pathways involved in endocrine-related diseases, with important implications for the study of hypo- or hyper- gonadism, as well as various metabolic disorders known to be regulated by sex hormones. Whether such associations also exist between maternal levels of sex hormones and the mothers growing foetus is not known. The project will look at the effects of sex hormones in mothers on DNA methylation in children, using both observational and genetic evidence. Maternal sex hormone genotype will be used as a proxy of circulating sex hormone levels in genetic analyses enabling true causal associations to be unpicked from those due to confounding. Paternal genotype will be used as negative control to determine whether associations are due to in utero exposure to maternal sex hormones or simply shared genotype between mother and offspring.

Impact of research: 
The results of this research could be used to identify children at risk of outcomes linked to exposure to extreme intrauterine sex hormone levels. High risk individuals would be candidates for preventative interventions. Inclusion of DNA methylation will allow generation of exposure biomarkers (as a methylation score) reflecting exposure to intrauterine sex hormones that may be informative in risk prediction of future adverse health outcomes, in cases where pregnancy hormone levels are not available. Methylation itself could also be investigated as a mediator of in utero sex hormone and later life health outcomes, with potential for intervention. The results of this project will be of particular interest to endocrinologists, studying the biological effects of sex hormones, as well as researchers (epidemiologists and epigeneticists) involved in investigating the developmental origins of health and disease hypothesis.
Date proposal received: 
Wednesday, 6 December, 2017
Date proposal approved: 
Wednesday, 6 December, 2017
Keywords: 
Endocrinology, Statistical methods, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3010 - Causal analysis of maternal substance use during pregnancy and offspring neurodevelopmental outcomes 24-10-2017 - 165436 - 07/12/2017

B number: 
B3010
Principal applicant name: 
Dheeraj Rai | Centre of Academic Mental Health, University of Bristol (United Kingdom)
Co-applicants: 
Mr Paul Madley-Dowd, Prof Stan Zammit, Dr Jon Heron, Dr Luisa Zuccolo, Mr Andrew Boyd, Prof Marcus Munafo
Title of project: 
Causal analysis of maternal substance use during pregnancy and offspring neurodevelopmental outcomes (24-10-2017 - 16:54:36)
Proposal summary: 

Alcohol and tobacco use during pregnancy have been shown to influence fetal brain development. These exposures have also been associated with intellectual disability, learning difficulties, autism spectrum disorder (ASD) and schizophrenia. Although such associations may be biologically plausible, whether they are causal or not is unclear. As a part of this project we aim to further investigate whether substance use by mothers during pregnancy is causally associated with childhood neurodevelopmental outcomes. To do this we will use a variety of statistical techniques which may improve our understanding. These techniques include comparison of mother and father’s substance use behaviours and the use of genetic methods which help to determine causality. These analyses will be undertaken in several large population based birth cohorts, including ALSPAC, in conjunction with other techniques such as sibling designs. The project will help to expand our understanding of the non-genetic causes of ASD, learning/intellectual disability and psychosis. Our research will provide a stronger evidence base to help future guidelines or policy regarding substance use during pregnancy.

Impact of research: 
If causal associations are detected and found to be robust following investigation using other cohorts, this would provide evidence supporting conservative governmental policy regarding the use of alcohol and tobacco use during pregnancy.
Date proposal received: 
Tuesday, 5 December, 2017
Date proposal approved: 
Wednesday, 6 December, 2017
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Developmental disorders - autism, Cognitive impairment, Learning difficulty, Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Epigenetics, Statistical methods, Birth outcomes, Cognition - cognitive function, Development, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Linkage, Intelligence - memory, Mothers - maternal age, menopause, obstetrics, Offspring, Siblings

B2989 - The association between hypodontia and maternal smoking and alcohol and caffeine consumption during pregnancy - 05/12/2017

B number: 
B2989
Principal applicant name: 
Camilla Miles-Hobbs | IEU Member
Co-applicants: 
Professor Debbie Lawlor, Mr Tom Dudding
Title of project: 
The association between hypodontia and maternal smoking and alcohol and caffeine consumption during pregnancy
Proposal summary: 

