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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B3825 - Parenting and child self-esteem and depression symptoms - 05/07/2021

B number: 
B3825
Principal applicant name: 
Ted Barker | University of Sussex (United Kingdom)
Co-applicants: 
Giulianna Tanner
Title of project: 
Parenting and child self-esteem and depression symptoms
Proposal summary: 

The aim of this study is to analyse the relationship between mothers’ and fathers’ parenting and child depression trajectories, focusing on aspects which have received limited attention in the literature. Past research has examined how parenting behaviour has influenced child wellbeing, highlighting the positive association of parental control, rejection and unsupportiveness with child depression trajectories and low self-esteem (McLeod, Weisz, & Wood, 2007; Yasmin & Hossain, 2014). Conversely, parental warmth (Del Barrio, Holgado-Tello, & Carrasco, 2016) and supportive behaviour (Juang & Silbereisen, 1999) have been identified as protective factors on that may limit the severity of depression symptoms. Nonetheless, the literature on child psychopathologies so far has prevalently focused on mothers’ parenting, or has failed to distinguish between the individual effects of mothers’ and fathers’ parenting on child outcomes (Parent, Forehand, Pomerantz, Peisch, & Seehuus, 2017). This appears to be limiting, as the role of fathers on child outcomes was found to be distinct from that of mothers (Jeynes, 2016; Connell & Goodman, 2002).

Very few papers have looked at the relationship between self-esteem and depression considering both mothers and fathers. As strong evidence has identified low self-esteem as a precursor for depression (Manna, Falgares, Ingoglia, Como, & De Santis, 2016; McClure, 2010; Orth, 2018), we hypothesise it should play an important mediating role between parenting and child depression. In addition, parental depression could be an important environmental factor to consider, as it is related to higher levels of depression in children (Kwong et al., 2019; Natsuaki et al., 2014), whilst a child’s friendships could be considered as a protective factor, since they have been found to be negatively associated with mental health difficulties (Preddy & Fite, 2012).

This study will therefore examine how both mothers’ and fathers’ parenting affect child depression. The relationship between parenting and child depression will be analysed taking into consideration the mediating effects of the child’s self-esteem. We will also examine any moderating effect of maternal and paternal depression, and a potentially protective role of friendships.

Impact of research: 
This research will provide further knowledge on the role that the parental figures might have in the development of children’s mental health, specifically giving more insight into how it might affect self-esteem and depression. In particular, this paper could help better understand the relationship between father variables and child outcomes. This could help psychologists in the future develop more targeted strategies to prevent the development of and treat poor self-esteem and depression in childhood and adolescence.
Date proposal received: 
Monday, 28 June, 2021
Date proposal approved: 
Monday, 5 July, 2021
Keywords: 
Epidemiology, Mental health, Statistical methods, Mothers - maternal age, menopause, obstetrics

B3824 - Multivariate Genetic Study of Impulsivity and Binge Drinking through Late adolescence and Early Adulthood - 05/07/2021

B number: 
B3824
Principal applicant name: 
Wendy Slutske | University of Missouri (United States)
Co-applicants: 
Alex Miller, Ian Gizer
Title of project: 
Multivariate Genetic Study of Impulsivity and Binge Drinking through Late adolescence and Early Adulthood
Proposal summary: 

Binge drinking behaviors in late adolescence and early adulthood have been shown to be important indicators of risk for developing problems with alcohol use and related consequences which may extend beyond early adulthood. Binge drinking behaviors are also thought to be influenced, in part, by impulsive personality traits such that more impulsive adolescents and emerging adults tend to binge drink more heavily, more frequently, and beyond early adulthood. However, the connection between impulsive personality and binge drinking has been clouded to some extent in past research because there is generally not a widely agreed upon “best” way to measure impulsive personality. Additionally, this measurement issue may obscure our ability to detect genetic influences on impulsive personality and binge drinking and their connection across the lifespan. The proposed study seeks to clarify the role that genetic factors might play in this relationship by using results from pre-existing genetic studies of impulsive personality and alcohol use to define genetic risk factors that reflect more succinct traits (e.g., the drive to behave impulsively in response to emotions and rewards, and the inability to stop or control these drives). These re-defined genetic risk factors will then be used to determine the extent to which genetic influences for impulsive personality predict changes in binge drinking across late adolescence and early adulthood in the ALSPAC sample.

Impact of research: 
Results from this study will expand current understanding of dual-systems genetic factors contributing to changes in alcohol use and impulsive personality traits across a critical developmental period, and more broadly, the genetic etiology of alcohol use disorder development. While there is emerging evidence that problematic alcohol use and impulsive personality traits are dynamically related, such that changes in these constructs appear to correlate during important developmental periods and changes in impulsivity and sensation seeking across late adolescence and emerging adulthood are positively associated with individual differences in heavy drinking (Littlefield et al., 2014; Quinn & Harden, 2013), the extent to which overlapping genetic influences for these traits contributes to the correlated longitudinal trajectories of said traits has yet to be examined to the extent proposed by this study. Finally, findings will also represent novel applications of state-of-the-art post-GWAS modeling of genetic data and an assessment of the benefits of these models in informing genetic prediction models of the etiology of problematic alcohol use and alcohol use disorders.
Date proposal received: 
Saturday, 26 June, 2021
Date proposal approved: 
Monday, 5 July, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, GWAS, Statistical methods, Development, Genetic epidemiology, Genetics, Genome wide association study, Psychology - personality, Statistical methods

