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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B3891 - Methylome sequencing using nanopore - a pilot analysis - 20/10/2021

B number: 
B3891
Principal applicant name: 
Josine Min | MRC IEU, University of Bristol (United Kingdom)
Co-applicants: 
Professor Jonathan Mill, Professor Caroline Relton, Dr Eilis Hannon
Title of project: 
Methylome sequencing using nanopore - a pilot analysis
Proposal summary: 

A powerful avenue into researching the functional consequences of changes in DNAm levels is to correlate DNA sequence variants such as single nucleotide polymorphism (SNPs) to DNAm levels to find both local and distal (for example on other chromosomes) effects. Having completed the largest genetic study of DNAm worldwide to date (through the Genetics of DNA Methylation Consortium) by scanning 10 million SNPs genome-wide, we have identified 270k SNP-DNAm associations. This was achieved by analysing about 400,000 DNAm sites in blood, which is only 2% of 28 million DNAm sites across the genome. There is a huge potential for improved understanding of DNAm variation between individuals and its influence on health and disease by studying other regulatory regions of the genome. We therefore will use novel sequencing technologies based on long reads with the ability to measure all 28 million sites and to determine both the DNAm level and the genotype at single molecule level.

Impact of research: 
Date proposal received: 
Wednesday, 29 September, 2021
Date proposal approved: 
Thursday, 30 September, 2021
Keywords: 
Epigenetics, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., methylome sequencing using nanopore

B3880 - Using genetics and longitudinal data to disentangle the complex relationship between sleep and mood disorders - 28/09/2021

B number: 
B3880
Principal applicant name: 
Katie Swaden Lewis | Cardiff University (UK)
Co-applicants: 
Prof Frances Rice, Prof Michael O'Donovan, Dr Jon Heron, University of Bristol
Title of project: 
Using genetics and longitudinal data to disentangle the complex relationship between sleep and mood disorders.
Proposal summary: 

Prior research in ALSPAC has shown that sleep problems in adolescence are associated with subsequent depression and anxiety (doi:10.1111/jcpp.13288). However, there is still much we do not understand about the complex relationship between sleep and mental health in young people. First, most genetic studies have been conducted in older adults (aged 40 years or older), with less research examining genetic influences on sleep in young people. Second, sleep problems appear to affect mental health more in some people than others but there is limited research exploring which factors influence these individual differences. This project will examine associations between sleep and depression/anxiety across adolescence and young adulthood and focus on the following areas: (i) whether genetic factors previously associated with sleep problems in adults are also associated with sleep problems in adolescence/young adulthood, and (ii) whether associations between sleep problems and anxiety/depression are influenced by genetic factors. Results from this work will impact our current understanding of the role sleep disturbance plays in the onset and recurrence of mood and anxiety disorders, in addition to informing mental health interventions and treatments.

Impact of research: 
This research will advance our knowledge of the genetic underpinnings of sleep disturbance in young people, and further our understanding of the link between sleep and depression/anxiety. This will help identify which individuals will be at greatest risk of depression/anxiety following sleep disturbance.
Date proposal received: 
Monday, 27 September, 2021
Date proposal approved: 
Tuesday, 28 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Sleep disorders/disturbances (e.g. insomnia, hypersomnia)., Statistical methods, mental health

B3768 - Epidemiological and genomic relationship and pleiotropic mechanisms across complex traits - 28/09/2021

B number: 
B3768
Principal applicant name: 
Hou-Feng Zheng | Westlake Univerisity (China)
Co-applicants: 
Title of project: 
Epidemiological and genomic relationship, and pleiotropic mechanisms across complex traits
Proposal summary: 

Evidence from epidemiological and twin studies has shown that some pairs of disorders, such as between brain disorders, often exhibited shared symptoms and comorbidity. However, there is a paucity of observational data on the correlation of other traits, especially for rheumatic diseases and musculoskeletal conditions. Additionally, it remains unknown whether the nature of co-occurrence of these diseases can contribute to potential etiological overlap or due to ascertainment bias and diagnostic misclassification. Recent advances in genetic methods, including the Mendelian randomization analyses, cross-trait meta-analysis, and transcriptome-wide association study, have enabled us to evaluate the degree of genetic overlap and to find the pleiotropic loci. Accordingly, by using data from the Avon longitudinal study of parents and children, we seek to systematically assess the correlation of different diseases, and how connected they on the genomic and environmental level.

