D2K, PEALS, Newcastle University

1958 birth cohort: METADAC project approvals

Title of Application Plain Language Summary Committee date Applicant Keywords
Institution
Co-Applicants
Funder
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. 12/09/2017 Prof Barbara MAUGHAN Emotional problems, polygenic risk scores, life course
Institute of Psychiatry, Kings College London
Ryu TAKIZAWA, Louise ARSENAULT, Karen HODGSON
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. 12/08/2017 Prof Darya GAYSINA Affective problems, mental health, cognition, genetics
University of Sussex
Amber JOHN, Jennifer RUSTED, Marcus RICHARDS
ESRC
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.
12/09/2017 Prof Cathryn LEWIS depression, polygenic risk scores, cardiovascular disease risk, pleiotropy
King’s College London
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. 12/09/2017 Prof Carmen SAPIENZA DNA methylation, lymphoblastoid cell lines, peripheral blood
Lewis Katz School of Medicine, Temple University
N/A
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. 03/07/2017 Prof Elina HYPPONEN chronic widespread pain, stress, depression, gene, environment
University of South Australia from 2015 (also, UCL Institute of Child Health.
Dr Ang ZHOU, Mr Cameron DICKSON, Prof Christine POWER
Australian Govt research training scheme
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. 11/04/2017 Dr Beate St POURCAIN Language and communication abilities as predictors of health and development during the life course – a genetic investigation.
Max Planck Inst. For Psycholinguistics
Prof Elina HYPPONEN
Max Planck Society core funding
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.
27/02/2017 COSSETTE, Dr Patrick Personalized medicine, epilepsy
CHUM Research Centre
MOREAU, Claudia; GIRArD, Prof Simon.
Genome Canada
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. 30/11/2016 Dr Edward HOLLOX Obesity, BMI, copy number variation
University of Leicester
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. 06/09/2016 ENNIS, Prof Sarah Next generation sequencing, macine learning, genomics
University of Southampton
Mr Enrico Mossotto
Hilary Marsden IfLS scholarship
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. 14/07/2016 Gustavo de los CAMPOS Complex Traits, Whole Genome Methods, Prediction
Michigan State University
Dr Ana Inés Vázquez, Prof Stephen HSU
NIH
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.
14/07/2016 RAUCH, Prof Anita Ciliopathies, joubert syndrome, phenotypic variability, genetic heterogeneity, recessive disorder, oligogenicity, genetic modifiers
University of Zurich
Ruxandra BACHMANN-GAGESCU, M.D.
Swiss National Science Foundation
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. 19/04/2016 MAHER, Prof Eamonn Renal Cancer, Genetics, Association Study, Complex Disease
University of Cambridge
Dr Ezequiel MARTIN, Dr Hannah WEST, Dr Graeme CLARCK
European Research Council (ERC)
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.
07/06/2016 SCHULZ, Dr Reiner Silver-Russell syndrome, Developmental disease, Mendelian disease, Whole exome
sequencing
King’s College
Dr Nick DAND, Prof Rebecca OAKLEY, Prof Michael SIMPSON
MRC
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 07/06/2016 NICODEMUS, Dr Kristin Social support, social dysfunction, personality, cognition, GWAS, mental health, cognitive ageing
University of Edinburgh
Elvina GOUNTOUNA, Thalia Perez SUAREZ, Kathy EVANS, Rosie WALKER, Lara Neira GONZALEZ, Daniel McCARTNEY
No outside funding.
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.
07/06/2016 BRAS Dr Jose Neurodegeneration, genetic risk factor, mutation, Alzheimer’s disease, Parkinson’s
disease, Fronto-temporal dementia, Dementia with Lewy Bodies
Institute of Neurology, UCL
Dr Rita GUERREIRO
Alzheimer’s Society, Alzheimer’s Research UK, National Institutes of Neurological
Disease and Stroke, Parkinson’s UK.
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. 07/06/2016 TISCHKOWITZ, Dr Marc IHCAP
University of Cambridge
Dr Alexey LARIONOV, Dr Mae GOLDGRABEN
European Research Council
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.
07/06/2016 LANDERS, Prof John Case-Control; Exome Sequencing; Neurodegenerative Diseases
Univeristy Massachusetts Medical School
Brendan KENNA
NIH
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.