Hypodontia, the absence of six teeth or less, is the most prevalent dentofacial malformation. The prevalence varies within populations, sex, dentitions and tooth-type. The prevalence in Europe is approximately 5%. Excluding third molars, mandibular second premolars and maxillary lateral incisors are most likely to be absent, with a prevalence of 2.5-4% and 2% respectively. The aetiology of hypodontia is multifactorial. Genetic syndromes found to be associated with hypodontia include ectodermal dysplasia, Down’s syndrome and cleft lip/palate. Examples of environmental factors are early childhood trauma to the alveolar process, and chemotherapy and radiotherapy in infancy. Intrauterine exposure of toxins, such as thalidomide, and maternal infections, rubella. Currently, there is limited research on maternal smoking, alcohol and caffeine consumption during pregnancy and its effect on hypodontia. The only study to investigate this was a case-control study in New Zealand with 89 patients. It found strong evidence that consumption of 10 or more cigarettes per day during pregnancy was associated with greater odds of the child having hypodontia (adjusted OR, 4.18; 95% CI, 1.48-11.8; P=0.007) . The conclusion from the paper is vague regarding mechanisms but suggests that oxidative stress from smoking affects foetal neural crest cells, which could explain the causal relationship between smoking and hypodontia. This interesting finding requires replication with a larger sample size, ideally using methods to pinpoint specific intrauterine effects. ALSPAC provides an opportunity to replicate this and use paternal smoking, alcohol and caffeine consumption as negative controls for the causal relationship between hypodontia and maternal smoking during pregnancy.

Impact of research: 
Children who suffer with hypodontia require continuous maintenance of dental treatment throughout their lives from a multidisciplinary team. They can experience extensive orthodontic treatment, prosthetic replacement and possible surgery (from impacted canines, teeth which are unable to erupt in the mouth ). In early adolescence, children can become concerned about their appearance which impacts on their psychological well-being, especially if diagnosed at a late age. Patients with missing teeth may suffer from malocclusion (misalignment of the bite), periodontal (gum) damage, insufficient bone growth in the jaw, reduced chewing ability, inarticulate pronunciation and other problems. If our results indicate that maternal smoking and alcohol consumption influence hypodontia this is likely to have a large dental health and public health impact, if not then it will have added to the knowledge base on hypodontia.
Date proposal received: 
Wednesday, 8 November, 2017
Date proposal approved: 
Tuesday, 5 December, 2017
Keywords: 
Dentistry, Hypodontia- congenitally missing teeth, Statistical methods, Dental

B2996 - Creating a West African BioResource for Nutritional Genetics and Epigenetics - 04/12/2017

B number: 
B2996
Principal applicant name: 
Nicholas Timpson | UoB, IEU (United Kingdom)
Co-applicants: 
Professor Andrew Prentice
Title of project: 
Creating a West African BioResource for Nutritional Genetics and Epigenetics
Proposal summary: 

So far we have created a truly unique resource for sub-Saharan Africa supporting a wide range of robust and innovative study designs providing novel insights into the complexities of nutrition-disease interactions. Recent outputs have appeared in journals covering basic science (PLoSGenetics, Genome Biology, Human Molecular Genetics, Nature Communications, FASEBJ and Scientific Reports, with papers currently under review at Genome Biology and Cell), medicine (EBioMedicine, PLoSMedicine, Lancet, JAMA) and global public health (Lancet Global Health, PNAS) as well as in the core nutrition journals (AJCN, J Nutr). We summarise some of these experimental approaches and the insights they have yielded below. To date these outputs have all been driven by the local MRCG investigators with assistance from expert international collaborators as appropriate to each study. This approach has been very successful but is necessarily constrained by the intellectual bandwidth of the core investigators, the time available and by funding. The resource has ample spare capacity to be used more intensively.

Our challenge now is to capitalise on the existing legacy of the MRC’s, investigators’ and participants’ investment to maximise academic outputs with strong pathways to impact in global health. To achieve this we wish to partner with a large team of investigators based in Bristol around the trio of infrastructure between the Avon Longitudinal Study of Parents and Children (ALSPAC), the Bristol Bioresource Laboratory (BBL) and the MRC Integrative Epidemiology Unit (IEU). Together they have created a world leading system of cohort curation, resource storage and use which is exemplified, inter alia, by the fact that ALSPAC has just celebrated its 1500th publication and remains routinely used (for bioresources and data) by a large and active international collaborator group. We will work with the Bristol teams across a wide range of disciplines (legal and governance, human tissue biobanking, laboratory practices, genotyping and epigenotyping, data archiving and mining, bioinformatics and publicity) to ‘clone and adapt’ their existing procedures in order to professionalise and externalise what we will term the West African BioResource (WABR).

