D2K, PEALS, Newcastle University

1958 Birth Cohort: METADAC project approvals

Project Title Plain Language Summary Keywords Applicant Meeting Date
Affiliation Decision Letter
Co-Applicants (Data-Users) Final Approval
Funders  
Genetic susceptibility for health and illness: Collaborative Genetic associations and gene-environment interaction analyses Lifestyle factors affect the effects of genetic factors on the patterns of growth and development, and how those translate into a future risk of diseases. There is great interest in establishing related gene-environment interactions and how these operate across the life-course. In this large-scale collaborative genetic epidemiological project, we propose to use information collected from the 1958 British birth cohort to investigate genetic influences, gene-environment interactions and life-course influences affecting patterns of growth, health and diseases risk. This work is important not only in helping us to understand how genes affect health and disease, but also in giving a better understanding on how by making changes to our lifestyles we can attenuate negative effects caused by possible genetic susceptibilities. Growth, health, cardiovascular disease, diabetes, metabolic risk markers, gene-environment interaction, genetic association HYPPONEN, Elina (Prof) 02/06/2015
University of South Australia from 2015 (also, UCL Institute of Child Health. 23-Jun-15
POWER, Christine (Prof) 30-Sep-15
Mason Memorial Foundation; NHMRC
Genetic associations and gene-environment interactions affecting cognition, behaviour and mental health: Collaborative analyses Genetic factors affect our behaviour, cognitive ability and mental health, and there is evidence to suggest that lifestyle factors can modify related influences. In this large-scale collaborative genetic epidemiological project, we propose to use information collected from the 1958 British birth cohort to investigate genetic influences and gene-environment interactions affecting behaviour, cognition, and mental health. This work is important not only in helping us to understand how genes affect our behaviour and health, but also in giving a better understanding on how we can attenuate possible negative effects caused by genetic susceptibilities by making changes to our lifestyles. Cognition, behaviour, mental health, gene-environment interaction, genetic association HYPPONEN, Elina (Prof) 02/06/2015
University of South Australia from 2015 (also, UCL Institute of Child Health. 30-Sep-15
POWER, Christine (Prof) 30-Sep-15
Mason Memorial Foundation; NHMRC
Genetic Studies of Methylation Genes and Cognitive Phenotypes Mutations within genes encoding methylation related proteins are known to cause or predispose individuals to developing brain diseases including familial forms of dementia and neurodevelopmental phenotypes. Common genetic variants within such genes have also been associated with differences in cognitive ability.  We are currently using the Oxford Project to Investigate Memory and Ageing cohort to explore genetic variation with cognitive performance and biochemical measures.
We want to conduct replication/follow-up studies using the NCDS datasets. Access to NCDS data is being sought for the: special License Biomedical Data set; sweep 8 cognitive assessments and health related variables; the GWAS resource. We wish to link these datasets together with the aim to explore genotype, cognitive performance and other factors which have the potential to affect health status for example, biochemical measures, physical activity; general health and diet; medication use and mental health measures.
Methylation, genes, cognition KNIGHT, Helen, Dr 13/07/2015
University of Nottingham 29-Jul-15
FLITTON, Miles, Mr 29-Jul-15
n/a
Exome Sequencing in Sudden Infant Death Syndrome Sudden Infant Death Syndrome (SIDS) or ‘cot death’ is the sudden death of an infant under 12-months old which remains unexplained after thorough testing. It is a leading cause of infant death in the developed world; affecting 1 in 2500 live births in the UK. Previous research on small numbers of SIDS cases has found heart-related genes being affected in up to 15% of cases. This project aims to assess the role of inherited heart conditions in SIDS by studying genetic samples from over 400 SIDS cases, the largest group ever brought together. Exome sequencing will be used to identify known and new genes that may be responsible for SIDS. The study will determine the role of inherited risk in SIDS and form the basis of guidelines for management of SIDS. This will aid earlier identification of inherited heart conditions and aim to prevent further sudden deaths in the family. Exome sequencing, sudden infant death syndrome, molecular autopsy SIMPSON, Prof Michael 13/07/2015
Kings College London 28-Jul-15
Dr Dr Elijah BEHR, Dr Leonie WONG 28-Jul-15
British Heart Foundation
The genetics of obesity We are interested in how genes influence human body weight. We are currently looking at severely obese individuals and comparing them to non-obese controls to find genetic variants that increase one’s risk of being obese. We are currently using controls that are not obese, but are diseased. The 1958 exome-sequencing data will enable us to check variants we find are specific to obesity and not due to the disease in controls. We will also be able to explore in more detail the effect of variants on BMI in the population using the exome-sequence and exome-chip genotype data available in the 1958 samples. obesity, genetics BARROSO, Dr Inês 13/07/2015
Wellcome Trust Sanger Institute 28-Jul-15
Eleanor WHEELER, Gaëlle MARENNE 28-Jul-15
Wellcome Trust Sanger Institute (core funding)
Extension of data approval to investigate genetic copy number variation on common complex anthropometric traits, namely height, body mass index (BMI), weight and waist-hip ratio As well as changes in the sequence of our DNA, genetic variation between individuals can occur as changes in the number of copies we have of certain stretches of DNA, for example, genes. Whilst genotyping array experiments primarily capture sequence variation, it is possible to use the raw data from these experiments to measure “copy number variation” (CNV). In this project, we will utilise this raw data to measure CNV in British 1958 Birth Cohort participants. We will test for association of CNV with the following related traits: height, weight, body mass index (BMI) and waist-hip ratio (WHR). The results from our analysis will be combined with results from other cohorts in the GIANT consortium in a single large experiment. BMI is a risk factor for multiple chronic diseases and of major public health importance. The results of this will provide important insights into the biological processes underlying height, weight, BMI and WHR. Copy number, height, weight, waisthip, BMI, GiANT consortium Tobin & Wain 07/09/2015