Impact of research: 
The clinical use of genetic data
Date proposal received: 
Thursday, 19 August, 2021
Date proposal approved: 
Tuesday, 28 September, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Bone disorders - arthritis, osteoporosis, Learning difficulty, Mental health, Obesity, Pain, Respiratory - asthma, Speech/language problem, Developmental disorders - autism, Chronic fatigue, Cognitive impairment, Congenital abnormalities, Diabetes, Eczema, Hypertension, Infection, Computer simulations/modelling/algorithms, DNA sequencing, Ageing, Birth outcomes, Environment - enviromental exposure, pollution, Fathers, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Intelligence - memory, Linkage, Mendelian randomisation, Mothers - maternal age, menopause, obstetrics, Blood pressure, Metabolic - metabolism, Offspring, Sex differences, Sleep, Statistical methods, Twins, Whole genome sequencing, BMI, Bones (and joints), Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Dermatology, Endocrine - endocrine disrupters

B3876 - Relative contribution and interaction of genetic susceptibility environment and behaviour for childhood obesity - 08/11/2021

B number: 
B3876
Principal applicant name: 
Jill Pell | Institute of Health and Wellbeing, University of Glasgow (UK)
Co-applicants: 
Ziyi Zhou, Dr Frederick K Ho, Prof. Naveed Sattar, Dr Carlos Celis-Morales, Prof. Nicholas John Timpson
Title of project: 
Relative contribution and interaction of genetic susceptibility, environment, and behaviour for childhood obesity
Proposal summary: 

Obesity is one of the most pressing public health challenges worldwide. It is caused by multifactorial causes and could lead to increased risk of cardiometabolic disease. Although obesity is not as common in children as adults currently, the temporal increase in the prevalence of childhood obesity is greater than that of adulthood obesity in multiple countries. However, current public health measures are mostly focused on adult obesity and may not translate to children.

Obesity and overweight were traditionally regarded as the result of an individual’s unhealthy lifestyle (diet and physical activity), but there is increasing recognition that these interact with many other factors; both upstream environmental factors (social, political, and economic) and individual (genetic, psychosocial and biological) factors. These are likely to impact over the life-course. Exposures to environmental obesogens in-utero and/or in early life might also be important. The interactions between these factors are complex. For example, with global economic growth, the reduction in walkability and green spaces are likely to reduce children’s physical activity level which, in turn, result in childhood obesity. These are also compounded with air pollution which might directly and indirectly (also through physical activity) influence obesity. Even though genetic factors account for 40%-70% of obesity risk, the independent effect of individual loci may not completely explain the pathogenesis of obesity because of gene-environment interaction.

Most studies to date focused on individual risk factors for obesity. However, to identify an effective public health strategy to tackle childhood obesity, this study will investigate the interactions between and relative importance of those factors. Additional, since childhood obesity may not necessarily track into adulthood, this study will also look into factors that could predict persistent obesity from childhood to adulthood, which should be clinically most relevant.

Impact of research: 
Current studies on childhood obesity often lack prospectively collected, serial measurements over infancy and childhood, and are mostly cross-sectional or case-control studies. This could lead to substantial reporting or recall bias. Besides, considering the lack of research around the individual and collective roles of upstream and downstream factors, multidisciplinary and transdisciplinary studies are urgently needed to systematically identify intervention/prevention targets for childhood obesity. Moreover, epidemiological studies on the early-life obesogenic effects of environmental exposures have almost exclusively evaluated the risks of single exposures, except for a few multipollutant studies that included chemicals from three or four different exposure groups. Obesity is recognised as a chronic condition that requires a comprehensive programme of complementary interventions. There has been a shift from simple weight loss interventions to holistic management of obesity-related complications. The findings from this PhD project could inform obesity prevention/interventions from early life, which could provide an important change to manage this important public health issue.
Date proposal received: 
Wednesday, 22 September, 2021
Date proposal approved: 
Tuesday, 28 September, 2021
Keywords: 
Epidemiology, Obesity, Statistical methods, BMI

B3866 - The role of sensory function for academic achievement in gene-environment correlations - 14/10/2021

B number: 
B3866
Principal applicant name: 
Judith Schmitz | Georg-August Univeritaet Goettingen (Germany)
Co-applicants: 
Prof Dr Lars Penke, Dr W. David Hill, Dr Charley Xia, University of Edinburgh
Title of project: 
The role of sensory function for academic achievement in gene-environment correlations
Proposal summary: 

What is it that makes us successful when it comes to education? The fact that human intelligence and educational attainment are partly genetically influenced has been incorrectly interpreted in favour of a genetic determinism. However, genetic and environmental factors are not completely independent from each other. For example, children with a genetic disposition towards higher educational attainment are more likely to enroll in advanced classes and therefore further increase their educational attainment. In this context, it is fundamental to pinpoint the specific genetically-influenced traits that affect likelihood for children to select cognitively stimulating environments. Sensory functions (hearing and vision) in childhood are less explored than personality and motivational traits, but are particularly interesting as they can be modified through appropriate aids. In this project, we aim to investigate the role of hearing and vision in childhood for educational attainment in the course of gene-environment correlations. If parts of the genetic factors associated with intelligence and educational success actually exert their influence via hearing and vision abilities in childhood, these findings contradict the idea of a genetic determinism. Analysing these associations on a longitudinal scale will help to determine time points for early interventions (such as correction of minor hearing and vision impairments). Since children with a lower socioeconomic status show reduced hearing as compared to those with a higher socioeconomic status, disadvantaged children could particularly benefit from interventions, which would result in a reduction of social inequalities.