19/04/2016 RODRIGUEZ, Dr Santiago Copy number variation; KLK3; deletions; prostate-specific antigen; exome sequencing; in silico CNV detection; laboratory work
University of Bristol
Dr Tom GAUNT, Dr Kim BURROWS, Miss Anna GUYATT, Mr Ryan Langdon
Wellcome Trust and CRUK PhD studentships
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. 02/03/2016 POWER, Prof Chris DNA methylation, prenatal tobacco exposure, childhood adversity, adult socio-economic position, child to adult health and growth outcomes and behaviour
UCL Institute of Child Health
Dr Caroline RELTON, Matthew SUDERMAN
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. 02/03/2016 HOLLM-DELGADO, Dr Maria-Graciela Genome-Wide Interactions, Vaccine, Vaccine-preventable illness, Non-communicable Disease, Life-course
Johns Hopkins University
PEVSNER, Prof Jonathan
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. 02/03/2015 TRAYNOR Genome-wide association study, amyotrophic lateral sclerosis, genetic risk
National Institute on Aging, NIH
Michael NALLS, Aude NICHOLAS, Ruth CHIA, Yevgeniya ABRAMZON, J. Raphael GIBBS
Intramural Research Program, National Institutes of Health
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. 02/03/2016 OFFIT, Dr Kenneth Cancer genetics, genomics, bioinformatics
Memorial Sloan Kettering Cancer Center
Anne LINCOLN, Vijai JOSEPH
fationallnstitutes of Health, Cycle for Survival, The V Foundation, The Kate and
Robert Niehaus Initiative
Characterization of KLK3 deletions related to very low PSA levels: implications to prostate cancer diagnosis and monitoring 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.
RODRIGUEZ, Santiago (Dr) Characterization of KLK3 deletions related to very low PSA levels: implications to prostate cancer diagnosis and monitoring
University of Bristol
DAY, Ian (Prof) / DONOVAN, Jenny / COX, Angela / HAMDY, Freddie / LANE, Athene / NEAL, David
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.
01/12/2015 MILLS, Prof Melinda Alcohol consumption, fertility behaviour, family formation
University of Oxford
BARBAN, Dr Nicola & TROPF, Felix. & Contact person: ARRIGHINI, Giacomo
European Research Council
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. 01/12/2015 TOPP, Simon ALS, Amyotrophic Lateral Sclerosis, Whole Exome Sequencing
Kings College London
Chris SHAW, Martina DE MAJO, Chun Hao WONG, Bradley SMITH, Michael SIMPSON
Medical Research Council
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.
01/12/2015 ORR, Nicholas (Dr) Breast cancer; Male breast cancer, DNA sequencing, Germline predisposition
Institute of Cancer Research
MAGUIRE, Sarah
Breast Cancer Now
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. 01/12/2015 BELL, Dr Jordana DNA methylation, Illumina Infinium HumanMethylationEpic BeadChip
Kings College London
Prof Alissa GOODMAN, Dr George PLOUBIDIS, Prof Diana KUH, Rebcca HARDY, Andrew WONG, Ana VALDES
ESRC
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. 01/12/2015 AL-CHALABI, Ammar (Prof) Amyotrophic Lateral Sclerosis, rare variants, gene-level burden analysis, DNA sequence analyses, candidate gene, exome, gene expression, methylation
Kings College London
Contact person: Dr Ashley JONES.  Dr William Sproviero, Dr Aleksey Shatunov, Dr Alfredo Iacoangeli, Dr Ahmad Al_Khleifat
ALS Association and Motor Neurone Disease Association
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. 07/09/2015 THAPAR, Anita (Prof) Childhood, neurodevelopmental, genetic risk score, polygenic, bullying
Cardiff University
Michael O’Donovan, Stephan Collishaw, Barbara Maughan, Ajay Thapar, Lucy Riglin, Frances Rice
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). 07/09/2015 COLLISHAW, Stephan, Dr Childhood, trends, neurodevelopmental, genetic risk score, polygenic
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
Prof Michael O’DONOVAN, Prof Anita THAPAR, Prof Barbara MAUGHAN, Prof Andrew PICKLES, Dr Ruth SELLERS, Dr Ajay THAPAR, Lucy RIGLIN
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. 07/09/2015 Tobin & Wain Copy number, height, weight, waisthip, BMI, GiANT consortium
University of Leicester
Louise WAIN, Martin TOBIN
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. 13/07/2015 BARROSO, Dr Inês obesity, genetics
Wellcome Trust Sanger Institute
Eleanor WHEELER, Gaëlle MARENNE
Wellcome Trust Sanger Institute (core funding)
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. 13/07/2015 SIMPSON, Prof Michael Exome sequencing, sudden infant death syndrome, molecular autopsy
Kings College London
Dr Dr Elijah BEHR, Dr Leonie WONG
British Heart Foundation
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.
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.
13/07/2015 KNIGHT, Helen, Dr Methylation, genes, cognition
University of Nottingham
FLITTON, Miles, Mr
Is skin tone associated with Vitamin D and associated outcomes.  A Mendelian Randomisation study. This project will investigate whether individuals with fairer skin have higher Vitamin D levels. We will then investigate whether this variation in skin tone and any variation in Vitamin D has an effect on BMI and blood pressure. We will predict variations in individuals skin tone using small variations in individuals genetic makeup that have been shown previously to be associated with skin tone. 13/07/2015 DAVEY SMITH, George skin tone; ethnicity; vitamin D
University of Bristol
Eleanor SANDERSON
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. 02/06/2015 HYPPONEN, Elina (Prof) Cognition, behaviour, mental health, gene-environment interaction, genetic association
University of South Australia from 2015 (also, UCL Institute of Child Health.
POWER, Christine (Prof)
Mason Memorial Foundation; NHMRC
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. 02/06/2015 HYPPONEN, Elina (Prof) Growth, health, cardiovascular disease, diabetes, metabolic risk markers, gene-environment interaction, genetic association
University of South Australia from 2015 (also, UCL Institute of Child Health.
POWER, Christine (Prof)
Mason Memorial Foundation; NHMRC

 

Last updated with approved projects 3/10/2017

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