University of Leicester 25-Sep-15
Louise WAIN, Martin TOBIN 17-Sep-15
unknown
Identifying the impact of mental disorder risk alleles on childhood neurodevelopment Mental disorders are common, and contribute more to the global burden of disease than any other type of disorder. Most mental disorders are thought to have their origins at least in part in childhood, although the characteristics in childhood may not be the same as the adult disorder. Mental disorders are heritable and studies have started to identify specific genetic variants that are associated with these. Genome-wide association studies involving large numbers of patients and controls can be used to provide an estimate of individuals’ genetic risk profiles for different mental disorders. We aim to identify childhood neurodevelopmental precursors in the general population that are associated with the genetic risk for adult mental disorders. We will then track longitudinally these risk effects using additional data on mental health and functional outcomes (ill health and pervasive psychosocial difficulties) collected later in development. Our main objective is to identify early origins of mental disorders in order to inform programmes that aim to prevent and target mental disorders as early as possible. Childhood, neurodevelopmental, genetic risk score, polygenic, bullying THAPAR, Anita (Prof) 07/09/2015
Cardiff University 17-Sep-15
Michael O’Donovan, Stephan Collishaw, Barbara Maughan, Ajay Thapar, Lucy Riglin, Frances Rice 17-Sep-15
Medical Research Council
Secular change in the impact of mental disorder risk alleles on psychosocial development. Our analyses of UK cohort data suggest that children with mental health problems today face greater social difficulties, educational problems and a poorer mental health prognosis than in previous generations. One unanswered question is whether this just reflects changes in the way that parents fill in mental health symptom questionnaires. We plan to repeat our analyses using a directly equivalent starting point. In particular, advances in psychiatric genetics has allowed researchers to estimate individual genetic risk scores for psychiatric problems. We will use these risk scores to examine whether the prognosis and social and educational impact for those at high genetic risk has also increased over time. To do this we will compare social, educational and mental health outcomes for children at high vs low genetic risk in two UK birth cohorts (NCDS born 1958 and ALSPAC born in the early 1990s). Childhood, trends, neurodevelopmental, genetic risk score, polygenic COLLISHAW, Stephan, Dr 07/09/2015
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University 17-Sep-15
Prof Michael O’DONOVAN, Prof Anita THAPAR, Prof Barbara MAUGHAN, Prof Andrew PICKLES, Dr Ruth SELLERS, Dr Ajay THAPAR, Lucy RIGLIN 17-Sep-15
n/a
Corticospinal motor neuron development control genes as candidates for human ALS susceptibility. A key problem in genetics is the interpretation of genetic variation and whether it is relevant to disease. This is particularly an issue for Amyotrophic Lateral Sclerosis (ALS). Current evidence suggests some of ALS is caused by a few genetic variants common in the general population, such as the hexanucleotide expansion in the gene C9orf72, but most is caused by variants much rarer in the population. We have chosen to study developmental genes that control growth of corticospinal motor neurons (CSMN; “upper motor neuron”). There is evidence that rare variants in these genes are detrimental to health of CSMNs. We have analysed CSMN developmental genes using multiple methods. Through a combination of analyses including DNA-sequence analyses, exomic analyses, and gene expression we have found evidence that variation in three of our candidate genes increases the risk of ALS. Amyotrophic Lateral Sclerosis, rare variants, gene-level burden analysis, DNA sequence analyses, candidate gene, exome, gene expression, methylation AL-CHALABI, Ammar (Prof) 01/12/2015
Kings College London 16-Dec-15
Contact person: Dr Ashley JONES.  Dr William Sproviero, Dr Aleksey Shatunov, Dr Alfredo Iacoangeli, Dr Ahmad Al_Khleifat 16-Dec-15
ALS Association and Motor Neurone Disease Association
DNA methylation profiling in 1958BC samples to assess epigenetic responses to social and environmental cues in early life and over the life course across four UK population-based cohorts. The epigenome provides a mechanism of interaction between the genome with the environment, and we hypothesize that early life stimuli and exposures over the life course leave an epigenetic mark. The proposal aims to explore epigenetic profiles in up to 200 whole blood samples from the 1958 birth cohort, to contribute towards a large discovery analysis of 4,000 samples from four British cohort studies in order to identify epigenetic signatures of early life experience and exposure to social, environmental, and biological stimuli over the life course, linking findings to changes in physical and cognitive function during ageing. Each cohort captures a range of early life experiences, longitudinal health measures and lifestyle questionnaire data from adult life and has available DNA samples. The proposal will address four research aims, with overall purpose of identifying epigenetic signatures of early-life events and exposures over life-course that may have impacts on functional health trajectories. DNA methylation, Illumina Infinium HumanMethylationEpic BeadChip BELL, Dr Jordana 01/12/2015
Kings College London 16-Dec-15
Prof Alissa GOODMAN, Dr George PLOUBIDIS, Prof Diana KUH, Rebcca HARDY, Andrew WONG, Ana VALDES 01-Aug-16
ESRC
Contribution of rare germline variants to risk of male breast cancer in the UK population Although predominantly a disease that occurs in women, breast cancer also affects men – there are on average 350 new cases

