D2K, PEALS, Newcastle University

1958 birth cohort: METADAC project approvals

METADAC date;

Decision Letter;

Final approval.

Principal applicant;

Principal Institution;

Co-applicants;

Funders.

Project Title Project summary Project Keywords
02 Jun 2015 HYPPONEN, Elina (Prof) 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
23 Jun 2015 University of South Australia
30 Sep 2015 POWER, Christine (Prof)
Mason Memorial Foundation; NHMRC
02 Jun 2015 HYPPONEN, Elina (Prof) 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
23 Jun 2015 University of South Australia from 2015 (also, UCL Institute of Child Health.
30 Sep 2015 POWER, Christine (Prof)
Mason Memorial Foundation; NHMRC
13 Jul 2015 George DAVEY-SMITH 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. skin tone; ethnicity; vitamin D
28 Jul 2015 University of Bristol
28 Jul 2015 Eleanor SANDERSON (contact)
n/a
13 Jul 2015 KNIGHT, Helen, Dr 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.
Methylation, genes, cognition
29 Jul 2015 University of Nottingham
29 Jul 2015 FLITTON, Miles, Mr
n/a
13 Jul 2015 BEESLEY, Alex, Prof NUT Midline Carcinoma Research Program NUT Midline Carcinoma (NMC) is the name of a very rare but lethal cancer that affects both children and adults. Even though NMC tumours initially respond to chemotherapy, all patients quickly relapse and there is no effective treatment. There are no thus survivors of this dreadful disease and patients usually succumb within a few months from diagnosis.
We are analysing the biology of the disease to try and find clues to better treatments. To do this we have used state of the art DNA sequencing technologies, however we are limited in our ability to analyse the data because of the scarcity of samples from NMC patients. In order to validate our results therefore we need to compare them to samples from normal individuals (i.e. people that do not have cancer or other known diseases). The purpose of this application is to request these normal samples from the EGA study EGAS00001000971 which is a UK study that has studied a large number of normal individuals.
NUT Midline Carcinoma, Drug resistance, cancer, relapse
28 Jul 2015 Telethon Kids Institute
28 Jul 2015 STIRNWEISS, Anja, Dr
Children’s Leukaemia and Cancer Research Foundation
07 Sep 2015 BEESLEY, Prof Alex Extension to “NUT Midline Carcinoma Research Program” Our group is analysing of a number of rare children’s diseases to try and find clues to better treatments. This includes paediatric leukaemias, brain tumours and rarer forms of cancer such as sarcomas and carcinomas. To do this we are using state of the art DNA sequencing technologies, however we are limited in our ability to analyse the data because of difficulties with obtaining control samples from every patient. In order to validate our results therefore we need to compare our samples to samples from a cohort of normal individuals (i.e. people that do not have cancer or other known diseases). The purpose of this application is to request these normal samples from the EGA study EGAS00001000971 which is a UK study that has studied a large number of normal individuals. rare paediatric cancer
Chair’s Action Telethon Kids Institute
17 Sep 2015 STIRNWEISS, Anja, Dr
Children’s Leukaemia and Cancer Research Foundation
13 Jul 2015 PROF SIMPSON, Michael 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
28 Jul 2015 Kings College London
28 Jul 2015 DR WONG, Leonie
British Heart Foundation
13 Jul 2015 BARROSO, Dr Inês 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
28 Jul 2015 Wellcome Trust Sanger Institute
28 Jul 2015 Eleanor WHEELER, Gaëlle Marenne
Wellcome Trust Sanger Institute (core funding)
07 Sep 2015 TOPP, Simon 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
17 Sep 2015 Kings College London
16 Dec 2016 Chris SHAW, Martina De MAJO, Chun Hao WONG, Bradley SMITH
Medical Research Council
01 Dec 2015 TOPP, Simon 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
20 Nov 2015 Kings College London
16 Dec 2016 Chris SHAW, Martina DE MAJO, Chun Hao WONG, Bradley SMITH, Michael SIMPSON
Medical Research Council
07 Sep 2015 COLLISHAW, Stephan, Dr 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
17 Sep 2015 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University
17 Sep 2015 Prof Michael O’DONOVAN, Prof Anita THAPAR, Prof Barbara MAUGHAN, Prof Andrew PICKLES, Dr Ruth SELLERS, Dr Ajay THAPAR, Lucy Riglin