B3823 - Genetic Covariation Between Alcohol Use Aggression ADHD and Executive Function Across Early Adolescence and Young Adulthood - 02/07/2021

B number: 
B3823
Principal applicant name: 
Wendy Slutske | University of Missouri (United States)
Co-applicants: 
Kellyn Spychala, Ian Gizer
Title of project: 
Genetic Covariation Between Alcohol Use, Aggression, ADHD, and Executive Function Across Early Adolescence and Young Adulthood
Proposal summary: 

The relationship between alcohol use and aggression and its public health consequences have long been established with some suggestions that executive functioning and attention-deficit/ hyperactivity disorder may play a role in this relationship. While it is generally accepted that these traits are similarly influenced by genetics, less is known about the specific genetic factors they share in common, and how this genetic overlap may change over time. The proposed project aims to use advanced genetic tools to identify biological contributions to the genetic overlap between alcohol use, aggression, ADHD, and executive function, to examine changes in their shared genetic influences across adolescence and young adulthood.

Impact of research: 
The contributions of the current proposal include utilization of individual level whole-genome data to examine whether genetic covariation among aggression, alcohol use, executive function, and ADHD changes as a function of age. While the literature has examined changes in heritability of these phenotypes across age, to date the literature has yet to examine whether the genetic covariation between these traits changes across time. The goal of the current project is to begin to address this question. Further, these types of analyses are novel to the literature and could elucidate our understanding of the changes in shared genetic influences between traits providing direction for future mediational analyses when appropriate modeling tools become available.
Date proposal received: 
Thursday, 24 June, 2021
Date proposal approved: 
Friday, 2 July, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, GWAS, Statistical methods, Development, Genetic epidemiology, Genetics, Genome wide association study, Psychology - personality, Statistical methods

B3816 - Association between early infant and young child feeding and BMI Z score trajectory among children under 5 years old - 30/06/2021

B number: 
B3816
Principal applicant name: 
Qianling Zhou | Peking University (China)
Co-applicants: 
Haoyue Chen (Miss.), Xiyao Liu (Miss.), Lulu Wang (Miss.), Meijing An (Miss.), Zhihuan Cai (Miss.)
Title of project: 
Association between early infant and young child feeding and BMI Z score trajectory among children under 5 years old
Proposal summary: 

In recent years, the rate of childhood obesity has risen rapidly in western countries. Systematic review showed that childhood obesity is associated with adult obesity and various adverse health outcomes in adulthood. In fact, overweight and obesity, and the relevant non-communicable diseases are largely preventable. Research has shown that infant and young child feeding is one of the important variables associated with early growth trajectory and later overweight and obesity. A pragmatic challenge of many previous studies is that Body Mass Index ((BMI); an indicator of obesity and overweight) is assessed at one point in time, which did not account for changes in BMI over time. The BMI Z score trajectory overcomes the limitations of static analysis and allows comparisons across ages. However, there are few studies exploring the association between infant feeding and BMI Z score trajectory in the UK. Relevant studies in other countries have different findings on the effects of complementary feeding and duration of breastfeeding on BMI Z score trajectory. It is controversial whether feeding pattern has an effect on BMI among children. No study has been found to explore the independent effect of the feeding pattern (on-demand vs. schedule) on BMI Z score trajectory among children.

Impact of research: 
The finding will help researchers to understand the associations between infant feeding practices and growth. The results will be used to guide professional worker to propagate scientific feeding practices to parents, which will help parents nurture children’s healthy eating behaviors and promote children to grow normally.
Date proposal received: 
Wednesday, 23 June, 2021
Date proposal approved: 
Wednesday, 30 June, 2021
Keywords: 
Social Science, Obesity, Statistical methods, BMI, Breast feeding, Childhood - childcare, childhood adversity, Growth, Nutrition - breast feeding, diet

B3822 - Pubertal Timing Physical Activity and Depression A Prospective Cohort Study - 28/06/2021

B number: 
B3822
Principal applicant name: 
Carol Joinson | University of Bristol (UK)
Co-applicants: 
Dr Jon Heron, Professor Abigail Fraser, Dana Tarif
Title of project: 
Pubertal Timing, Physical Activity and Depression – A Prospective Cohort Study
Proposal summary: 

There is growing global concern about the rise in mental health problems in young people.
Rates of depression are known to increase after puberty, with a robust finding that early puberty in girls is linked to increased depressive symptoms. These findings support the ‘early timing’ hypothesis’, which proposes that early maturing girls find puberty more challenging as they are not yet prepared to cope with the biological, psychological and social changes. However, the relationship between pubertal timing and depression is less clear in boys. Understanding the mechanisms that explain the increase in depression during the
critical period of adolescence is vital to developing effective preventative interventions.
Levels of physical activity during adolescence might play a role in contributing to young people’s risk of depressive symptoms. There is some evidence that higher levels of physical activity are associated with lower levels of depression. Participating in physical activity may provide protection from developing depressive symptoms, for example by increasing self-esteem and improving social support. In adolescent girls there is evidence for a decline in physical activity levels at onset of puberty, particularly in those who develop earlier. In contrast, later maturing boys may have an athletic disadvantage which might discourage involvement in physical activity.
The proposed project will use repeated data on age at onset of puberty, physical activity, and depressive symptoms/depression to examine the role of physical activity as a potential mechanism that could explain the link between pubertal timing and depression in boys and girls in adolescence and young adulthood.