of breast cancer in men every year in the UK. Because it is quite uncommon, little is known about why men get breast cancer.

However, it now appears that some risk factors, particularly those that are inherited (genetic risk factors) are common to both

male and female forms of the disease. For a subset of these genetic factors, the risk of breast cancer attributable seems to be

larger in men than in women. This suggests that analysis of a modest number of cases of male breast cancer may uncover

additional novel risk factors for the disease. We are currently conducting such a study by sequencing the DNA of more than

1,000 men with breast cancer.

Breast cancer; Male breast cancer, DNA sequencing, Germline predisposition ORR, Nicholas (Dr) 01/12/2015
Institute of Cancer Research 18-Mar-16
MAGUIRE, Sarah 18-Mar-16
Breast Cancer Now
Exome Sequencing in Familial Amyotrophic Lateral Sclerosis Amyotrophic Lateral Sclerosis is a disease of the brain, nerves and muscles with an average age of onset of about 50. The average life expectancy is under 3 years from first symptoms, normally due to respiratory failure. We are attempting to determine the genetic causes of this disease, especially amongst patients with affected family members, by sequencing the portion of their genomes that encode for proteins. In order to determine which genetic variants are likely to be involved in disease we need access to a similar dataset from people without the condition. ALS, Amyotrophic Lateral Sclerosis, Whole Exome Sequencing TOPP, Simon 01/12/2015
Kings College London 17-Sep-15
Chris SHAW, Martina DE MAJO, Chun Hao WONG, Bradley SMITH, Michael SIMPSON 16-Dec-16
Medical Research Council
Identifying the impact of alcohol dependence on family formation and dissolution: from inherited propensities to contextual vulnerabilities Alcohol dependence (AD) is a complex condition influenced by both genetic and socio‐environmental factors, with a lifetime

prevalence of 12.5%. Previous studies have shown that AD has a strong genetic component. The goal of this project is to

examine the relationship between AD and demographic life course events of family formation (postponement of childbirth,

union formation) and dissolution (divorce).We propose to use the 1958 British birth cohort to investigate how genetic

propensities for AD and social influences and gene‐environmental interactions impact family formation and dissolution

patterns. This work is important to not only help us understand the relationship between AD and family events, but also

examine causal relationships and the importance of genetic and social determinants in shaping family life course trajectories.

Alcohol consumption, fertility behaviour, family formation MILLS, Prof Melinda 01/12/2015
University of Oxford 16-Dec-15
BARBAN, Dr Nicola & TROPF, Felix. & Contact person: ARRIGHINI, Giacomo 16-Dec-15
European Research Council
Germline susceptibility to cancer We propose to use this data as a set of convenience controls to compare against sets of cases with cancers.  We will use this for common cancer types such as breast, gynacologic, urologic, and gastrointestinal.  The basic premise is that the genotype data gneerated from the ICR1000 UK exome series will act as a control set when matched properly for genes covered and when adequate quality matching has been performed. Cancer genetics, genomics, bioinformatics OFFIT, Dr Kenneth 02/03/2016
Memorial Sloan Kettering Cancer Center 18-Mar-16
Anne LINCOLN, Vijai JOSEPH 18-Mar-16
fationallnstitutes of Health, Cycle for Survival, The V Foundation, The Kate and