Impact of research: 
The overarching goal of this project is to provide specific recommendations on the design of intervention studies (i.e. early correction of minor hearing and vision impairments) that aim to strengthen academic achievement. As mentioned above, the strong associations with socioeconomic status suggests that this would reduce the effects of social inequality and have positive effects on neurodevelopment and physical health.
Date proposal received: 
Wednesday, 22 September, 2021
Date proposal approved: 
Tuesday, 28 September, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Developmental disorders - autism, Cognitive impairment, Learning difficulty, Mental health, Speech/language problem, GWAS, Statistical methods, Cognition - cognitive function, Development, ENT - hearing, Environment - enviromental exposure, pollution, Genetic epidemiology, Genome wide association study, Intelligence - memory, Mendelian randomisation, Psychology - personality, Vision

B3881 - Associations between mitochondrial and nuclear DNA variants in human populations - 28/09/2021

B number: 
B3881
Principal applicant name: 
Gavin Hudson | Newcastle Univerisity (United Kingdom)
Co-applicants: 
Dr Mauro Santibanez-Koref
Title of project: 
Associations between mitochondrial and nuclear DNA variants in human populations
Proposal summary: 

Present in nearly all types of human cells, mitochondria generate the majority of our cellular energy and are thus often referred to as the ‘powerhouse of the cell’. In addition, mitochondria play important roles in signalling between cells and cell death (known as apoptosis). Although most of our DNA is within the nucleus (the ‘nuclear genome’ or nDNA), mitochondria contain their own DNA (the ‘mitochondrial genome’ or mtDNA), and human health is dependent upon the coordination of the products of these two genomes.

Genetic variants within mtDNA can cause disease (1) and are also linked to a growing number of age-related complex diseases (2), particularly neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, schizophrenia and multiple sclerosis (3). In addition, there are examples where the progression or severity of mtDNA disease is modulated by nDNA variants (e.g. LHON (4, 5)). Conversely, there is evidence in complex diseases where nuclear susceptibility factors are implicated, that common, inherited, mtDNA variation can influence traits such the age of onset (e.g. Alzheimer’s disease (6) and cardiomyopathy (7)).

More recently, the development of mitochondrial replacement therapy, a technique designed to avoid transmission of defective mitochondria from parents to offspring, sparked discussions on mitochondrial nuclear incompatibilities that would require matching donor and recipient mitochondrial and nuclear backgrounds, and more generally on whether the genetic makeup of healthy individuals reflects such incompatibilities (8).

This raises the question whether specific variant combinations of nuclear and mitochondrial alleles are depleted or enriched in the general population. This can be assessed by comparing their frequencies with the frequencies expected from the frequencies of the corresponding nuclear and the mitochondrial alleles assuming independent segregation. Such associations between variants can reflect mixing of different populations or selection against or in favour of particular variant combinations. Associations between nuclear and mitochondrial variants have been repeatedly reported (9, 10). However, it is unclear to what extent the observations reflect population stratification. This is of particular interest because mitochondrial genetic variants have been extensively used to track migration of populations and ancestry.

The aim of this study is to use the ALSPAC cohort genotyping data to: 1) identify combinations of mitochondrial and nuclear variants that are over or underrepresented in a well-characterised population, 2) ascertain whether under or over representation can be explained by heterogeneity within the population and 3) assess the effects of factors such as age or sex. The results will also provide a reference for studying the role of such combinations in human disease.