Impact of research: 
The research findings have the potential to advance understanding of the mechanisms that underlie the link between pubertal timing and depression. If physical activity is a mediator of this relationship, there is the potential for the research findings to impact on the development of activity-based interventions in secondary schools to improve mental health and to improve identification of young people who are at risk of developing depression.
Date proposal received: 
Wednesday, 23 June, 2021
Date proposal approved: 
Wednesday, 23 June, 2021
Keywords: 
Epidemiology, Mental health, Statistical methods, Puberty

B3820 - Cannabis tobacco and mental illness isolating their relationship through triangulation of evidence - 23/06/2021

B number: 
B3820
Principal applicant name: 
Hannah Sallis | University of Bristol
Co-applicants: 
Miss Chloe Burke, Dr Gemma Taylor, Dr Tom Freeman, Dr Robyn Wootton, Professor George Davey Smith
Title of project: 
Cannabis, tobacco and mental illness: isolating their relationship through triangulation of evidence
Proposal summary: 

Cannabis and tobacco are two of the most commonly used substances worldwide. A substantial body of evidence documents an association between cannabis use and increased risk of psychotic and affective disorders. Tobacco use has also been associated with increased risk of several psychiatric outcomes. Co-use of cannabis and tobacco is a common practice, comprising concurrent co-use (i.e. use of both products in a pre-defined time-period) and co-administration (i.e. used simultaneously within the same delivery method). The high degree of overlap between these substances, and insufficient measurement in existing research, introduces complexity in accurately assessing how these substances impact on risk of subsequent mental illness. Therefore, it is possible that unmeasured tobacco exposure has confounded observed associations between cannabis and multiple psychiatric outcomes. Furthermore, the potential impact of co-use for mental health is an underexplored area. Studying populations where cannabis and tobacco are typically not administered together (e.g. USA) compared to populations where co-administration is common practice (e.g. Europe), offers an avenue through which to explore this issue. This project will explore the individual and combined roles of cannabis and tobacco in mental illness, through triangulating data from countries with differing cannabis-tobacco co-administration profiles. To further strengthen basis for causal inference, this project will also triangulate evidence across statistical and design-based approaches for studying causal effects.

Impact of research: 
Cannabis is becoming increasingly liberalised as a medicinal and recreational drug. Accurately understanding the potential risks of cannabis use for mental health is crucial to developing evidence-based policies and preventative measures. The predicted impact of this research will be advancing our current understanding of the relationship between cannabis use, tobacco use and mental illness through employing innovative methods and robust approaches to causal inference. The findings from this research are expected to inform international cannabis and tobacco control policies. Integration of findings into policy and practice is being pursued through research group non-academic collaborations with influential panels.
Date proposal received: 
Tuesday, 22 June, 2021
Date proposal approved: 
Wednesday, 23 June, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Mental health, Statistical methods, Mendelian randomisation, Mental health, Substance use

B3821 - OLINK inflammation markesr in G0/G1 - 24/06/2021

B number: 
B3821
Principal applicant name: 
Jean Golding | UOB
Co-applicants: 
Prof Abi Fraser, Dr Kate Northstone, Dr Matt Suderman, Yaz lles Caven, Dr Carol Joinson
Title of project: 
OLINK: inflammation markesr in G0/G1
Proposal summary: 

As part of the large Templeton grant (B3397) investigating funds are available to generate inflammation data from blood samples. This proposal formalises the request for the relevant samples

Impact of research: 
Date proposal received: 
Wednesday, 23 June, 2021
Date proposal approved: 
Wednesday, 23 June, 2021
Keywords: 
Epidemiology, Infection, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc.

B3818 - Epigenome-wide association study of depression and antidepressant use - 05/07/2021

B number: 
B3818
Principal applicant name: 
Doretta Caramaschi | MRC IEU
Co-applicants: 
Alex Kwong, Ms Holly Fraser
Title of project: 
Epigenome-wide association study of depression and antidepressant use
Proposal summary: 

At least 7 million adults in the UK are prescribed antidepressants every year. Antidepressant prescriptions in teenagers are rising. In nearly 50% of people on antidepressants the depression symptoms do not improve after the pharmacological treatment. We will investigate the biological pathways that lead to depression by looking at biomarkers in their blood DNA, as well as molecular markers that antidepressant treatments might leave on blood cells in young adults. We will assess antidepressant use in young adults and potential reasons for stopping the medications, with the ultimate aim to explore the possibility of personalized treatment options.

Impact of research: 
Due to the multi-cohort nature of the project (consortium will have a final N of >20000 participants) and the importance of the research questions (depression and antidepressant use) we expect that we will generate conclusive results that will be relevant to a high number of people in the community as well as health professionals.
Date proposal received: 
Monday, 21 June, 2021
Date proposal approved: 
Wednesday, 23 June, 2021
Keywords: 
Molecular genetics and genomics, Mental health, Microarrays, Epigenetics

B3808 - The association between epigenetic prediction signatures of complex traits and health outcomes in ALSPAC - 22/06/2021

B number: 
B3808
Principal applicant name: 
Ryan Langdon | University of Bristol (United Kingdom)
Co-applicants: 
Chloë Fabbricatore, Matt Suderman
Title of project: 
The association between epigenetic prediction signatures of complex traits and health outcomes in ALSPAC
Proposal summary: 

Modelling complex phenotypes using DNA methylation (DNAm) is becoming increasingly common in Epigenetic Epidemiology. This process often includes the use of weighted DNAm “scores” to differentiate between classes of categorical exposures, estimate continuous exposures and/or predict disease outcomes. The reason DNAm can do this is because it bridges the gap between your biology and your environment; one function of DNAm is that it will work to alter gene expression in response to an environmental stimulus. Accordingly, it can be thought of as a “biosocial archive”.