Robert Niehaus Initiative

Genome-wide association study of amyotrophic lateral sclerosis We are undertaking laboratory experiments to find genes that may cause amyotrophic lateral sclerosis (ALS). ALS is a fatal condition that kills approximately 1,500 UK residents every year. Individuals with this condition become weak due to muscle wasting and typically die with two to three years of the onset of their symptoms. There is no currently no cure for this disease. Knowing the genes that cause this disease may help us to design therapies to help patients. A person who does not have the disease being studied is known as a control subject. We will use the DNA obtained from the British 1958 Birth Cohort as control subjects in our genetic study. Results from control subjects will be compared to results from British ALS patients. The availability of this control information is crucial to the success of our project and increases our power to find the causative genes. Genome-wide association study, amyotrophic lateral sclerosis, genetic risk TRAYNOR 02/03/2015
National Institute on Aging, NIH 18-Mar-16
Michael NALLS, Aude NICHOLAS, Ruth CHIA, Yevgeniya ABRAMZON, J. Raphael GIBBS 18-Mar-16
Intramural Research Program, National Institutes of Health
Epigenomics in the 1958 British birth cohort: an extension from pilot studies on social adversity It is widely accepted that early life influences shape our development, health and behaviour across the life-course. Epigenetic mechanisms are increasingly implicated in these complex interactions. In a pilot study of 40 participants in the 1958 birth cohort we have contributed important evidence to this research by showing that DNA methylation (commonly used in epigenetic studies in human populations) has distinct associations with childhood socio-economic position and abuse. Building on this work we now plan to collaborate with several other cohorts to address questions that advance understanding on what aspects of our environment impact upon gene regulation, how our environment and way of living become embodied in human biology, over what timeframe and with what degree of persistence and how social and biological inequality may influence development and health. DNA methylation, prenatal tobacco exposure, childhood adversity, adult socio-economic position, child to adult health and growth outcomes and behaviour POWER, Prof Chris 02/03/2016
UCL Institute of Child Health 18-Mar-16
Dr Caroline RELTON, Matthew SUDERMAN 01-Aug-16
ESRC/BBSRC epigenetics initiative ‘Environment, embodiment and equality’ (PI Relton, Bristol)
A genome-wide interaction study on life course health effects from childhood immunomodulation to micropathogens Childhood immunization is a powerful tool in reducing deaths related to infectious diseases. Several lines of evidence now suggest vaccination may confer additional unintended health benefits. While the biological mechanisms and range of these vaccine health effects have not been fully clear, chronic infection is known to trigger non-communicable diseases through inflammation and other immunological processes. Using phenome-wide data from the CLS cohorts, we recently characterized specific health changes throughout a person’s life, following certain types of vaccination and vaccine-preventable illness. The goal of this study is to now pinpoint the genetic drivers of these non-specific health effects and identify how external factors such as lifestyle and environment may influence these pharmacogenetic effects. The research will use a combination of high-dimensional, causal-based inference methods and computational genomics to analyze this data. Genome-Wide Interactions, Vaccine, Vaccine-preventable illness, Non-communicable Disease, Life-course HOLLM-DELGADO, Dr Maria-Graciela 02/03/2016
Johns Hopkins University 18-Mar-16
PEVSNER, Prof Jonathan 18-Mar-16
n/a
Mapping of breakpoints in KLK3 deletions using exome sequence data, GWAS data, and laboratory validation. Prostate specific antigen (PSA) can be measured in blood and is used in the screening, diagnosis and monitoring of prostate cancer. The gene encoding PSA is called kallikrein-3 (KLK3).

PSA levels vary: some people exhibit very low levels, and we found that some of these people may have deletions (parts of the gene are not present) or single-base mutations (changes of one ‘letter’ in the genetic code) in the KLK3 gene. These genetic changes may explain why these people have low PSA levels. It is possible that these individuals are more likely to have false-negative PSA test results.

We think that ~1-2% of people may have KLK3 deletions (usually of one of two copies). We have determined the approximate location of these deletions, but not their exact location. We would like to use genetic sequence data and new genetic data from KLK3 to find the exact location of these deletions.

Copy number variation; KLK3; deletions; prostate-specific antigen; exome sequencing; in silico CNV detection; laboratory work RODRIGUEZ, Dr Santiago 19/04/2016
University of Bristol 03-May-16
Dr Tom GAUNT, Dr Kim BURROWS, Miss Anna GUYATT, Mr Ryan Langdon 03-May-16
Wellcome Trust and CRUK PhD studentships
Identification of Genes Contributing to Neurodegenerative Diseases The requested exome data will be used as controls in a study to identify genes contributing to ALS,

Parkinson’s disease and other neurodegenerative diseases.

Case-Control; Exome Sequencing; Neurodegenerative Diseases LANDERS, Prof John 07/06/2016
Univeristy Massachusetts Medical School 17-Jun-16
Brendan KENNA 26-Aug-16
NIH
Investigating Hereditary Cancer Predisposition – a combined genomics approach The future of diagnosing cancer earlier, especially in patients with strong family history for cancer, is in the identification of further inherited genes relating to cancer development. The genes identified as predisposing (or increasing the likelihood) of cancer, could then be screened within the family to alert relatives of their increased risk, whilst also potentially assisting with therapy of the original patient by providing more tailored treatment options. We will use the ICR1000 data from the 1958 Birth Cohort, collected with similar technologies and population background to our patient samples, as a standard reference dataset. We will compare it with our data and identify the most likely predisposing genes in our sample sets. IHCAP TISCHKOWITZ, Dr Marc 07/06/2016
University of Cambridge 17-Jun-16
Dr Alexey LARIONOV, Dr Mae GOLDGRABEN 17-Jun-16
European Research Council extended with NIHR BRC from 2019
Identification of novel risk factors and causative mutations of neurodegenerative syndromes Clear evidence for a genetic component to many neurodegenerative diseases comes from the fact that relatives of patients have an increased chance of getting the disease themselves. However, few cases have an identified “spelling mistake” mutation in the known disease genes. We believe there are further disease-causing genes to be

identified. Next-generation sequencing technology now allows us to analyse all the protein coding regions of an individual’s genome in a single experiment (called exome sequencing). By using exome sequencing, we aim to identify novel genes/mutations that cause disease and genetic changes that modulate risk. Using the control data

from the 1958BC will allow us to more accurately determine if newly identified mutations/genes are involved in the disease process. New mutations identified would help lead to a better understanding of the genetic makeup and disease mechanisms of diseases, which could lead to the development of more appropriate strategies to combat them.