Impact of research: 
Based on our preliminary studies in smaller diseased and unselected cohorts, we believe we will be able to detect mitonuclear associations in the ALSPAC cohort. This is also supported by recent studies which have detected co-segregation of mtDNA and nDNA in the population (PMID: 34002094 and 26378221). However, these studies did not assess specific variant combinations or their relevance for disease. Identifying and characterising mitonuclear DNA combinations in the population will improve our understanding of mitochondrial/nuclear interactions at the genetic level, and how common mtDNA variants may contribute to complex disease. References 1. Gorman GS, Chinnery PF, DiMauro S, Hirano M, Koga Y, McFarland R, et al. Mitochondrial diseases. Nature reviews Disease primers. 2016;2:16080. 2. Hudson G, Gomez-Duran A, Wilson IJ, Chinnery PF. Recent mitochondrial DNA mutations increase the risk of developing common late-onset human diseases. PLoS Genet. 2014;10(5):e1004369. 3. Chinnery PF, Gomez-Duran A. Oldies but Goldies mtDNA Population Variants and Neurodegenerative Diseases. Front Neurosci. 2018;12:682. 4. Hudson G, Keers S, Yu-Wai-Man P, Griffiths P, Huoponen K, Savontaus ML, et al. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet. 2005;77(6):1086-91. 5. Pickett SJ, Grady JP, Ng YS, Gorman GS, Schaefer AM, Wilson IJ, et al. Phenotypic heterogeneity in m.3243A>G mitochondrial disease: The role of nuclear factors. Ann Clin Transl Neurol. 2018;5(3):333-45. 6. Andrews SJ, Fulton-Howard B, Patterson C, McFall GP, Gross A, Michaelis EK, et al. Mitonuclear interactions influence Alzheimer's disease risk. Neurobiol Aging. 2020;87:138 e7- e14. 7. McManus MJ, Picard M, Chen HW, De Haas HJ, Potluri P, Leipzig J, et al. Mitochondrial DNA Variation Dictates Expressivity and Progression of Nuclear DNA Mutations Causing Cardiomyopathy. Cell Metab. 2019;29(1):78-90 e5. 8. Yonova-Doing E, Calabrese C, Gomez-Duran A, Schon K, Wei W, Karthikeyan S, et al. An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank. Nat Genet. 2021;53(7):982-93. 9. Sloan DB, Fields PD, Havird JC. Mitonuclear linkage disequilibrium in human populations. Proc Biol Sci. 2015;282(1815). 10. Yamamoto K, Sakaue S, Matsuda K, Murakami Y, Kamatani Y, Ozono K, et al. Genetic and phenotypic landscape of the mitochondrial genome in the Japanese population. Commun Biol. 2020;3(1):104. 11. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559-75. 12. Zheng J, Erzurumluoglu AM, Elsworth BL, Kemp JP, Howe L, Haycock PC, et al. LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics. 2017;33(2):272-9. 13. Liu Y, Zhang L, Xu S, Hu L, Hurst LD, Kong X. Identification of two maternal transmission ratio distortion loci in pedigrees of the Framingham heart study. Sci Rep. 2013;3:2147.
Date proposal received: 
Tuesday, 21 September, 2021
Date proposal approved: 
Tuesday, 28 September, 2021
Keywords: 
Genetics, Bone disorders - arthritis, osteoporosis, GWAS, Statistical methods, Genetics, Genomics, Genome wide association study

B3883 - Data Note-ALSPAC participants and the Bristol Self-Harm Register - 28/09/2021

B number: 
B3883
Principal applicant name: 
Mark Mumme | University of Bristol
Co-applicants: 
Title of project: 
Data Note-ALSPAC participants and the Bristol Self-Harm Register
Proposal summary: 

To describe and cross reference the incidence of self-harm episodes of ALSPAC participants in (i) the Bristol Self-Harm Register collected by the local NHS Trusts, (ii) nationally collected Hospital Episode data from NHS-Digital, (iii) nationally collected Mental Health data from NHS-Digital, and (iv) self-reported in ALSPAC survey responses. This is intended to provide a future resource for researchers.

Impact of research: 
This is intended to provide a future resource for researchers.
Date proposal received: 
Wednesday, 22 September, 2021
Date proposal approved: 
Tuesday, 28 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Data note - descriptive, Cohort studies - attrition, bias, participant engagement, ethics

B3884 - Intergenerational effects of parental substance use on child substance use and mental health outcomes - 28/09/2021

B number: 
B3884
Principal applicant name: 
Hannah Sallis | MRC IEU (United Kingdom)
Co-applicants: 
Prof. Marcus Munafo, Dr Gemma Sharp, Dr Kayleigh Easey
Title of project: 
Intergenerational effects of parental substance use on child substance use and mental health outcomes
Proposal summary: 

This project aims to investigate the effect of parental substance use (smoking, alcohol and coffee consumption) both during and after pregnancy on offspring outcomes and the mechanisms via which these effects act. We will initially look at how parental substance use is associated with offspring substance use as a proof of concept. Once the triangulation approach has been validated using offspring substance use as an outcome, we will use the same approach to investigate the association between parental substance use and offspring mental health (including depression and anxiety).