Impact of research: 
MRC Gambia data use.
Date proposal received: 
Wednesday, 15 November, 2017
Date proposal approved: 
Monday, 4 December, 2017
Keywords: 
Epidemiology

B2997 - GDF15 and its role in nausea and vomiting in pregnancy - 04/12/2017

B number: 
B2997
Principal applicant name: 
Nicholas Timpson | UoB, IEU (United Kingdom)
Co-applicants: 
Professor Steve O'Rahilly
Title of project: 
GDF15 and its role in nausea and vomiting in pregnancy.
Proposal summary: 

Based on what is known about the biology of the TGFbeta like molecule GDF15, it has been hypothesised to play a role in the nausea and vomiting or pregnancy. In ~700 samples from the Cambridge Baby Growth study, plasma levels at 15 weeks of pregnancy are significantly associated with vomiting in the second trimester and with anti-emetic use . Indeed, analysis of hyperemesis in Biobank (John Perry) finds nominally significant results of SNPs close to the GDF15 gene

At a recent meeting, evidence was shown illustrating further support for this relationship and as a result, the proposed experiment here aims just to assess the contribution of genetic variation (in mother child) to hyperemesis in ALSPAC index mothers.

All analyses will be carried out by Laura Corbin who is in my group and who is a direct used.

Impact of research: 
We feel that given recent interest in this condition, this work will provide a substantive contribution.
Date proposal received: 
Wednesday, 15 November, 2017
Date proposal approved: 
Monday, 4 December, 2017
Keywords: 
Epidemiology, Bone disorders - arthritis, osteoporosis, Association testing., Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc.

B3007 - Trauma exposure and cardiometabolic health - 04/12/2017

B number: 
B3007
Principal applicant name: 
Abigail Fraser | University of Bristol (UK)
Co-applicants: 
Ms Soraya Safazadeh, Dr Sarah Halligan, Dr Gemma Hammerton, Professor Stan Zammit
Title of project: 
Trauma exposure and cardiometabolic health
Proposal summary: 

Young people who go through potentially traumatic experiences are vulnerable to a range of adverse mental health outcomes. Increasing evidence links trauma exposure and associated mental health problems to increased risk of cardiovascular disease (CVD).

However, there are important limitations to our knowledge in this area. First, most existing research has taken a disorder specific approach (i.e. studied PTSD, psychosis, and depression separately), whereas available evidence shows that traumatic stress underlies a range of mental health difficulties, suggesting that a transdiagnostic approach is appropriate. Second, many existing studies are limited by sample size and retrospective reporting of the traumatic event. Third, we have limited understanding of the factors mediating associations between trauma related psychopathology and CVD. For example, trauma related symptoms of depression may lead to physical inactivity, which in turn increases CVD risk. In addition, inflammation, autonomic nervous system reactivity, endothelial dysfunction, and oxidative stress are all putative biological mechanisms.

The project straddles psychology and epidemiology, working at the interface between mental and physical health.

Impact of research: 
The proposed project is an emergent research area with potential for clinical impact, as individuals exposed to trauma are disproportionately represented in health, social care and criminal justice services. This research will further our understanding of the impact of traumatic events on physical health, and how mental health and inflammation play a role in this relationship. Inflammation is currently a hot topic in the field of psychology, as it could explain links between mental and physical health. The proposed project will test this explanation. Results of the project will be presented at relevant conferences, and there is potential for resulting papers to be published in high impact journals.
Date proposal received: 
Thursday, 30 November, 2017
Date proposal approved: 
Monday, 4 December, 2017
Keywords: 
Epidemiology, Infection, Mental health, Cardiovascular disease, Epigenetics, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Blood pressure, Cardiovascular, Childhood - childcare, childhood adversity, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Hormones - cortisol, IGF, thyroid, Immunity, Metabolic - metabolism, Offspring, Statistical methods, Trauma