Neurodegeneration, genetic risk factor, mutation, Alzheimer’s disease, Parkinson’s

disease, Fronto-temporal dementia, Dementia with Lewy Bodies

BRAS Dr Jose 07/06/2016
Institute of Neurology, UCL 17-Jun-16
Dr Rita GUERREIRO 17-Jun-16
Alzheimer’s Society, Alzheimer’s Research UK, National Institutes of Neurological

Disease and Stroke, Parkinson’s UK.

Genomics of social support, personality and cognition and their relation to mental health and cognitive ageing Genes play an important role in shaping the social behaviour and cognition/cognitive ageing as they modulate the brain activity through molecular pathways; therefore, it can be said that genes regulate the expression of behaviour. Social support and cognition are correlated with an individual’s mental health as these social interactions require effective communication and participation. We would like to use information from the 1985 birth cohort to: (1) assess the impact and associations between social behaviour (social support) and cognition in individuals with and without symptoms of depression and anxiety, (2) perform a genetic analysis of social support and cognition within the same population by studying changes in the DNA of individuals, and (3) harmonise these data with data from different cohorts Social support, social dysfunction, personality, cognition, GWAS, mental health, cognitive ageing NICODEMUS, Dr Kristin 07/06/2016
University of Edinburgh 17-Jun-16
Elvina GOUNTOUNA (contact), Thalia Perez SUAREZ, Kathy EVANS, Rosie WALKER, Lara Neira GONZALEZ, Daniel McCARTNEY
No outside funding. The project will be undertaken in the laboratories of Dr. Nicodemus and in collaboration with Dr. Kathy Evans, Reader, University of Edinburgh.
The Role of Protein-altering Genetic Variation in the Pathogenesis of Silver-Russell Syndrome Silver-Russell syndrome (SRS) is a developmental disorder with varied features. These include very small size at birth, poor

subsequent growth, a triangular face, asymmetrical body, and a range of other possible minor problems. The precise cause of

SRS is unknown. However, previous investigations suggest some cases of SRS are caused by genetic mutations, meaning errors

which provides the blueprint for normal development. In this project we aim to test whether two

types of genetic errors could cause SRS: (a) a single mutation with a large effect, or (b) many smaller-effect mutations in

regions of DNA which are important for development. To do this will study the DNA sequences of 21 SRS patients. We will

compare these sequences against 1,000 unaffected people to help pick out the mutations which may cause SRS from the

many non-harmful genetic errors which will also be present.

Silver-Russell syndrome, Developmental disease, Mendelian disease, Whole exome

sequencing

SCHULZ, Dr Reiner 07/06/2016
King’s College 17-Jun-16
Dr Nick DAND, Prof Rebecca OAKLEY, Prof Michael SIMPSON 17-Jun-16
MRC (end-date passed)
Renal Cancer Genetic Association Study Following Different Strategies Understanding the role that the genetic information we all carry in our genomes have on the onset and course of a complex disease like renal cancer is key to achieve a better treatment and earlier detection for the patients suffering from this disorder. For this purpose, we will analyse a group of patients presenting the most severe manifestations of this disorder comparing them to healthy individuals to uncover the underlying mechanisms that predispose to its development. This approach has already been used successfully in the study of other human traits and will very likely yield new insights into the genetic component of renal cancer to a lesser or greater extent. Renal Cancer, Genetics, Association Study, Complex Disease MAHER, Prof Eamonn 19/04/2016
University of Cambridge 11-May-16
Dr Ezequiel MARTIN, Dr Hannah WEST, Dr Graeme CLARCK 17-Jun-16
European Research Council (ERC)
Investigating oligogenicity and genetic modifiers in ciliopathies Joubert syndrome (JBTS) is a genetic disorder defined by a specific brain malformation accompanied by intellectual disability and problems with movement coordination. In addition, the clinical presentation can be very variable since some affected patients additionally develop disease of the retina, kidneys and liver. JBTS can be caused by mutations in both copies of one among 30 different genes, but because the genetic cause has still not been identified in one third of affected families, alternative inheritance mechanisms have been proposed, whereby single mutations in two or more different genes could also cause the disorder (“digenic/oligogenic inheritance mechanism”).

Moreover, the variability in clinical presentation is thought to arise from combined effects of variants in multiple genes (“genetic modifiers”). The focus of this work is to systematically investigate these hypotheses by comparing the proportion of JBTS patients with mutations in multiple genes, to that in healthy control individuals.