Impact of research: 
Date proposal received: 
Thursday, 23 September, 2021
Date proposal approved: 
Tuesday, 28 September, 2021
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Childhood - childcare, childhood adversity, Environment - enviromental exposure, pollution, Genetic epidemiology, Mendelian randomisation, Mothers - maternal age, menopause, obstetrics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3885 - Unraveling the co-morbidities of mental ill-health - 28/09/2021

B number: 
B3885
Principal applicant name: 
Jorien Treur | Amsterdam UMC, location AMC, University of Amsterdam
Co-applicants: 
Professor Marcus Munafò
Title of project: 
Unraveling the co-morbidities of mental ill-health
Proposal summary: 

Serious mental illnesses (depressive disorder, bipolar disoder, psychotic disorder) are among the leading causes of disability. On top of the burden that mental illness itself poses, individuals affected by it are often also at higher odds of substance use (smoking, alcohol, cannabis) and cardiovascular disease. Together, these so-called co-morbidities of mental illness drive the low life expectancy in individuals with mental illness compared to the general population. It is unclear however, what the causal nature is of these relationships. It may be that symptoms of mental illness increase the risk of substance use and cardiovascular disease, but there is also evidence that these co-morbidities can increase the risk of developing mental ill-health. In this project we strive to elucidate the causal nature of the relationship between mental illness and its co-morbidities, by investigating how symptoms of mental illness and (precursors of) co-morbidities develop and associate to each other from early adolescence up to early adulthood.

Impact of research: 
Date proposal received: 
Friday, 24 September, 2021
Date proposal approved: 
Tuesday, 28 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Cognitive impairment, Diabetes, Hypertension, Mental health, Obesity, Computer simulations/modelling/algorithms, Blood pressure, BMI, Cardiovascular, Cognition - cognitive function, Intelligence - memory, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Physical - activity, fitness, function

B3882 - Treatment for Childrens Disruptive Behaviour Understanding parent-child relationships as mechanisms of change - 28/09/2021

B number: 
B3882
Principal applicant name: 
Jon Heron | CAMH (Centre for Academic Mental Health) (United Kingdom)
Co-applicants: 
Emily Midouhas, Dr Bonamy Oliver
Title of project: 
Treatment for Children’s Disruptive Behaviour: Understanding parent-child relationships as mechanisms of change
Proposal summary: 

One in six school-aged children now have a probable mental health disorder -- up from one in nine three years ago (NHS digital, 2020). Services for children and young people’s mental health are stretched more than ever before, such that maximising resources is a key priority (Lennon, 2021). The effectiveness of mental-health interventions can be optimised by enhancing our understanding of the mechanisms of change – that is, how an intervention translates into events that lead to improved outcomes (Kazdin, 2007). Parent and child behaviours are primary intervention targets for children’s mental health (WHO, 2009), yet little is known about their assumed mechanistic role, that is, how parent-child dynamics change as a function of, or during intervention. We aim to address this gap, with specific focus on children’s disruptive behaviour as one of the most common reasons for children to receive mental-health services (Achenbach & Edelbrock, 1987; Hinshaw & Lee, 2003).

Impact of research: 
As described above, the ALSPAC work-package forms part of a wider plan of work with a view to inform intervention use for high-risk individuals and understand mechanism of change. We anticipate further intensive data collection (EMA) within a clinical setting which is in-part influenced by ALSPAC findings but not involving ALSPAC participants.
Date proposal received: 
Tuesday, 21 September, 2021
Date proposal approved: 
Tuesday, 28 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition

B3886 - Gambling data collection 30 - 30/09/2021

B number: 
B3886
Principal applicant name: 
Agnes Nairn | School of Management, UoB (UK)
Co-applicants: 
Sharon Collard, Emeritus Professor Alan Emond, Dr Kate Northstone
Title of project: 
Gambling data collection @ 30
Proposal summary: 

This proposal is to obtain funding for a repeat of the gambling measures that have previously been obtained from G1 at 17, 20, 24 and during lockdown.

Impact of research: 
This data collection will enable a wide range of analyses to be undertaken, potentially leading to policy implicaitons.
Date proposal received: 
Monday, 27 September, 2021
Date proposal approved: 
Monday, 27 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Gambling

B3875 - Food frequency questionnaire validation study - 14/10/2021

B number: 
B3875
Principal applicant name: 
Caroline Taylor | Centre for Academic Child Health, Bristol Medical School, University of Bristol (UK)
Co-applicants: 
Dr Pauline Emmett, Professor Deborah Lycett, Professor Petra Wark, Dr Kate Northstone
Title of project: 
Food frequency questionnaire validation study
Proposal summary: 

From the start ALSPAC has included data collections on diet. The first collection was in the mothers during their pregnancy, and it's been repeated three other times with them. We've also got a wealth of information on the diets of the children from birth into teenage years. This has been an incredibly rich source of data for us on changing patterns on diet during childhood and is still on constant use today, mainly to study the effects of diet in pregnancy and in childhood on markers of health in later years. This type of long-term data on diet is very unusual in the UK so we are fortunate to have this in ALSPAC.