A recent study found that a DNAm proxy of smoking explained more variance in certain mental and physical health outcomes than someone self-reporting their smoking status. This is important because it highlights that DNAm can either augment or improve on how we define self-report traits such as smoking, and could potentially extend to other traits such as alcohol consumption, BMI and educational attainment. Further, using DNAm either in conjunction with, or instead of self-report, may allow researchers to identify targeted interventions for a variety of disease outcomes.

Accordingly, in this project we will be investigating whether DNAm proxies vs self-report smoking, BMI, alcohol consumption and educational attainment, respectively, explain more variance in cardiovascular, mental health, socioeconomic, clinical, metabolic and addiction outcomes in ALSPAC.

Impact of research: 
Generating evidence to support downstream use (or not) of DNA methylation to improve how epidemiologically-relevant phenotypes are defined
Date proposal received: 
Monday, 21 June, 2021
Date proposal approved: 
Tuesday, 22 June, 2021
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Diabetes, Hypertension, Mental health, Obesity, Respiratory - asthma, Computer simulations/modelling/algorithms, Metabolomics, Microarrays, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Physical - activity, fitness, function, Statistical methods, Blood pressure, BMI, Cardiovascular, Environment - enviromental exposure, pollution, Epigenetics, Metabolic - metabolism, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Microbiome

B3815 - Cholesterol trajectories throughout childhood and associations with growth and carotid intima-media thickeness - 28/06/2021

B number: 
B3815
Principal applicant name: 
Laila J Tata | School of Medicine, University of Nottingham (United Kingdom)
Co-applicants: 
Professor Nadeem Qureshi, Professor Steve Humphries
Title of project: 
Cholesterol trajectories throughout childhood and associations with growth and carotid intima-media thickeness
Proposal summary: 

Cholesterol is a type of fat that is essential for our body to work well. Among its roles, it helps the body make use of hormones and vitamins. Our bodies make cholesterol, but we also get cholesterol from food. When we eat too many foods high in fat we can start to have a build-up of cholesterol in our bodies, especially in our blood vessels. We know that having too much bad cholesterol (called Low-Density Lipoprotein or LDL-cholesterol) in our blood can result in forming a layer that sticks to the inside walls of our blood vessels, making them thinner and sometimes blocking them, which can result heart disease, such as having a heart attack.

We know what levels of LDL-cholesterol are considered too high in adults, but we know very little about what normal and high levels of LDL-cholesterol are in children. We know cholesterol is important for brain development, that cholesterol may go up and down at certain ages in children, but there are very few studies of how cholesterol changes normally throughout childhood and adolescence. We also know little about how young people’s cholesterol is related to their growth and health (for example, weight and blood pressure), or whether it is related to early signs of heart disease in early adulthood.

We will answer these questions using this cohort. The results will be important for the general population and for children who have certain conditions that require medications to lower their cholesterol in childhood.

Impact of research: 
We believe this study will provide important information in characterising cholesterol profiles in childhood and that this information will fill an important evidence gap that will be valuable for many studies of cardiovascular health not only in the UK but internationally. As described in the previous section, in addition to providing standalone valuable information for the general population of children and useful information for predicting future risk of cardiovascular health, this ALSPAC analysis will be used to provide more immediate impact for informing a study on the treatment of FH in childhood. We will assess whether cholesterol trajectories in children with untreated FH are similar to those in the general ALSPAC population, or how they differ. We will also use information from the ALSPAC study to model the risk of early evidence of atherosclerosis in children with FH because there are no available following up children with FH long enough to incorporate childhood and early adulthood. The latter will inform our economic models to estimate the benefits of starting statins at different ages in childhood. By the end of the 5-year project on FH, we aim to provide clearer evidence on what age and LDL-C level children with FH should ideally start statins, based on their clinical risk profile. The impact could be changing or strengthening current clinical guidelines in treatment of FH.
Date proposal received: 
Thursday, 17 June, 2021
Date proposal approved: 
Monday, 21 June, 2021
Keywords: 
Epidemiology, Hypercholesterolaemia, cardiovascular disease, Statistical methods, Cardiovascular

B3810 - Birth order and cord blood DNA methylation - 21/06/2021

B number: 
B3810
Principal applicant name: 
Giulia Mancano | IEU, University of Bristol
Co-applicants: 
Dr Gemma Sharp, Sebastian (Shaobo) Li
Title of project: 
Birth order and cord blood DNA methylation
Proposal summary: 

Birth order has strong correlations with developmental and environmental aspects. Birth order is a presumed factor affecting multiple diseases including leukemia (1, 2, 3), atopy (4), type I diabetes (5), non-Hodgkin lymphoma (6) and synovial sarcoma (7). Moreover, first born subjects have unique in utero characteristics including less sufficient placentation, higher estrogen levels, and lower insulin sensitivity. Birth order might therefore play a role in shaping DNA methylation pattern and influence the initiation of the diseases mentioned above.