Ciliopathies, joubert syndrome, phenotypic variability, genetic heterogeneity, recessive disorder, oligogenicity, genetic modifiers RAUCH, Prof Anita 14/07/2016
University of Zurich 18-Jul-16
Ruxandra BACHMANN-GAGESCU, M.D. 26-Aug-16
Swiss National Science Foundation
Prediction of complex traits using whole-genome methods We will use this data set in combination with other data sets  to assess the effects of sample size, marker density and of the estimation method on the prediction accuracy of Whole Genome Regression methods when applied to a variety of complex human traits, including anthropometric and health-related traits. Complex Traits, Whole Genome Methods, Prediction Gustavo de los CAMPOS 14/07/2016
Michigan State University 20-Jul-16
Dr Ana Inés Vázquez, Prof Stephen HSU 19-Oct-16
NIH
Advanced modelling of genomic data With the advent of new and cheap technologies for reading the human genome, we are now able to collect data from thousands of patients. However, making sense of this incredible amount of data is not always easy and old analytical tools are no longer effective. Our project involves the application of modern mathematical computational algorithms, called machine learning algorithms, to genomic data. These mathematical tools can learn patterns by reading genomic data and identify series of mutations that might be crucial in defining a particular condition. However, in order to extract this kind of information, we also need data from healthy individuals. The 1958 birth cohort study is an excellent control dataset that will make possible the application of machine learning algorithms to many different complex and rare disorders, such as cancer, diabetes and chronic diseases. Next generation sequencing, machine learning, genomics ENNIS, Prof Sarah 06/09/2016
University of Southampton 23-Sep-16
Mr Enrico Mossotto 23-Sep-16
Hilary Marsden IfLS scholarship
Causal role of fatty acids metabolites in reading and spelling measures We have observed that higher levels of unsaturated fatty acids are correlated with higher scores for reading and spelling tests in 7 year old children.  (Fatty acids are a form of fats and oils that can be carried by the blood to different parts of the body.)  Previous evidence suggested that these fatty acids are involved in brain development, maintenance, and function.  In this project we will investigate whether variations in fatty acids can result in changes in school test scores.  Instead of trying to change the amount of fatty acids, for example by changing children’s diets, we will use the genetically-influenced natural variation in fatty acids in 1958 birth cohort to explore whether fatty acid levels improve school performance. Natural genetic variants previously linked to fatty acids will be tested for association with education performance.  This method can show the true effect of fatty acids on education performance, as it is not influenced by factors like diet which can impact on both education and fatty-acid levels.  This evidence could help show whether dietary intervention is likely to enhance school performance. Fatty acids, education, Mendelian Randomisation DRENOS Dr Fotios 13/10/2016
University of Bristol 24-Oct-16
Dr Neil DAVIES 23-Oct-17
n/a
Beta-defensin copy number variation and obesity Obesity is a common trait. People’s weight is dependent both on their genetic makeup and lifestyle choices, such as amount of exercise. Understanding the variation in genes that is responsible for the genetic component has identified many variants in the DNA, each of which contribute a small amount to an individual’s weight (usually measured as body mass index, BMI). In this study, we have new functional evidence that the beta-defensin genes are important in modulating an individual’s weight. However, these beta-defensin genes are usually ignored by current genetic studies, because they are in a region of the human genome that is not well-measured by most approaches. Beta-defensins show variation in the numbers of genes in the genome. We wish to investigate whether there is a correlation between the number of beta-defensin genes an individual has and their BMI. This will help to establish the functional role of beta-defensins as a modulator of BMI in humans, and therefore deepen our understanding of the physiological responses that lead to obesity. Obesity, BMI, copy number variation Dr Edward HOLLOX 30/11/2016
University of Leicester 14-Dec-16
n/a 14-Dec-16
n/a
Cognitive capability across the lifespan:  the interplay between the APOE gene and  environmental factors As part of a PhD project at the University of Sussex into cognitive function over the lifespan, funded by the Alzheimer’s Society, we wish to investigate whether one of the key genetic risks for late life dementia, the Apolipoprotein E gene (APOE), can be modified by environmental factors. It has been shown that carriers of a certain variant of this gene (the ε4-allele), are at increased risk of developing Alzheimer’s disease and demonstrate poorer cognitive ageing. It has been reported that higher engagement in cognitively stimulating activities can improve an individual’s likelihood of good cognitive ageing. We wish to explore how early life activities play into this interaction.  This project examines how the APOE gene interacts with early and late life cognitive and leisure activities (e.g., reading books, physical activity, etc.) to affect cognitive performance over the lifespan. Ageing; Alzheimer’s disease; cognition; cognitive activity; education; socioeconomic status; Apolipoprotein E; APOE GAYSINA, Dr Darya 30/11/2016
University of Sussex 14-Dec-16
ATKINSON, Rebecca; RUSTED, Professor Jenny 15-Mar-17
Alzheimer’s Society
Personalized medicine in epilepsy Epilepsy affects around 3% of individuals, with half the cases starting in childhood. More than 30% of patients are resistant to treatments and continue to have seizures. These pharmaco-resistant epilepsies have substantial human and social costs, including unemployment, hospitalisation and high mortality. Other diseases frequently occur on top of epilepsy. Intellectual disability occurs in around 25% of epileptic individuals and is associated with resistance to anti-epileptic drugs. Uncontrolled seizures in the developing brain may contribute to cognitive decline. There is currently no way to predict who will respond to anti-epileptic drugs, or to identify epileptic children at risk for intellectual disability. Little is known about the underlying genetic (family trait) mechanism for resistance to anti-epileptic drugs. Classic genetic studies, to date, have not explained familial epilepsies.

