Quantitative Traits in Health and Disease

Lead Research Organisation: University of Edinburgh

Abstract

Our aim is to understand the genetic and environmental causes of variation in complex traits and diseases. These include common conditions such as heart disease, obesity and disorders of the eye. We develop and apply a range of statistical analysis methods to identify genetic differences that are connected with either good or bad health throughout a person’s lifetime. This will help to predict the risk of people developing particular conditions, as well as providing a foundation for the future development of personalised and precision medicine.
To achieve this we are using “Biobanks” of large numbers of volunteer research participants, to enable research ranging from simple postal surveys to clinical studies with hospital visits, and detailed and wide-ranging analyses of the collected biological samples, such as blood and urine.
The volunteers in our biobanks also gave consent for researchers to link to their NHS electronic health record data, allowing for long-term follow-up of their health via medical records, and relating this to their genetic make-up
The results will help to understand the relationships between genetic variation, gene function and health, integrating computational and experimental approaches. This will allow new scientific discoveries to be made that are relevant to a wide range of conditions and will contribute to advances in medical research and customised healthcare for patients and populations.

Technical Summary

This programme aims to deliver biological understanding of the genetic and environmental causes of variation in complex traits and diseases. To do this we will harness the special population structures in our population cohorts, together with the unparalleled capacity in Scotland to achieve extensive linkage to eHealth records, the creation of uniquely high dimensional phenotype datasets, and the effective multidisciplinary team. We will capitalise upon the special features of our study populations together with data from Generation Scotland, UK Biobank and collaborators to dissect trait genetic architecture and identify genetic variants associated with a broad range of quantitative traits of biomedical importance. We will develop and apply computational approaches to provide understanding of the genetic and environmental sources of biomedical trait variation together with their interactions. In order to exploit the “jackpot effect” of otherwise rare variants with increased frequencies in population isolates, we focus our research on Scottish (Orkney and Shetland) and Croatian (Vis and Korcula) cohorts, increasing both the size and power of our cohorts and the depth of their phenotyping. High kinship within our isolate populations facilitates imputation of variants into all genotyped individuals, with an increase in sample size enhancing detection power for both rare and common variants, using association and gene-based mapping methods. Biobanked samples (plasma, serum and urine) allow expansion of deep phenotyping (including proteomics, metabolomics, glycomics, urine traits), enabling more detailed exploration of the biology underlying associations. We will use these rich intermediate phenotype and other data to identify pathways from the genome and epigenome, through the proteome and metabolome, and to assess their impact on human health and disease using multivariate genome-wide association studies (GWAS), phenomics, two-sample Mendelian Randomisation and other integrative approaches. We also continue to functionally characterise a number of the associations, taking findings further along the translational pathway and illuminating mechanisms. The programme will contribute to our understanding of the relationships between genetic variation, gene function and health, integrates computational and experimental approaches and strengthens population cohorts towards development of precision medicine. This research programme will complement resources such as UK Biobank, which do not focus on related individuals and have limited molecular phenotyping, identifying low frequency variants and familial environmental contributions that are opaque to such studies, and leveraging the multi-omics data to suggest causality and mechanisms through, e.g. MR approaches. In the near future as long-read DNA sequencing becomes sufficiently affordable and many thousands of proteins can be assayed inexpensively, our resources will be ideal for exploring the role of novel genomic variation and further characterisation of the protein architecture of disease.

Publications

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Bouhaddani SE (2018) Integrating omics datasets with the OmicsPLS package. in BMC bioinformatics

 
Title Genome-wide pleiotropy and shared biological pathways for resistance to bovine pathogens 
Description The database represents data on disease and production traits in dairy cattle that was the basis or our collaborative research and can be used for further analyses by ourselves and others. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact None as yet 
URL https://datashare.is.ed.ac.uk/handle/10283/3040
 
Description CHARGE 
Organisation Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE)
Country Global 
Sector Academic/University 
PI Contribution The MRC HGU QTL group, particularly through Caroline Hayward and Jenny Huffman, has a long-standing collaboration with CHARGE with data from the isolates cohorts contributing to a wide range of Phenotype Working Groups, and more recently data from Generation Scotland has also been included in the collaboration.
Collaborator Contribution The CHARGE Consortium was formed to facilitate genome-wide association study meta-analyses and replication opportunities among multiple large and well-phenotyped longitudinal cohort studies. CHARGE has provided statistical and analytical methods development and facilitated the publication of many high impact papers.
Impact PubMed ID 22589738, 22199011, 22001757, 21502573, 24068962, 23583979
Start Year 2009
 
Description CKDgen 
Organisation CKDGen Consortium
Country Global 
Sector Academic/University 
PI Contribution Genotype and phenotype data relevant to chronic kidney disease.
Collaborator Contribution Analysis plans and meta-analysis.
Impact PubMed ID 22962313, 22797727, 22479191, 22492995, 24029420
Start Year 2008
 