1. Dockerty JD, Draper G, Vincent T, Rowan SD, Bunch KJ. Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers. Int J Epidemiol. 2001. doi:10.1093/ije/30.6.1428
2. Hjalgrim LL, Rostgaard K, Hjalgrim H, et al. Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway, and Iceland. J Natl Cancer Inst. 2004. doi:10.1093/jnci/djh287
3. Westergaard T, Andersen PK, Pedersen JB, et al. Birth characteristics, sibling patterns, and acute leukemia risk in childhood: A population-based cohort study. J Natl Cancer Inst. 1997. doi:10.1093/jnci/89.13.939
4. Upchurch S, Harris JM, Cullinan P. Temporal changes in UK birth order and the prevalence of atopy. Allergy Eur J Allergy Clin Immunol. 2010. doi:10.1111/j.1398-9995.2009.02312.x
5. Cardwell CR, Stene LC, Joner G, et al. Birth order and childhood type 1 diabetes risk: A pooled analysis of 31 observational studies. Int J Epidemiol. 2011. doi:10.1093/ije/dyq207
6. Grulich AE, Vajdic CM, Kaldor JM, et al. Birth order, atopy, and risk of non-Hodgkin lymphoma. J Natl Cancer Inst. 2005. doi:10.1093/jnci/dji098
7. Wiemels JL, Wang R, Feng Q, et al. Birth characteristics and risk of early-onset synovial sarcoma. Cancer Epidemiol Biomarkers Prev. April 2020:cebp.0093.2020. doi:10.1158/1055-9965.EPI-20-0093

Impact of research: 
Build evidence to elucidate the effect of birth order on neonatal DNA methylation and investigate its possible implication on system development and disease risk.
Date proposal received: 
Tuesday, 15 June, 2021
Date proposal approved: 
Monday, 21 June, 2021
Keywords: 
Epigenetic Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., EWAS, Birth outcomes, Development, Epigenetics, Offspring

B3809 - Comprehensive Prenatal Smoking Assessment and Newborn Methylation - 21/06/2021

B number: 
B3809
Principal applicant name: 
Giulia Mancano | IEU, University of Bristol
Co-applicants: 
Dr Gemma Sharp, Dr Thanh T. Hoang
Title of project: 
Comprehensive Prenatal Smoking Assessment and Newborn Methylation
Proposal summary: 

The detriment of maternal smoking on offspring is well known while the biological mechanism regulating the relationship are not fully understood. Epigenetic profile has emerged as a potential link between the two. Sustained maternal smoking during pregnancy, here defined as smoking past the first trimester, has been associated with deferentially methylated CpG sites in the offspring (1-6) and a dose-response effect might also be plausible (2, 4, 7).

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. Ladd-Acosta C, Shu C, Lee BK, Gidaya N, Singer A, Schieve LA, et al. Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood. Environmental research. 2016;144(Pt A):139-48.
3. Lee KW, Richmond R, Hu P, French L, Shin J, Bourdon C, et al. Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environ Health Perspect. 2015;123(2):193-9.
4. Markunas CA, Xu Z, Harlid S, Wade PA, Lie RT, Taylor JA, et al. Identification of DNA methylation changes in newborns related to maternal smoking during pregnancy. Environ Health Perspect. 2014;122(10):1147-53.
5. Rzehak P, Saffery R, Reischl E, Covic M, Wahl S, Grote V, et al. Maternal Smoking during Pregnancy and DNA-Methylation in Children at Age 5.5 Years: Epigenome-Wide-Analysis in the European Childhood Obesity Project (CHOP)-Study. PLoS One. 2016;11(5):e0155554.
6. Witt SH, Frank J, Gilles M, Lang M, Treutlein J, Streit F, et al. Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation. BMC Genomics. 2018;19(1):290.
7. 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: 
To expand the portfolio of evidence of the impact of prenatal smoking on offspring DNA-methylation by investigating a series of smoking-related exposures.
Date proposal received: 
Tuesday, 15 June, 2021
Date proposal approved: 
Monday, 21 June, 2021
Keywords: 
Epigenetic Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., EWAS, Epigenetics, Fathers, Smoking

B3799 - Exploratory ML Based Longitudinal Modelling Approaches to Map Genetic-Phenotypic Multi-Trait Predictors of Fibrosis - 28/06/2021

B number: 
B3799
Principal applicant name: 
Nathan Lawless | Boehringer Ingelheim (Germany)
Co-applicants: 
Zhihao Ding, Dr
Title of project: 
Exploratory ML Based Longitudinal Modelling Approaches to Map Genetic-Phenotypic Multi-Trait Predictors of Fibrosis
Proposal summary: 

Global Computational Biology & Digital Sciences (GCBDS) is a department in Boehringer Ingelheim’s Innovation Unit (IU) and is principally engaged in early discovery research programs. In 2020 the IU embarked on a curriculum to more deeply explore healthcare databases and biobank initiatives. The overall objective of the program is to explore advanced analytical methods to harness genomic & phenotypic data in order to better understand causative pathological mechanisms for disease which have the long-term potential to support patients.

Boehringer has a longstanding heritage in a number of unmet areas of medical need we consider our core disease areas; These include cardio-metabolic diseases, central nervous system diseases, immunology, respiratory and oncology as well as fields of active research that are currently covered by Research Beyond Borders (e.g. infectious diseases or regenerative medicines).