Our project will look for genetic differences between 1000 patients who are resistant to treatments, 1000 patients who respond to treatment, and 1000 members of the 1958 birth cohort. We will analyse all three groups to identify genetic causes of resistance to anti-epileptic treatments.

Personalized medicine, epilepsy COSSETTE, Dr Patrick 27/02/2017
CHUM Research Centre 09-Mar-17
MOREAU, Claudia; GIRArD, Prof Simon. 02-Jun-17
Genome Canada
Genetic determinants of Human Reproductive Behavior (HRB) – a collaborative meta-analysis Recent studies have informed us about how our genes (inherited differences) affect reproductive behaviour such as: age at first birth and number of children ever born. The aim of this current project is to extend this work, and to identify further genes affecting reproductive health. This type of work can inform us of biological mechanisms which affect reproductive health in humans, and in the longer-term help us to develop new treatment strategies for those who need support. Genomewide analysis, reproductive behaviour HYPPONEN, Prof Elina 27/02/2017
University of South Australia from 2015 (also, UCL Institute of Child Health. 14-Mar-17
McCARTHY, Mark; POWER, Christine; MAHAJAN, Anubha; ZHOU, Ang 11-May-17
n/a
Language and communication abilities as predictors of health and development during the life course – a genetic investigation Language is a distinct and complex human feature that plays a crucial role during a child’s development and has been linked to later behavioural, cognitive, social and health outcomes. Genes may mediate this relationship, although their exact role, especially within typically developing children, is still not well understood. This project aims to identify sets of genetic variants (that are shared to a different extent between all of us) contributing to language abilities. We will then use these variants to investigate relationships between childhood language skills and later life outcomes by means of a study design that is free of distorting influences. Thus, this research can help to predict future health and development and contribute towards educational tasks aiming to improve language-related skills during early life. Language and communication abilities as predictors of health and development during the life course – a genetic investigation. Dr Beate St POURCAIN 11/04/2017
Max Planck Inst. For Psycholinguistics 02-May-17
Prof Elina HYPPONEN, Chin Yang SHAPLAND, Ellen VERHOEF, Fenja SCHLAG, Lara CLAUSS 02-Jun-17
Max Planck Society core funding
Gene-environment interactions in the female reproductive life course The period of female fertility begins at first menstruation (menarche) and ends at menopause. Although the timings of both menarche and menopause have been studied in terms of heritability and environmental influences, the two events have rarely been considered together in a genetic context. Furthermore, the reproductive history of the studied population has not been taken into account as factors affecting the fertility timings. In this project, we propose to study the heritability of the length and position of the female fertility window.

Additionally, we intend to combine the genetics with detailed reproductive history of the female participants to establish whether the timing of menopause is affected in part by their reproductive past (e.g. number and timings of pregnancies, miscarriages, terminations, and use of contraception).

Heritability, fertility, life history, menopause, menarche Professor David STEINSALTZ 11/04/2017
University of Oxford 02-May-17
Julia BRETTSCHNEIDER, Maria CHRISTODOULOU, Stine MOLLEGAARD. Left: Ella KAYE 02-Jun-17
ESRC SocGen grant
Chronic Pain, Stress & Depression: Exploring Causal drivers Depression and chronic widespread pain (CWP) frequently co-exist and interact in influencing health and well-being, often with devastating individual and societal consequence This project will investigate the relationship between chronic widespread pain and depression in mid-life, and whetehr chronic pain earlier in life affects depression risk later on. Furthermore, we will look to establish whether genetic variants which influence stress responses modify the relationship between chronic pain and depression. By investigating the role of genetic factors affecting stress responses as possible effect modifiers in this context, we hope to provide insights into more precise prevention strategies, and possibly, into biological pathways mediating the effects of chronic pain on depression. chronic widespread pain, stress, depression, gene, environment Prof Elina HYPPONEN 03/07/2017
University of South Australia from 2015 (also, UCL Institute of Child Health. 06-Jul-17
Dr Ang ZHOU, Mr Cameron DICKSON, Prof Christine POWER 10-Jul-17
Australian Govt research training scheme
Investigating the genetic relationships between anxiety, depression, stressful life events, and cardiovascular risk factors and disease. This study aims to use cardiovascular risk measurements and diagnosis, together with questionnaire data on mental and physical health in NCDS in two ways: 1- To discover and validate previous findings from large psychiatric genetics studies. These studies identified inherited genetic changes which may increase risk of depression. 2- To investigate shared genetic factors affecting mental and cardiovascular health (heart disease), as these conditions often occur together.