B3003 - Emotion recognition in cannabis users - 30/11/2017

B number: 
B3003
Principal applicant name: 
Michelle Taylor | MRC Integrative Epidemiology Unit, University of Bristol (UK)
Co-applicants: 
Prof. Marcus Munafo, Prof Ian Penton-Voak
Title of project: 
Emotion recognition in cannabis users
Proposal summary: 

Cannabis users report increased feelings of friendship, empathy and interpersonal warmth while experiencing the acute effects of cannabis. However, previous studies have reported that cannabis users find it harder to identify other emotions while under the influence of cannabis. Few studies have examined the long-term effects of using cannabis on an individual’s ability to perceive emotion. Additionally, previous studies have not examined differences in emotional perception at different levels of cannabis use.
In a small pilot study of 20 cases (heavy cannabis users) and 20 controls (non-users), we found evidence that cannabis users had a stronger bias to correctly identifying emotions, in particular anger. They were also less likely to incorrectly perceive disgust, fear and surprise. However, due to the small sample size of this study, results are currently underpowered.
We aim to extend this research into the ALSPAC cohort. Using data on cannabis use between the ages of 18 and 21 and emotion recognition data at age 25, we will be able to examine this is a much larger sample that is representative of the young adult population in the UK.

Impact of research: 
Facial expression allows individuals to understand the reactions of their interaction with other people and adjust their future behaviour. Understanding how cannabis users process emotions will allow us to better understand their personal relationships, which could in turn impact on other outcomes such as mental health.
Date proposal received: 
Monday, 27 November, 2017
Date proposal approved: 
Thursday, 30 November, 2017
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Mental health, emotion recognition, Statistical methods, Offspring, Social science

B2998 - Age specific BMI SNP effects SNP effect look up - 29/11/2017

B number: 
B2998
Principal applicant name: 
Nic Timpson | UoB, IEU (UK)
Co-applicants: 
Dr Eleanor Wheeler
Title of project: 
Age specific BMI SNP effects (SNP effect look up)
Proposal summary: 

This is a simple look up request for basic association signals for BMo in ALSPAC by age. This is to help address reviewer comment for a paper being written by Dr Wheeler.

Impact of research: 
Date proposal received: 
Wednesday, 15 November, 2017
Date proposal approved: 
Wednesday, 29 November, 2017
Keywords: 
Genetics, Obesity, GWAS, BMI

B2999 - Developmental trajectories of bone mass and associations with markers of pubertal timing - 29/11/2017

B number: 
B2999
Principal applicant name: 
Ahmed Elhakeem | MRC Integrative Epidemiology Unit at University of Bristol
Co-applicants: 
Professor Debbie Lawlor, Professor Jon Tobias
Title of project: 
Developmental trajectories of bone mass and associations with markers of pubertal timing
Proposal summary: 

The aim f this study is to examine the patterns of bone mass acquisition from age 9 up to age 25 years (based on measures extracted from DXA scans performed on ALSPAC index offspring at (approx.) ages 9, 11, 13, 15, 17 and 25). The study will explore sex differences in the patterns of these developmental bone mass trajectories and examine how these patterns relate to pubertal timing, specifically the age at peak height velocity and genetic markers/risk scores for timing of puberty.

Impact of research: 
Date proposal received: 
Thursday, 16 November, 2017
Date proposal approved: 
Wednesday, 29 November, 2017
Keywords: 
Epidemiology, Bone disorders - arthritis, osteoporosis, Genomics - structural variants, Statistical methods, Bones (and joints), Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Development, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Growth, Metabolic - metabolism, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Puberty, Sex differences

B3000 - The influence of breech presentation on adolescent skeletal health and indicators of skeletal loading - 29/11/2017

B number: 
B3000
Principal applicant name: 
Alex Ireland | Manchester Metropolitan University
Co-applicants: 
Prof Jon Tobias, Prof Debbie Lawlor
Title of project: 
The influence of breech presentation on adolescent skeletal health and indicators of skeletal loading
Proposal summary: 