As part of BI’s preparatory research, a meta-analysis was undertaken to identify initiatives which focus on longitudinal multi-generational familial analysis in the field of fibrosis research (lung, liver). Two area’s of interest are of high priority (i) developing computational based method development programs focused on accurate and interpretable statistical approaches and (ii) Exploring methods to undertake trans biobank analysis on individuals from diverse ethnic backgrounds, but sharing similar phenotypic traits.

Impact of research: 
As previously outlined, Boehringer has a longstanding heritage in treating patients with a range of heterozygous respiratory diseases often underpinned by fibrosis. In these early exploratory analysis we aim to shed new light on the disease progression underpinning fibrosis and leverage our existing experience to support disease understanding.
Date proposal received: 
Saturday, 19 June, 2021
Date proposal approved: 
Monday, 21 June, 2021
Keywords: 
Bioinformatics, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Allergy, Epilepsy, Gastrointestinal, Hypertension, Incontinence, Infection, Learning difficulty, Mental health, Obesity, Pain, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Respiratory - asthma, Sexually transmitted diseases, chlamydia, gonorrhoea, Developmental disorders - autism, Cancer, Chronic fatigue, Cognitive impairment, Congenital abnormalities, Diabetes, Eating disorders - anorexia, bulimia, Computer simulations/modelling/algorithms, Gene mapping, RNA, Statistical methods, GWAS, Mass spectrometry, Medical imaging, Metabolomics, Microarrays, NMR, Proteomics, Qualitative study, Ageing, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Equipment - MRI, Endocrine - endocrine disrupters, ENT - hearing, Environment - enviromental exposure, pollution, Epigenetics, Expression, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Blood pressure, Immunity, Linkage, Liver function, Mendelian randomisation, Statistical methods, Whole genome sequencing, BMI, Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Cognition - cognitive function, Communication (including non-verbal), Development

B3814 - Polygenic susceptibility in chronic air pollution exposure associated adverse respiratory health in adolescents a meta-analysis - 05/07/2021

B number: 
B3814
Principal applicant name: 
Raquel Granell | MRC Integrative Epidemiology Unit
Co-applicants: 
Dr Tamara Schikowski, Sara Kress, Dr Claudia Wigmann
Title of project: 
Polygenic susceptibility in chronic air pollution exposure associated adverse respiratory health in adolescents: a meta-analysis
Proposal summary: 

Several studies support an association between being exposed to air pollution and having respiratory health problems in adolescence. However, only some of those who are highly exposed to air pollution develop respiratory diseases. Genetics play a role in how an individual respons to air pollution exposure as well as in the probability to develop air pollution induced respiratory health problems. We want to investigate if there is a difference in how air pollution affects our respiratory health, when comparing 'genetic low-risk' and 'genetic high-risk' groups of people.

Impact of research: 
Date proposal received: 
Thursday, 17 June, 2021
Date proposal approved: 
Monday, 21 June, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation)

B3811 - Alcohol Consumption And Hypertensive Disorders Of Pregnancy A Negative Control Analysis In ALSPAC - 14/06/2021

B number: 
B3811
Principal applicant name: 
Luisa Zuccolo | MRC Integrative Epidemiology Unit (United Kingdom)
Co-applicants: 
Miss Florence Martin, Professor Abigail Fraser
Title of project: 
Alcohol Consumption And Hypertensive Disorders Of Pregnancy: A Negative Control Analysis In ALSPAC
Proposal summary: 

Drinking alcohol when pregnant has been shown to be associated with reduced risk of having high blood pressure disorders during pregnancy. However, given that the opposite is true outside of pregnancy, that drinking alcohol is associated with increased blood pressure and risk of stroke and heart attack, the effect in pregnancy may be a result of other factors, not alcohol itself. We aim to use the Avon Longitudinal Study of Parents and Children (ALSPAC) to compare women who drank alcohol during their pregnancy and those who didn't, to see if drinkers were more likely to develop high blood pressure disorders during pregnancy than non-drinkers. We also aim to use information on partner's alcohol use during pregnancy and mum's risk of these disorders, to try and understand if the effect seen in mum is caused by alcohol or whether it is related to other factors shared by mum and her partner. In other words, given that a partner's drinking can't have a physical effect on mum's risk of these disorders, if we see a decreased risk when comparing drinking and non-drinking partner's, we can assume that maybe there are other factors shared by both mum and partner that is causing the reduced risk, not the alcohol itself.

Impact of research: 
Adequately powered estimates of the causal effect of alcohol use in pregnancy on hypertensive disorders of pregnancy
Date proposal received: 
Friday, 11 June, 2021
Date proposal approved: 
Monday, 14 June, 2021
Keywords: 
Epidemiology, Hypertension, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Blood pressure, Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics, Fathers, Mothers - maternal age, menopause, obstetrics

B3812 - Trajectories of problematic cannabis use in adolescence and their association with childhood psychological risk factors - 14/06/2021

B number: 
B3812
Principal applicant name: 
Lindsey Hines | University of Bristol
Co-applicants: 
Rachel Lees, Dr Tom Freeman
Title of project: 
Trajectories of problematic cannabis use in adolescence and their association with childhood psychological risk factors
Proposal summary: 