The ultimate aim is to uncover biological pathways underlying the relationship between cardiovascular disease and depression. The proposed work will be achieved through analysis of genetic and health data, using existing methods. This research will assist in risk prediction, informing treatment, and forming a better understanding of the shared genetics between traits.

depression, polygenic risk scores, cardiovascular disease risk, pleiotropy Prof Cathryn LEWIS 12/09/2017
King’s College London 19-Sep-17
19-Sep-17
Comparison of genome-wide DNA methylation between peripheral blood and lymphoblastoid cell lines. Epigenetics is the study of the molecular switches by which genes are normally turned “on” or “off”. There are three factors that influence whether these molecular switches are switched “on” or “off”. The first is heredity (whether your parents had workable or defective switches, for example, and passed them on to you), the second is aging and the third is the environment (i.e., diet, exercise, pollution, etc.). We plan to compare the switching pattern of genes from individuals in the 1958BC with the switching pattern of multiple siblings from large families (using data from the ‘CEPH families’ project). This comparison will distinguish the effects of aging (because the 1958BC are all the same age) from the effects of heredity (because the siblings share half of their genes). Our hypothesis is that the remaining differences in switching pattern are the result of environmental factors. Ultimately, we hope this study will identify which environmental factors are most important in switching genes on or off. DNA methylation, lymphoblastoid cell lines, peripheral blood Prof Carmen SAPIENZA 12/09/2017
Lewis Katz School of Medicine, Temple University 19-Sep-17
N/A 02-Oct-17
tbc
Investigating risk factors for continuities and discontinuities in emotional problems across the life course Some childhood emotional difficulties persist into adulthood, while others do not.  We plan to use the detailed information collected from members of the 1958 British birth cohort to identify people with different long-term patterns of emotional problems, and explore individual and family factors that differ between them.  Because emotional problems run in families, we will include markers of genetic risk, as well as factors such as relationships with parents and educational progress.  We will also test whether the same factors can be helpful for children facing more severe stressors in their families, or who were bullied in childhood.  If we can find factors that ‘protect’ some children with emotional problems from facing long-term emotional difficulties, this may give helpful pointers for treatment. Emotional problems, polygenic risk scores, life course Prof Barbara MAUGHAN 12/09/2017
Institute of Psychiatry, Kings College London 19-Sep-17
Ryu TAKIZAWA, Louise ARSENAULT, Karen HODGSON 03-Oct-17
n/a
Associations between affective problems across the life course and cognitive function in midlife. The primary aims of the proposed project are to investigate how affective problems, such as depression and anxiety, are linked with cognitive function in midlife. We also aim to identify specific social, behavioural and biological factors that may be involved in this relationship. The research is part of an Economic and Social Research Council (ESRC) funded PhD at the University of Sussex. Past research has shown that affective problems are associated with an increased risk of dementia and faster cognitive decline. However, much of this research focuses on older adults only and has not followed these individuals up for long periods of time. The current study therefore aims to investigate the association between affective problems from childhood to midlife and cognitive function in midlife. This will allow us to explore how this association develops over time, and to identify specific factors which may be involved within this relationship. This research has important implications for identifying people who may be at a greater risk for poorer cognitive outcomes. Affective problems, mental health, cognition, genetics Prof Darya GAYSINA 12/09/2017
University of Sussex 19-Sep-17
Amber JOHN, Jennifer RUSTED, Marcus RICHARDS 02-Oct-17
ESRC
Eczema remains common in adulthood: Results from 2 prospective British Cohort Studies Eczema, an itchy autoimmune skin disease, is now one of the most common childhood diseases in industrialized countries. It waxes and wanes over time and has not been well studied beyond childhood. Using two longitudinal data sets representative of the UK general population (the 1958 and 1970 British Cohort Studies), our objective is to calculate how common active eczema is at multiple ages throughout childhood and adulthood and identify long-term patterns of disease activity.  We will then test whether patient characteristics, including genetic factors, predict patterns of persistent, resolving, or late-onset disease. The anticipated benefits of this research include better information for patients on the likely progress of the disease.  Data on how risk factors change over time could be used to design future preventative studies. Eczema, atopic dermatitis, epidemiology, filaggrin Dr Katrina ABUABARA 27/11/2017
University of California 05-Dec-17
Dr YEW Yik Weng, Dr Sinead LANGAN, Morgan Ye 13-Dec-17
UCSF Center for Health and Community Robert Wood Johnson Pilot Grant
Biological embedding of childhood bullying, suicidal ideation and depressive ideas Over a third of adolescents report being bullied by their peer group. Prior research indicates that being bullied in childhood is often associated with poorer mental health. Depressive symptoms, suicidal thoughts and behaviours can occur at the time, and sometimes persist into midlife. The underlying processes linking childhood bullying to increased suicidal thoughts and depressive ideas in adults are unknown.  One possibility is that being bullied, like other stressful experiences, can result in biological changes such as the addition of molecules called methyl groups to various locations in DNA.  When these methyl groups are added at the beginning of genes, they can change how strongly different genes work.   These methylation marks may fade with time or remain for decades.  This study will investigate whether people who were bullied in childhood tend to have different patterns of methylation marks as adults. We hope this will improve understanding of suicide risks associated with childhood bullying. DNA methylation, peer victimization, epigenetic, genome-wide Marie-Claude GEOFFROY 05/03/2018
Douglas Hospital 08-Mar-18
Lea C PERRET; Matthew SUDERMAN; Gustavo TURECKI; Chris POWER 21-May-18
American Foundation for Suicide Prevention 2017

 

Last updated with approved projects 5/6/2018