It's been some time since we've able to collect new information on diet in ALSPAC in the children, but we have an opportunity to do this in some upcoming questionnaires. This will add to our existing long-term data and add greatly to the potential for future scientific work linking diet and health.

As previously we are using a method called a 'food frequency questionnaire' (FFQ) in which participants are asked how often they usually eat particular foods. The FFQ is very similar to that used before in ALSPAC, but we have updated it for changes in the types of food people eat nowadays. In order to sure that the FFQ is correctly reflecting what participants actually eat, we need to do an additional 'validation' study in which we ask some of the participants to record their diet in another way.

For this validation study, we'll be asking some of the participants who fill in the FFQ to access an electronic platform on their smartphones or other device to record one day's food and drink intake in detail (food diary). We'll then ask them to repeat this twice at monthly intervals (so on three separate days in all). We can then compare the two ways and see how well the FFQ is performing against the electronic food diary and whether we get similar data from the two methods. If they are similar, we have can confidence in the data collected from the FFQ and can use it state this in our scientific publications so that others will know we have accurate data.

Impact of research: 
Evidence of validation of dietary data collection tools is now considered essential. We would find it very difficult to get publications accepted from a fresh FFQ data collection without evidence of validation of the tool.
Date proposal received: 
Thursday, 23 September, 2021
Date proposal approved: 
Friday, 24 September, 2021
Keywords: 
Epidemiology, Any outcome associated with diet, Quantitative study - diet, Nutrition - breast feeding, diet

B3873 - Linking Longitudinal Changes in Structural and Functional Connectivity to Persistence of Psychotic Experiences - 23/09/2021

B number: 
B3873
Principal applicant name: 
Sarah Morgan | University of Cambridge
Co-applicants: 
Isaac Sebenius, Edward Bullmore, Kate Merrit, Anthony David
Title of project: 
Linking Longitudinal Changes in Structural and Functional Connectivity to Persistence of Psychotic Experiences
Proposal summary: 

This project will use longitudinal neuroimaging to study the network features of structural and functional connectivity that characterize subclinical psychotic experiences (PEs) and their development over time. Previous work with the ALSPAC cohort has shown that compared to healthy controls, subjects with a history of PEs show schizophrenia-like topological changes in structural connectivity (Drakesmith et al. 2015). Moreover, the presence of PEs has been associated with mild changes in frontoparietal network configuration during a working memory task (Fonville et al. 2015).

Extending this prior work, this study will examine how changes in connectivity over time correspond with the persistence of psychotic experiences. We hypothesize that subjects with PEs that persist will show increasingly divergent connectivity phenotypes from healthy controls, while people with transient PEs will show evidence of ‘recovery’ towards the phenotype of people with no history of PEs. We will then use machine learning to integrate multimodal connectivity data and predict PE trajectories. Finally, we will compare our results to those identified as showing case/control differences in clinical populations to bridge the gap in our understanding of the connectivity signatures of PEs and fully-fledged psychotic disorders.

Impact of research: 
We believe that this work will lead to a greater understanding of the brain connectivity signatures of psychotic experiences as well as the biological patterns underlying them. From an academic perspective, we believe that this work will result in the publication of one or more articles in a high-level academic journals.
Date proposal received: 
Wednesday, 8 September, 2021
Date proposal approved: 
Thursday, 23 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Cognition - cognitive function, Genetics, Statistical methods, Psychosis, machine learning, neuroimaging

B3874 - Biodiversity inflammation and aversive bodily symptoms - 08/11/2021

B number: 
B3874
Principal applicant name: 
Abby Tabor | University of the West of England (United Kingdom)
Co-applicants: 
Dr Ann Smith
Title of project: 
Biodiversity, inflammation and aversive bodily symptoms
Proposal summary: 

It is increasingly realised that urban environments constitute complex ecosystems, from microscopic organisms to social networks. As the principal human habitat, the design of our urban environments has the capacity to determine the health of the populace, across the lifespan. Over the past 150 years, health in the urban environment has largely been determined by pathogen control and automation; consequently, health and safety in the city has come to reflect sanitation and efficiency. Through design we have sought to reduce our exposures to potential stressors, from the cleanliness of our homes to highly prescriptive civic spaces. Although proving vital to the mitigation of many communicable diseases and physical dangers, an inadvertent side-effect of such urban environmental control is an exponential rise in non-communicable diseases (NCDs), which now account for 80% of years lived with disability globally. Although people are living longer, they are not necessarily living better. This suggests that while our cities prioritise safety, they do so at the expense of other health outcomes and human wellbeing. Specific to this project, we will consider the link between environmental exposures (biodiversity, green space), inflammation, and persistent symptoms.