Skeletal health (bone shape/size/density/mass, and joint shape) is an important determinant of mid-life musculo-skeletal diseases including osteoporosis/fractures and osteoarthritis. Factors acting across the lifecourse from in-utero to older age influence skeletal health and our previous research suggests early-life skeletal loading may be important for healthy skeletal development. For example, we have shown that children who reach motor milestones, e.g. walking, jumping, at older ages than average have smaller, weaker bones and different joint shapes even in adolescence and old age. We postulate that this is due to both delayed early-life leg loading and because late walkers tend to be less active throughout life which also affects skeletal health.
Skeletal growth is quickest during the intrauterine period, when the skeleton is first assembled. However, there is little information on how skeletal loading during intrauterine development influences bone health. Objective assessment of fetal movements are difficult, but fetal position – breech or cephalic – will influence movements with these likely to be lower in breech infants as leg movement is constrained. Our research, and that of others supports this, showing that breech-born babies have smaller bones and different hip shape at birth compared to cephalic-born children. However, it is unclear whether these differences continue into later childhood, and whether they are explained by differences in activity post-birth. The aim of this study is to examine skeletal health in breech and cephalic-born children in adolescence, and to what extent any differences are explained by differences in physical activity and body composition between these two.

Impact of research: 
An understanding of the long-term contributions of prenatal loading to skeletal health would be an important finding. Breech position can be reverted manually (cephalic version), but this is currently only performed to prevent complications at birth. In addition, physiotherapy interventions in pre-term children are effective in improving bone mass accrual, although effects on joint development have not been reported. Therefore prenatal and early life could offer an opportune period to promote long-term skeletal health. This information would also support further investigations to identify key timepoints within the prenatal period where skeletal mechanosensitivity is greatest.
Date proposal received: 
Wednesday, 29 November, 2017
Date proposal approved: 
Wednesday, 29 November, 2017
Keywords: 
Developmental biology, Bone disorders - arthritis, osteoporosis, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Medical imaging, Development, Growth, Mothers - maternal age, menopause, obstetrics, Physical - activity, fitness, function

B3004 - PACE analysis of maternal depression anxiety and life stress during pregnancy and methylation profiles in the children - 04/12/2017

B number: 
B3004
Principal applicant name: 
Charleen Adams | University of Bristol (UK)
Co-applicants: 
Gemma Sharp, Lotte Houtenpen
Title of project: 
PACE analysis of maternal depression, anxiety, and life stress during pregnancy and methylation profiles in the children
Proposal summary: 

Prenatal maternal stressors can affect a child’s later life health (Van den Bergh et al., 2017). Candidate gene studies indicate DNA methylation is a potential underlying mechanism (Nagarajan et al., 2016), but to date no individual locus survived multiple testing correction in epigenome-wide studies (Rijlaarsdam et al., 2016). Thus, we aim to examine the association between prenatal maternal stress (depression, anxiety, and stressful life events) and offspring DNA methylation in a meta-analytical setting (the Pregnancy and Childhood Epigenetics, PACE, Consortium).

Impact of research: 
The results will increase our knowledge about the impact of in utero exposures on child early-life health.
Date proposal received: 
Tuesday, 28 November, 2017
Date proposal approved: 
Wednesday, 29 November, 2017
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Epigenetics, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc.

B2983 - Multivariate genotypephenotype association in the human face - 15/11/2017

B number: 
B2983
Principal applicant name: 
Philipp Mitteroecker | University of Vienna, Dept. of Theoretical Biology (Austria)
Co-applicants: 
Dr. Anne Le Maitre, Dr. Sonja Windhager
Title of project: 
Multivariate genotype–phenotype association in the human face
Proposal summary: 

The human cranium is the most complex skeletal structure in the human body. It houses the brain and sensory organs, the airways as well as the masticatory apparatus. Precise and well-coordinated growth of cranial components thus is an inevitable prerequisite of functional development of the human head. Presumably, different regimes of stabilizing selection have enforced the evolution of mechanisms that protect aspects of cranial development against perturbations. These mechanisms are important for non-pathological cranial development, but at the same time, they may impede orthodontic and surgical treatment. In this project, we want to explore multivariate patterns of genotype–phenotype association in the human face together with the stability of facial development, i.e., we want to explore and quantify the spatial and temporal pattern of auto-regulation during facial development. Our newly developed statistical methods and empirical results can find application in numerous biological and medical contexts, including medical genetics and neonatology, anthropology, and forensics.