Description Consortium for Refractive Error & Myopia (CREAM) 
Organisation Consortium for Refractive Error and Myopia
Country Singapore 
Sector Charity/Non Profit 
PI Contribution Contribution of detailed eye-related phenotype and genome-wide genotype data to meta-analyses by the CREAM consortium.
Collaborator Contribution Analysis plans and meta-analysis across a range of cohorts.
Impact Not multi-disciplinary. PubMed ID 22665138, 23474815, 23396134, 24144296,
Start Year 2012
 
Description ECUT 
Organisation European Consortium of Urinary Traits
Country European Union (EU) 
Sector Charity/Non Profit 
PI Contribution Urine samples from participants in isolate and general population cohorts for detailed laboratory analysis of a range of phenotypic measures relevant to kidney function.
Collaborator Contribution Expertise in high-throughput analytical methods for analysis of urine samples, data from other cohorts and prediction of functional consequences.
Impact PMID: 24578125
Start Year 2010
 
Description GIANT 
Organisation Broad Institute
Department The Genetic Investigation of ANthropometric Traits (GIANT)
Country United States 
Sector Academic/University 
PI Contribution Genome-wide genotype and many anthropometric trait measures from a range of cohorts.
Collaborator Contribution Development of analysis plans and new software and methodologies for genetic analyses.
Impact PubMed ID
Start Year 2008
 
Description Generation Scotland 
Organisation Generation Scotland
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution To date in this collaboration, DNA from 14,000 GS:SFHS participants has been analysed by high density genome-wide chip genotyping. These results are being compared with those in published meta-analyses and the genome-wide data are being used by the QTL group in a range of research projects involving both international consortia and local experts. Our research team has recently been asked by the Generation Scotland Executive to form an Expert Working Group" in Genome-Wide Genetic Analysis. It has the remit to undertake and quality assure work on the GS:SFHS genome-wide genotype and its subsequent analysis and accessibility.
Collaborator Contribution The Generation Scotland Scottish Family Health Study (GS:SFHS) is a family-based genetic epidemiology cohort with DNA, other biological samples (serum, urine and cryopreserved whole blood) and socio-demographic and clinical data from approximately 24,000 volunteers, aged 18-98 years, in ~7,000 family groups. GS has been made possible through a unique partnership between the Scottish people, the NHS in Scotland and the Scottish University Medical Schools. Generation Scotland operates as a biobank and provided phenotype data and DNA samples for genome-wide analyses by the QTL group.
Impact PMID: 23521772 PMID: 25293386 PMID: 24944428 PMID: 24554214 PMID: 25078964 PMID: 24929828
Start Year 2012
 
Description Genetic correlations between diseases and production traits in dairy cattle 
Organisation Justus Liebig University Giessen
Country Germany 
Sector Academic/University 
PI Contribution We provided scientific input to a visiting scientist to implement a novel analysis based on human genetic approaches to estimate for the first time the genetic correlations between resistance to various infectious diseases and between diseases and production traits (e.g. early growth, milk production) in dairy cattle. This was the first time that this novel approach which allows genetic estimates of correlations between traits recorded in different animals to be used, had been applied in livestock
Collaborator Contribution The collaborators had collected a very large body of data on diseases and production traits on 20,000 dairy cattle together with whole genome genotypes on the relevant animals. Such data took several years to collect and involved many veterinarians and others to collect and classify disease traits. The genotyping alone of the cattle is likely to have cost 1,000,000 Euros. The data analysis was performed by a PhD student sponsored by the collaborators whilst he was visiting and based in our group in Edinburgh.
Impact The results of the analysis have been published (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194374) The data used in the analysis is stored in Edinburgh datashare and is available for our own future analyses and those of others (https://datashare.is.ed.ac.uk/handle/10283/3040) The collaboration involved animal scientists, geneticists and bioinformaticians.
Start Year 2017
 
Description Global Lipids Genetic Consortium 
Organisation Global Lipids Genetic Consortium (GLGC)
Country United States 
Sector Charity/Non Profit 
PI Contribution Genome-wide genotype and data generated by the EUROSPAN consortium, together with phenotype data relevant to the study of lipids.
Collaborator Contribution Analysis plans, methods and meta-analyses.
Impact PubMed ID 22359512
Start Year 2011
 
Description ICBP 
Organisation International Consortia of Blood Pressure (ICBP-GWAS)
Country United States 
Sector Public 
PI Contribution Genome-wide and imputed genotype data and detailed phenotype data relating to blood pressure.
Collaborator Contribution Analysis plans and meta-analyses.
Impact PubMed ID 21909115
Start Year 2009
 