This project will investigate the relationship between inflammatory biomarkers, geospatial characteristics, specifically biodiversity and longitudinal health outcomes (symptoms of non-communicable diseases including pain and fatigue). It will first consider the relationship between the levels of inflammatory biomarkers and geospatial characteristics of one's environment (biodiversity index). Second, it will consider the relationship between inflammatory biomarkers and the prevalence of pain and fatigue symptom reporting. Third, it will investigate the potential influence of geospatial characteristics (biodiversity index) on the relationship between inflammatory biomarkers and health symptom reports (pain, fatigue, breathlessness).

Impact of research: 
This research aims to address a gap in the literature, which considers the influence of one's environmental exposures on health outcomes, specifically pain and fatigue. These symptoms, indeed, disease processes in their own right, constitute enormous individual and population level burden, to which there must be an appropriate response. One approach to this is creating environments that in the public interest reduce the prevalence of such cases. This research looks to consider biodiversity as a key method of intervention, relevant to the furnishing of one's immune system.
Date proposal received: 
Wednesday, 8 September, 2021
Date proposal approved: 
Tuesday, 21 September, 2021
Keywords: 
Clinical research/clinical practice, Chronic fatigue, Cell culture

B3844 - MR-PREG Consortium 26-07-2021 - 103144 - 20/09/2021

B number: 
B3844
Principal applicant name: 
Amy Taylor | University of Bristol (United Kingdom)
Co-applicants: 
Carolina Borges, Deborah Lawlor, Alice Carter, Marwa Al Arab, Nancy Mcbride, Ana Luiza Soares, Qian Yang, Alba Fernandez-Sanles, Fanny Kilpi
Title of project: 
MR-PREG Consortium (26-07-2021 - 10:31:44)
Proposal summary: 

ALSPAC contributes to a group of studies called MR-PREG which aims to investigate the impact of maternal exposures during pregnancy (such as BMI, smoking, blood pressure) on pregnancy complications, perinatal outcomes and later offspring outcomes. MR-PREG uses genetic data to explore whether associations between maternal exposures and these outcomes are likely to be causal.

Impact of research: 
There are already several papers in progress from the initial MR-PREG analyses. This work will be important for identifying the impact of maternal exposures during pregnancy and possible targets for intervention (e.g. healthy BMI ranges for pregnant women to prevent preterm birth).
Date proposal received: 
Monday, 6 September, 2021
Date proposal approved: 
Monday, 20 September, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., GWAS, Mothers - maternal age, menopause, obstetrics

B3865 - Global Lung Function Initiative Exhaled Nitric Oxide FENO Data Request - 20/09/2021

B number: 
B3865
Principal applicant name: 
Raquel Granell | MRC Integrative Epidemiology Unit (IEU) (United Kingdom)
Co-applicants: 
Prof Steve Turner, Dr Sadia Haider, Dr Cole Bowerman, Dr Sanja Stanojevic
Title of project: 
Global Lung Function Initiative Exhaled Nitric Oxide (FENO) Data Request
Proposal summary: 

The Global Lung Function Initiative (GLI) has collected measures of respiratory function from researchers and health care professionals from around the world and has produced reference equations for:

-Spirometry (respiratory testing) which take into account age, sex, height and race or ethnic origin;
-The Transfer Factor for Carbon Monoxide (TLCO) in the Caucasian population;
-Lung Volumes

The ERS has now approved a GLI Task Force for developing GLI reference equations for exhaled nitric oxide (FENO).

These reference equations allow studies to compare their values againts 'normal' values to aid diagnosis.

For more information about the FENO Task Force or to keep up to date with the GLI activities, you can visit the GLI website http://www.lungfunction.org/.

Impact of research: 
The equations will be published and made available to all clinicians and researchers for future studies; This publication will be referenced in most future papers involving analyses with FENO data. The ERS initiative may be newsworthy and suitable for any ALSPAC participant bulletin/website.
Date proposal received: 
Friday, 17 September, 2021
Date proposal approved: 
Monday, 20 September, 2021
Keywords: 
Epidemiology, Respiratory - asthma, Statistical methods, Statistical methods

B3872 - Genome wide association study of progression from impaired fasting glucose to type 2 diabetes - 20/09/2021

B number: 
B3872
Principal applicant name: 
April Hartley | Integrative Epidemiology Unit (UK)
Co-applicants: 
Professor Kate Tilling, Professor George Davey Smith, Dr Venexia Walker
Title of project: 
Genome wide association study of progression from impaired fasting glucose to type 2 diabetes
Proposal summary: 

Pre-diabetes is a condition where blood glucose levels are elevated above normal, but below the threshold to be defined as type 2 diabetes. It is estimated that 70% of those meeting the criteria for pre-diabetes will eventually progress to type 2 diabetes, which is a chronic, incurable condition associated with various other comorbidities. It is therefore important to understand why some individuals progress from pre-diabetes to type 2 diabetes, so that we can develop interventions to stop this happening. We therefore aim to identify the genetic basis for why some individuals progress from pre-diabetes to type 2 diabetes.