Cannabis is the most commonly used illicit drug worldwide, with use particularly prevalent in adolescents. The number of under-18’s in treatment for cannabis as a primary problem in the UK in 2019-2020 was 11,136, 78% of all treatment entrants in this age group. Whilst this demonstrates a current clear demand for treatment of cannabis problems, the majority of people with cannabis problems do not seek out professional treatment. Further, current psychosocial treatment options lack data on their long-term efficacy, and there are no approved pharmacological treatments. One approach to tackle the global burden of cannabis use disorder (CUD) is to develop early targeted interventions, directed towards reducing the incidence of CUD. Identifying key variables that are associated with development of cannabis problems could help to ascertain which groups are most at risk. Previous research in adolescent and adult populations indicates that cannabis use profile, mental health problems and other drug use are all associated with increased risk of sustained problems related to cannabis use, compared to those with stable-low risk of cannabis problems. However, these studies either did not investigate childhood risk factors, or only assessed these retrospectively, and did not collect data specifically prior to cannabis initiation. This project aims to identify distinct trajectories of cannabis problems, and assess whether mental health and cognition in childhood (8-10 years old), prior to onset of cannabis use, represent potential modifiable risk factors for likelihood of experiencing problems with cannabis use, in order to inform early interventions to potentially reduce the incidence of cannabis problems.

Impact of research: 
The likely impact of this research will be improving our current understanding of how cannabis problems develop and are sustained over time in adolescence and young adulthood. The research should also give insight into whether potentially modifiable risk factors in earlier childhood could help create targeted interventions to reduce incidence of cannabis problems, thus potentially improving mental health for many young people. We intend to disseminate our findings widely, including as a peer-reviewed publication and at conference presentations.
Date proposal received: 
Friday, 11 June, 2021
Date proposal approved: 
Monday, 14 June, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Statistical methods, Cognition - cognitive function, Mental health Substance use

B3801 - HMOX1 imputation testing and impact on outcomes - 10/06/2021

B number: 
B3801
Principal applicant name: 
Nic Timpson | University of Bristol (United Kingdom)
Co-applicants: 
Fergus Hamilton, Ruth Mitchell
Title of project: 
HMOX1 imputation, testing and impact on outcomes
Proposal summary: 

This PhD proposal aims to look at a gene, the HMOX1 gene, that is critical for managing the breakdown of haemoglobin in humans. Previous studies have shown that this gene is critical for management of infection. In animal studies, loss of function of this gene is associated with much worse outcomes in infection (more likely to die). In humans, there is much more uncertainty about the role of this gene and its importance. It has previously been shown that a small region of DNA in this gene is comprised of a dinucleotide repeat, where the two bases guanine and thymine are repeated. This is called a “GT” repeat. In this region, the DNA code is of variable length between patients, with an average of 31 repeats across the whole population, although some people have as little as 20 repeats, and some as high as 45. In previous small studies, the length of this repeat has altered the amount the gene is switched on and off (gene expression), and some studies have shown this has important impacts on lots of diseases, including in infection. Previous studies have shown those with longer repeats are more likely to be diagnosed with Type 2 diabetes, for example. Importantly, multiple studies in malaria have shown that carriage of the longer repeats is associated with much better outcomes, with a large reduction in severe malaria. However, all of the previous studies (in all clinical diseases) have been performed in small cohorts. In this proposal, we aim to measure this repeat using bioinformatic tools in ALSPAC using whole genome sequencing data. We also then plan to measure this repeat using another methodology, by imputing it from array data. These two methods will be compared to test the accuracy of repeat calling from array data. This will also be used to allow confidence in the imputation method so this can be used in other databases (e.g. UK Biobank). Subsequently, we will then look at the relationship between the repeat length and various clinical and bioinformatic measurements. In particular, we will focus on whether repeat length relates to immunological function (e.g. antibody levels, T-cell function (where measured)), clinical outcomes (both self-reported and healthcare linked), and metabolomic outcomes. Finally, we will also look at the impact of this repeat on the transcriptome, to see if gene expression truly changes with the repeat length. Further work will compare results from ALSPAC with other cohorts e.g. UK Biobank. All participants who have genetic data will be included.

Impact of research: 
The question of HMOX1 repeat length variability and clinical outcome is hotly debated. A previous systematic review identifying links with clinical outcomes has been cited >400 times[2]. However, no biobank scale analysis has ever been performed looking at this locus. It is likely that regardless of the findings, there will be significant clinical interest in whether HMOX1 repeat length variability has impact on clinical outcomes or on the transcriptome in ALSPAC. 2 Exner M, Minar E, Wagner O, et al. The role of heme oxygenase-1 promoter polymorphisms in human disease. Free Radic Biol Med 2004;37:1097–104
Date proposal received: 
Tuesday, 8 June, 2021
Date proposal approved: 
Thursday, 10 June, 2021
Keywords: 
Immunology, Infection, DNA sequencing, Genetic epidemiology, Genetics, Genomics, Immunity, Whole genome sequencing

B3806 - Examining the genetic architecture of depression in and around pregnancy in the ALSPAC study - 07/06/2021

B number: 
B3806
Principal applicant name: 
Alex Kwong | University of Bristol
Co-applicants: 
Ruxin Luo, Dr Rebecca Pearson, Dr Hannah Sallis, Ms Holly Fraser
Title of project: 
Examining the genetic architecture of depression in and around pregnancy in the ALSPAC study
Proposal summary: 

Depression is a common and complex disease, influenced by both genetic and environmental factors, with heritability estimated to be from 31% to 42%. However, a recent genome-wide association study meta-analysing data on 807,553 individuals from three largest GWAS studies identified 102 independent variants and 269 genes associated with depression. This result suggests that depression is a polygenetic trait and enables researchers to use these polygenic risk scores to investigate how genetic liability for depression manifests over the life course.