Impact of research: 
Date proposal received: 
Friday, 3 November, 2017
Date proposal approved: 
Wednesday, 15 November, 2017
Keywords: 
Anthropology, Human facial shape variation, Epigenetics, Gene mapping, GWAS, Geometric Morphometrics, BMI, Development, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Face - face shape, Growth, Hormones - cortisol, IGF, thyroid, Mothers - maternal age, menopause, obstetrics, Sex differences, Statistical methods

B2984 - Genetic heterogeneity between studies - 15/11/2017

B number: 
B2984
Principal applicant name: 
Neil Davies | University of Bristol
Co-applicants: 
Dr Gib Hemani, Hannah Wilson, Prof George Davey Smith
Title of project: 
Genetic heterogeneity between studies
Proposal summary: 

There is increasing concern that the non-random sampling of participants into major cohort studies may lead to spurious GWAS and Mendelian randomisation results.
The UK Biobank, ALSPAC and the 1958 cohort sampled individuals in different ways. The UK Biobank invited around 9 million individuals to attend a clinic, and around 0.5 million responded. These individuals are not a random sample of those invited to take part, for example they are more educated. Whereas ALSPAC sampled all mothers who gave birth within the Avon area. The 1958 cohort sampled all people born within a specific week in 1958.

This project will investigate whether there are any systematic genetic differences between the participants of the three studies.

Impact of research: 
Understanding the limitations of these large cohort studies is important. By assuming that these studies are representative of the whole population, we are also assuming that any findings (biomarkers, treatments etc) using data from these cohorts will be the same across the whole population. If, however, these cohorts are under-represented in certain ethnic or socioeconomic groups, these under-represented groups could be genetically quite different. If this is the case, the findings that have been proposed based on information from these studies may not work for the entire population. Determining if there are detectable genetic differences between the studies is important to help provide context to findings from the data sets and to help design large cohort studies in the future.
Date proposal received: 
Friday, 3 November, 2017
Date proposal approved: 
Wednesday, 15 November, 2017
Keywords: 
Epidemiology

B2985 - Using Mendelian randomization to verify reverse paradox for the association of birth weight with blood pressure in later life - 15/11/2017

B number: 
B2985
Principal applicant name: 
Neil Davies | University of Bristol
Co-applicants: 
Nic Timpson, Qian Yang
Title of project: 
Using Mendelian randomization to verify 'reverse paradox' for the association of birth weight with blood pressure in later life
Proposal summary: 

Low birth weight has been classified as a risk factor for cardiovascular disease by the World Health Organization (WHO).1 This strategy was supported by many observational studies since 1980s, showing lower birth weight was associated with higher blood pressure in later life.2-4 Some researchers explained this inverse association as a 'reverse paradox', which resulted from an over-adjustment for current weight status.5 A recent study of the 1958 British birth cohort used twin status as an instrumental variable, and reported no effect of birth weight on hypertension.6 Nevertheless, it remains unclear that to what extent the effects of birth weight on blood pressure are mediated by body mass index (BMI) throughout life.

Impact of research: 
Date proposal received: 
Friday, 3 November, 2017
Date proposal approved: 
Wednesday, 15 November, 2017
Keywords: 
Epidemiology

B2987 - Genomic prediction to refine ASD genetic risk model - 15/11/2017

B number: 
B2987
Principal applicant name: 
Pauline Chaste | INSERM U894 (France)
Co-applicants: 
Bernie Devlin
Title of project: 
Genomic prediction to refine ASD genetic risk model
Proposal summary: 

Autism spectrum disorder (ASD) is a complex disorder involving both genetic and environmental contributions to the risk. It appears that heritable genetic factors play a large role in liability at the population level. There are, however, some results that seem at odds with our understanding of ASD genetic risk. For example, there is a low correlation of parents and probands in autistic traits. This deviation could be due to ascertainment in research studies, or it could be due to a lack of fit of the model. Thus an important part of the ASD risk puzzle could be missing.
To form a complete picture of the architecture of genetic risk for ASD, we must understand better the relationship between genetic risk for ASD and autistic traits in the population. We propose to do so here by examining this relationship both in ASD families and in the general population.