Impact of research: 
The ALSPAC data will contribute to a larger GWAS meta-analysis which will hopefully identify genes involved in progression from pre-diabetes to type 2 diabetes. The resulting summary statistics will also be used for two-sample Mendelian randomization analyses to identify non-genetic risk factors. Identifying risk factors for progression from pre-diabetes to diabetes may aid the development of interventions to prevent diabetes onset in those at high risk.
Date proposal received: 
Tuesday, 7 September, 2021
Date proposal approved: 
Monday, 20 September, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Diabetes, GWAS, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Genetic epidemiology, Genetics, Genomics, Genome wide association study, Mendelian randomisation, Metabolic - metabolism, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Statistical methods

B3871 - Identifying clusters of LongCOVID symptoms - 27/09/2021

B number: 
B3871
Principal applicant name: 
Alex Kwong | IEU / PHS
Co-applicants: 
Renin Toms, Professor Nic Timpson, Dr Kate Northstone
Title of project: 
Identifying clusters of LongCOVID symptoms
Proposal summary: 

This project will identify if people with longCOVID share specific symptoms or clusters of specific symptoms. Using the intense data on symptoms collected in ALSPAC, we will identify if people with longCOVID share a specific set of symptoms and how this varies by time. Results will be pooled with similar cohorts and meta-analysed.

Impact of research: 
Date proposal received: 
Tuesday, 7 September, 2021
Date proposal approved: 
Monday, 20 September, 2021
Keywords: 
Immunology

B3877 - Immuno-Metabolic Predictors of Anhedonic Depression and Treatment Response The IMPACT Programme - 16/09/2021

B number: 
B3877
Principal applicant name: 
Golam Khandaker | University of Bristol - MRC IEU (UK)
Co-applicants: 
Title of project: 
Immuno-Metabolic Predictors of Anhedonic Depression and Treatment Response: The IMPACT Programme
Proposal summary: 

The current work looks to examine the underpinnings of anhedonic depression - i.e. depression associated with an inability to feel pleasure. This is an important group and little is know about the factors that characterise and are important for this outcome. The work will use detailed questionnaires to examine the likely presence or absence of this presentation in ALSPAC participants and there will be extremely detailed followup of a sub-set of participants likely to have this condition. This work will be in parallel with that in a study called NESDA in The Netherlands - providing important replication and sample size.

Impact of research: 
Discovery science re. this presentation with likely information re. augmented therapeutic strategies.
Date proposal received: 
Sunday, 12 September, 2021
Date proposal approved: 
Thursday, 16 September, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Questionnaires, imaging (MRI), biosamples, possible randomised sub study intervention allocation. , Psychiatry, Imaging, Trial, Experimental Medicine

B3868 - Investigating oscillating DNA methylation signals to provide insights into biological rhythmicity - 23/09/2021

B number: 
B3868
Principal applicant name: 
Rebecca Richmond | University of Bristol (United Kingdom)
Co-applicants: 
Dr Matthew Suderman, Prof George Davey Smith, Prof Caroline Relton, Dr Paul Yousefi, Mr George Richenberg
Title of project: 
Investigating oscillating DNA methylation signals to provide insights into biological rhythmicity
Proposal summary: 

Cytosine modifications to DNA (such as DNA methylation) have been found to display temporal rhythms. This temporal dimension of epigenetics, coined “chrono-epigenetics”, may have been previously overlooked. In particular, the timing of sample collection may introduce randomness into epigenetic data and may serve as a potentially important correction factor in epigenetic studies. Furthermore, the oscillating nature of cytosines has been suggested to underlie biological rhythmicity, ageing processes and the development of complex diseases such as cancer.

Impact of research: 
Identification of oscillating DNA methylation signals may provide insights into biological rhythmicity, ageing processes and the development of complex diseases. In addition, the use of oscillating DNA methylation sites for predicting the time of sample collection could be particularly useful where this information has not been recorded, and any discordance between predicted and actual collection time of the samples could indicate temporal or circadian misalignment of the participants.
Date proposal received: 
Thursday, 2 September, 2021
Date proposal approved: 
Thursday, 16 September, 2021
Keywords: 
Bioinformatics, Cancer, Microarrays, Statistical methods, Ageing, Biological samples -e.g. blood, cell lines, saliva, etc., Epigenetics, Statistical methods

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