Depression is more common in women during childbearing age, but it has particular importance during pregnancy and after birth due to additional potential consequences for the child. There are many women worldwide suffering from perinatal depression, and according to a meta-analysis, the prevalence of it ranges from 6.5% to 13% at different time points during pregnancy. Perinatal depression has been reported to be associated with many complications, such as hypertension, preeclampsia, and gestational diabetes for mothers and premature birth, low birth weight, fetal growth restriction for foetuses. Furthermore, some pregnant women with depression are reported to have suicidal ideation and thoughts of harming their child. It is clear that perinatal depression is important for both the mother and the child, and thus it is important to examine its aetiology in order to identify potential treatments and interventions. The role of genetics in perinatal presentation of depression is one particular path that could further enhance our understanding of the disease.

There are many studies on heritability of depression, but few about the genetic architecture of perinatal depression. This study will use the polygenetic risk score based on GWAS study on broad depression and examine the association between greater genetic liability to depression and depression across the perinatal period.

Impact of research: 
Further understanding of the aetiology of depression
Date proposal received: 
Friday, 4 June, 2021
Date proposal approved: 
Monday, 7 June, 2021
Keywords: 
Epidemiology, Mental health, Statistical methods, Genetic epidemiology

B3803 - Inflammation and Health The causes and consequences of GlycA and its role in the inflammatory system - 07/06/2021

B number: 
B3803
Principal applicant name: 
Abigail Fraser | University of Bristol (UK)
Co-applicants: 
Miss Daisy Crick
Title of project: 
Inflammation and Health: The causes and consequences of GlycA and its role in the inflammatory system
Proposal summary: 

Inflammation is known to be associated with adverse non-communicable diseases (NCDs). However, the most commonly used biomarkers in inflammation research (namely C-Reactive Protein and Interleukin-6) are potentially not valid measures of chronic and cumulative inflammation. This is because they respond to short-term, acute inflammatory changes in the body. This therefore limits our knowledge of the true association between chronic inflammation and NCDs, but also limits our understanding of the role certain exposures (such as adverse childhood experiences; ACEs) have on levels of chronic inflammation.
A novel biomarker GlycA may be a more reflective of chronic inflammation because it is not affected by short-term inflammatory changes, given that it is a composite biomarker. Therefore GlycA may be a more valid measure compared to previously used biomarkers. This project aims to use GlycA to investigate the causes and consequences of chronic inflammation more accurately, with a focus on mental health (such as depression). The project will collaborate with the work being done by Debbie Lawlor’s group investigating the association between GlycA and cardiovascular disease.

Impact of research: 
In many Western populations, the lifetime prevalence of NCDs such as mental health disorders is approaching 50%, creating societal, health and economic impacts. However, the pathway of their development is still not fully understood. My research will build on previous literature to understand one of the potential pathways leading to such negative outcomes. We hope to provide evidence that the novel biomarker GlycA is a useful tool for measuring cumulative and chronic inflammation and investigate its application in the relationship with NCDs such as depression.
Date proposal received: 
Thursday, 3 June, 2021
Date proposal approved: 
Monday, 7 June, 2021
Keywords: 
Epidemiology, Mental health, Metabolomics, Childhood - childcare, childhood adversity

B3800 - Body Mass Index trajectories across childhood and young adulthood and risk for disordered eating in young adulthood - 07/06/2021

B number: 
B3800
Principal applicant name: 
Naomi Warne | University of Bristol
Co-applicants: 
Eleanor Wade, Dr Helen Bould, Professor Golam Khandaker, Dr Ben Perry
Title of project: 
Body Mass Index trajectories across childhood and young adulthood and risk for disordered eating in young adulthood.
Proposal summary: 

Disordered eating behaviours (such as fasting, purging, binge-eating and excessive exercise) are common in young adulthood, and have the potential to cause serious long-term harm. Identifying risk factors that precede the onset of disordered eating in young adulthood is important for our understanding of how disordered eating develops. Furthermore, these risk factors may be useful for identifying individuals at high risk of developing disordered eating and for designing effective treatments.
Although diagnosis for an eating disorder often depends on Body Mass Index (BMI) and this can be a barrier for treatment, there is less evidence on whether changes in BMI across childhood and adolescence precede later disordered eating. Previous research using the ALSPAC sample (Perry et al. 2021) has found 5 different BMI trajectories from 1-24 years: stable average, gradually decreasing, puberty-onset minor increase, puberty-onset major increase and persistently high BMI. Compared to those with a stable average BMI, those with a puberty-onset major increase trajectory had higher risk of a depressive episode and depressive symptoms. However it is unclear whether these BMI trajectories are differentially associated with subsequent disordered eating.
This study investigates the associations between BMI trajectories across childhood up to age 24 with disordered eating behaviours at age 24. This study will improve our understanding of how BMI can lead to the development of disordered eating behaviours.

Impact of research: 
This project will lead to a greater understanding of how differences in BMI across childhood and adolescence are associated with disordered eating behaviours in young adulthood.
Date proposal received: 
Tuesday, 1 June, 2021
Date proposal approved: 
Monday, 7 June, 2021
Keywords: 
Epidemiology, Eating disorders - anorexia, bulimia, BMI

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