Description MAGIC 
Organisation MAGIC
Country United Kingdom 
Sector Public 
PI Contribution Genotype and phenotype relating to insulin and glucose measures and related traits.
Collaborator Contribution Analysis plans and meta-analysis.
Impact PubMed ID 21962509, 22885924, 22581228
Start Year 2008
 
Description Regeneron Exome Sequencing 
Organisation Regeneron Pharmaceuticals, Inc.
Country United States 
Sector Private 
PI Contribution All fieldwork to collect samples and data, preparation of data dictionaries, pedigree verification, provision of purified DNA for sequencing. Analysis of the resulting exome sequencing data will be a collaboration involving both researchers from the QTL Group and from Regeneron.
Collaborator Contribution Library preparation and exome sequencing of approximately 9,000 DNA samples.
Impact No outcomes yet.
Start Year 2017
 
Description Reprogen 
Organisation ReproGen Consortium
Country Global 
Sector Academic/University 
PI Contribution Contribution of genome-wide genetic and detailed phenotype data relevant to reproductive health.
Collaborator Contribution Analysis plans and meta-analysis.
Impact Not multi-disciplinary. PubMed IDs 22267201
Start Year 2010
 
Description Spirometa 
Organisation SpiroMeta Consortium
Country Global 
Sector Academic/University 
PI Contribution Contribution of lung function phenotype and genome-wide genotype data to the Consortium.
Collaborator Contribution Analytical project plans and meta-analyses. Expertise in the lung function phenotype.
Impact Not multi-disciplinary. PubMed ID 21946350 PMID: 24929828
Start Year 2008
 
Description Stratifying Anxiety and Depression Longitudinally (STRADL) 
Organisation University of Aberdeen
Department Institute of Biological and Environmental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribution to design and performance of genetic analyses of data
Collaborator Contribution Contribution of data and trait domain expertise
Impact Publications are listed separately: Zeng et al (2017); Zeng et al. (2016 a, b); McIntosh et al. (2016); Fernandez-Pujals et al. (2016)
Start Year 2015
 
Description Stratifying Anxiety and Depression Longitudinally (STRADL) 
Organisation University of Dundee
Department College of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribution to design and performance of genetic analyses of data
Collaborator Contribution Contribution of data and trait domain expertise
Impact Publications are listed separately: Zeng et al (2017); Zeng et al. (2016 a, b); McIntosh et al. (2016); Fernandez-Pujals et al. (2016)
Start Year 2015
 
Description Stratifying Anxiety and Depression Longitudinally (STRADL) 
Organisation University of Glasgow
Department Institute of Health and Wellbeing
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribution to design and performance of genetic analyses of data
Collaborator Contribution Contribution of data and trait domain expertise
Impact Publications are listed separately: Zeng et al (2017); Zeng et al. (2016 a, b); McIntosh et al. (2016); Fernandez-Pujals et al. (2016)
Start Year 2015
 
Description Edinburgh International Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Edinburgh International Science Festival 2018 activities as part of College-wide exhibition, which sparked questions and discussions.
Year(s) Of Engagement Activity 2018
URL https://www.sciencefestival.co.uk/
 
Description MRC Festival 2018 - Celebrating Generation Scotland Participants 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Study participants or study members
Results and Impact Volunteers of the Generation Scotland cohort attended visited HGU/IGMM facilities and attended four short talks about some of the research that is done locally using Generation Scotland data.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/generation-scotland/news-events/latest-news/celebrating-generation-scotland-par...
 
Description Open Doors Day at the IGMM 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Part of the "Doors Open" initiative which allows members of the public to visit locations normally closed to public access. Presentations and demonstrations on work of the IGMM led to questions and discussions from visitors.
Year(s) Of Engagement Activity 2018
 
Description Orkney International Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact On 10th September 2018, researchers from the QTL Programme at the University of Edinburgh took part in the Orkney International Science Festival.
A number of talks were given, including four involving the ORCADES or VIKING cohorts.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/viking/whats-new/events/orkney-international-science-festival
 
Description Science Insights work experience week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Over the course of the busy Science Insights work experience week, 16 year old school pupils from 28 Scottish schools took part in interactive sessions with scientists, toured research facilities, met students, and visited a farm. They also participated in group discussions on ethics in research, the use of animals in research, and explored the relationship between science and the media. This is particularly useful for school pupils considering a degree course or other training in biomedical research.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/mrc-human-genetics-unit/news-and-events/news-2018/science-insights-work-experie...
 
Description Scottish group of the Society of Occupational Medicine meeting - Invited talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact SOM Scottish Regional Group, Autumm Meeting 2018. The programme covered informative talks about general medical issues which impact on fitness for work and are commonly seen in Occupational Health practice.
Year(s) Of Engagement Activity 2018
URL https://www.som.org.uk/scotland