n/a
07 Sep 2015 THAPAR, Anita (Prof) 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
17 Sep 2015 Cardiff University
17 Sep 2015 Michael O’Donovan, Stephan Collishaw, Barbara Maughan, Ajay Thapar, Lucy Riglin, Frances Rice
Medical Research Council
07 Sep 2015 Tobin & Wain 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
Chair’s approval University of Leicester
17 Sep 2015 Louise WAIN, Martin TOBIN
unknown
01 Dec 2015 AL-CHALABI, Ammar (Prof) 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
16 Dec 2015 Kings College London
16 Dec 2015 Contact person: Dr Ashley JONES
ALS Association and Motor Neurone Disease Association
01 Dec 2015 ORR, Nicholas (Dr) 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
16 Dec 2015 Institute of Cancer Research
18 Mar 2016 MAGUIRE, Sarah
Breast Cancer Now
01 Dec 2015 MILLS, Prof Melinda 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
16 Dec 2015 University of Oxford
16 Dec 2015 BARBAN, Dr Nicola & TROPF, Felix. & Contact person: ARRIGHINI, Giacomo
European Research Council
07 Sep 2015 RAYCHAUDHURI, Soumya (Prof) Sequencing projects of rheumatoid arthritis Sequencing DNA samples from patients with rheumatoid arthritis and healthy controls to identify rare variants or genes and gene sets enriched for rare variants associated with rheumatoid arthritis.
A total of 1080 genes related with rheumatoid arthritis or other immune traits are selected as targets of sequencing.
About 2000 cases and 1300 controls will be sequenced.
The samples from 1958BC will be used for controls.
Rheumatoid arthritis, genetics, rare variants
30 Sep 2015 Brigham and Women’s Hospital
30 Sep 2015 Stephen EYRE (Manchester)
National Institutes of Health
02 Mar 2016 Dr Kenneth OFFIT 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
18 Mar 2016 Memorial Sloan Kettering Cancer Center
18 Mar 2016 Anne LINCOLN, Vijai JOSEPH
fationallnstitutes of Health, Cycle for Survival, The V Foundation, The Kate and
Robert Niehaus Initiative
02 Mar 2016 Dr Maria-Graciela HOLLM-DELGADO 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
18 Mar 2016 Johns Hopkins University
18 Mar 2016 none
n/a
19 Apr 2016 Prof Eamonn MAHER Renal Cancer Genetic Association Study Following Different Strategies Understanding the role that genetic variants have on the onset and course of a complex disease like renal cancer is key to achieve a better treatment for the patients suffering from this disorder. Renal cancer (as most cancers) is a highly genetically heterogeneous disorder, and in this sense we intend to tackle with a different approach, use a cohort of renal cancer patient with extreme phenotype, which should reduce considerably the heterogeneity of the genetic component involved in this subgroup of the disease. This approach has already been used successfully in the study of the genetic component of other human traits and will surely yield new insights into the genetic component of renal cancer. Renal Cancer, Genetics, Association Study, Complex Disease
11 May 2016 University of Cambridge
17 Jun 2016 Dr Ezequiel MARTIN, Dr Hannah WEST, Dr Graeme CLARCK
European Research Council (ERC)
07 Jun 2016 Dr Marc TISCHKOWITZ 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
17 Jun 2016 University of Cambridge
17 Jun 2016 Dr Alexey LARIONOV, Dr Mae GOLDGRABEN
European Research Council
07 Jun 2016 Dr Jose BRAS 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
17 Jun 2016 Institute of Neurology, UCL
17 Jun 2016 Dr Rita GUERREIRO
Alzheimer’s Society, Alzheimer’s Research UK, National Institutes of Neurological
Disease and Stroke, Parkinson’s UK.
07 Jun 2016 Dr Reiner SCHULZ 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
17 Jun 2016 King’s College
17 Jun 2016 Dr Nick DAND, Prof Rebecca OAKLEY, Prof Michael SIMPSON
MRC
02 Mar 2105 Dr Bryan TRAYNOR 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
18 Mar 2016 National Institute on Aging, NIH
18 Mar 2016 Michael NALLS, Aude NICHOLAS, Ruth CHIA, Yevgeniya ABRAMZON, J. Raphael GIBBS
Intramural Research Program, National Institutes of Health
19 Apr 2016 Dr Santiago RODRIGUEZ 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
03 May 2016 University of Bristol
03 May 2016 Dr Tom GAUNT, Dr Kim BURROWS, Miss Anna GUYATT, Mr Ryan Langdon
Wellcome Trust and CRUK PhD studentships