Impact of research: 
This study should provide new insight on the continuous risk model for autism spectrum disorder.
Date proposal received: 
Tuesday, 7 November, 2017
Date proposal approved: 
Wednesday, 15 November, 2017
Keywords: 
Genetics, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Developmental disorders - autism, Cognitive impairment, Statistical methods, Cognition - cognitive function, Communication (including non-verbal), Development, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc., Intelligence - memory, Statistical methods

B2988 - DNA methylation as a biomarker of risk of adverse pregnancy outcomes - 15/11/2017

B number: 
B2988
Principal applicant name: 
Matthew Suderman | MRC Integrative Epidemiology Unit
Co-applicants: 
Nancy McBride, Professor Caroline Relton, Professor Debbie Lawlor
Title of project: 
DNA methylation as a biomarker of risk of adverse pregnancy outcomes
Proposal summary: 

The management of reproductive and perinatal care has never been so advanced. However, a high proportion of pregnancies still have adverse outcomes. These can range from hypertensive disorders of pregnancy to preterm or stillbirth.

Gestational diabetes mellitus (GDM) affects between 1 and 14% of pregnant women, depending on the sample and criteria used. Due to overnutrition and underactivity in the developing world, this number is expected to rise. In GDM, there are extensive complications for both mother and offspring. Postnatal complications for the mother include type 2 diabetes, obesity and cardiovascular dysfunction. The offspring of mothers born with GDM have nearly double the risk of being obese and hyperglycaemic, both have been linked to long-term health complications.

Many interventions are in place to reduce the prevalence and severity of GDM. However, there is a need for GDM to be diagnosed earlier during the pregnancy and treated accordingly. DNA methylation is a mechanism by which certain environmental exposures affect gene expression without altering DNA sequence and has been used as a biomarker for diseases including a variety of cancers. In this project, we aim to use longitudinal birth cohorts to investigate the relationship between DNA methylation, GDM and related factors such as body mass index, smoking, maternal age and parity.

We hope that these investigations will improve our understanding of the mechanisms underlying GDM and possibly lead to the development of a tool that uses DNA methylation in pregnant mothers for early detection of GDM. Ultimately, we hope to identify effective strategies for the prevention and management of GDM.

Impact of research: 
We hope that these investigations will improve our understanding of the mechanisms underlying GDM and possibly lead to the development of a tool that uses DNA methylation in pregnant mothers for early detection of GDM. Evidence indicates that early appropriate treatment of GDM leads to significantly fewer perinatal complications (Horvarth, Koch, Jeitler et al., 2010).
Date proposal received: 
Tuesday, 7 November, 2017
Date proposal approved: 
Wednesday, 15 November, 2017
Keywords: 
Epidemiology, Diabetes, Epigenetics, Gestational diabetes mellitus

B2993 - Genome-wide association meta-analysis of internalising problems in childhood and adolescence - 15/11/2017

B number: 
B2993
Principal applicant name: 
Hannah Sallis | MRC Integrative Epidemiology Unit (IEU), University of Bristol (UK)
Co-applicants: 
Prof. Marcus Munafò
Title of project: 
Genome-wide association meta-analysis of internalising problems in childhood and adolescence
Proposal summary: 

Internalising problems are highly prevalent in childhood and classical twin studies have shown that the phenotype is partly heritable. However, no genetic variants have been unambiguously identified to be associated with childhood internalizing problems. It is likely that with increased sample sizes will yield sufficient power to detect genome-wide significant effects of single nucleotide polymorphisms (SNPs). The main aim of the current investigation is to conduct a large-scale genome-wide association meta-analysis of internalising problems in childhood and adolescence by combining data from multiple cohorts.
A GWAS of emotional problems as measured by the SDQ throughout childhood and adolescence will be performed using imputed genome-wide SNP data from the offspring. Summary results will be transferred to the analytical team in Amsterdam who will meta-analyse the ALSPAC data along with several other cohorts from the EAGLE consortium.

Impact of research: 
Date proposal received: 
Friday, 10 November, 2017
Date proposal approved: 
Wednesday, 15 November, 2017
Keywords: 
Genetics, Mental health, GWAS, Childhood - childcare, childhood adversity, Genetics - e.g. epigenetics, mendelian randomisation, UK10K, sequencing, etc.

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