Quantitative trait locus (QTL) identification in a Croatian isolate

Lead Research Organisation: University of Edinburgh

Abstract

The aim of this project is to identify genetic variants influencing susceptibility to common diseases. We are studying a large number of quantitatively varying traits (QTs) (>100 per person) in adult volunteers from isolated communities on the Dalmatian cost of Croatia. These communities have been studied for several decades by our Croatian collaborators. We then carry out whole genome association scans of the DNA samples from each individual using 320,000 genetic markers in order to identify susceptibility genes or regulatory variants. Positive associations are then replicated in other population samples.

Technical Summary

The aims of the study are, firstly, to genetically map and identify quantitative trait loci (QTL) influencing common human traits and disorders in isolated populations.

We have performed whole genome association analyses in samples obtained from an epidemiological field survey of 1,041 individuals from the island of Vis on the Dalmatian coast of Croatia and a similar number from the island of Korcula. Our Croatian collaborators are currently sampling volunteers from the city of Split on the Croatian mainland.

We propose to replicate and fine map the most significant QTL in other isolate and general population samples. Once this has been achieved, QTL will be identified by further genotyping and direct sequencing of candidate genes within each identified region.

In addition, we propose to estimate the genetic parameters and analyse the distributions of the >100 quantitative traits (QTs) analysed to date.

We are currently extending the field work by analysing further QTs (total of approximately 100) and harmonising the methods and choice of QTs with other members of the EUROSPAN FP6 consortium of isolate populations (Sweden, Netherlands, Croatia, Scotland, Italy).

We have carried out a 320,000 single nucleotide polymorphism (SNP) whole genome scan in 2,000 members from the Croatian isolate, to carry out a QT genetic association study.

Publications

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Ellis JW (2012) Validated SNPs for eGFR and their associations with albuminuria. in Human molecular genetics

 
Description DATA TRANSFER AND PERMITTED USE AGREEMENT
Amount £101,520 (GBP)
Organisation Pfizer Inc 
Sector Private
Country United States
Start 11/2014 
End 06/2015
 
Title Stable LCLs with targeted shRNA to IL6ST and IKZF1 
Description Lymphoblastoid cell line MATAT6 was chosen from a range of such lines previously generated at MRC HGU, for high level of IgG secretion. The genes encoding the interleukin-6 signal transducer (IL6ST) and IKZF1, encoding the transcription factor Ikaros-1, have been successfully targeted by multiple shRNAs, resulting in significant reductions (30-80%) in gene expression in six independent stable lines. Functional consequences are under investigation. 
Type Of Material Cell line 
Provided To Others? No  
Impact No impact as yet, but it is anticipated the research tool will be an important part of a forthcoming peer-reviewed research paper, and will be made available to other research groups on request, following publication. 
 
Description CCACE 
Organisation University of Edinburgh
Department MRC Centre for Cognitive Ageing and Cognitive Epidemiology
Country United Kingdom 
Sector Public 
PI Contribution The general cognitive ability (g) factor is strongly correlated with the other cognitive traits examined and shows high heritability. It is strongly predictive of many health related outcomes, including cognitive decline, dementia, cardiovascular disease and age at death and is a major focus of the current genome-wide association analyses being carried out in collaboration between the QTL and CCACE research groups.
Collaborator Contribution Participants in the CROATIA cohorts, the Viking Health Study and the Generation Scotland Scottish Family Health Study have undergone a range of tests, including detailed testing for cognitive traits using the same validated methods. These tests were led by the partners at CCACE who are experts in these phenotypic measures.
Impact Not multi-disciplinary. PubMed ID 17601350, 19290744, 18946731, 19077176, 25201988, 24944428, 24828478, 24573858, 24554214, 23722424, 22628180
Start Year 2006
 
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 CORNET 
Organisation Cortisol Network (CORNET)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Samples of plasma for cortisol measurement, together with genome-wide genotype data and analytical expertise and project management.
Collaborator Contribution Expertise in analytical measurements and additional genotypes for meta-analyses.
Impact Functional work on-going plus manuscript in preparation. Not multi-disciplinary. PubMed ID 23636447
Start Year 2009
 
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 DIAGRAM 
Organisation Diabetes Genetics Replication and Meta-Analysis (DIAGRAM) Consortium
Country United Kingdom 
Sector Academic/University 
PI Contribution Genome-wide genotype data and diabetes-related phenotype data on a variety of isolate cohorts.
Collaborator Contribution Analysis and meta-analysis methods.
Impact PubMed ID
Start Year 2008
 
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 GUGC 
Organisation Global Urate Genetics Consortium (GUGC)
Country Global 
Sector Charity/Non Profit 
PI Contribution Genome-wide genotype and detailed phenotypic data relevant to the study of gout.
Collaborator Contribution Analysis plans and meta-analyses.
Impact Not multi-disciplinary. PubMed ID 23263486
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 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 High Glycans 
Organisation High Glycans
Country Netherlands 
Sector Private 
PI Contribution Contributing plasma samples for analysis of glycans on a variety of different platforms. Performing meta-analysis of the output data.
Collaborator Contribution Quantifying glycan profiles in samples provided and returning data to the MRC HGU team.
Impact PubMed ID 22395466, 23274891, 24012618, 23382691, 21908519
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 MIMOMICS 
Organisation European Commission
Department Seventh Framework Programme (FP7)
Country European Union (EU) 
Sector Public 
PI Contribution Phenotype and genotype data for glycomics and lipidomics on isolates cohorts in support of the development of new analysis methods.
Collaborator Contribution Developing novel analysis methods using bioinformatics and other high throughput technologies.
Impact No outputs yet
Start Year 2013
 
Description NMR Metabolomics in Isolate Cohorts 
Organisation University of Edinburgh
Department Usher Institute of Population Health Sciences and Informatics
Country United Kingdom 
Sector Academic/University 
PI Contribution All fieldwork for sample collection and phenotyping, DNA extraction, genotyping and QC, transfer of samples for analysis.
Collaborator Contribution Funding provided in kind through a British Council Award for analysis of additional samples from isolate populations
Impact No outputs yet
Start Year 2017
 
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
 
Title Biomarkers for Pain 
Description A Data Use Licence was signed by MRCT with the University of Dundee, for the provision of data on genetic biomarkers associated with pain. These data were generated through MRC funding for the QTL Programme ie this award. 
IP Reference  
Protection Protection not required
Year Protection Granted 2014
Licensed Yes
Impact Research paper published (McIntosh et al, PLoS Medicine 2016, PMID 27529168)
 
Description ?        Presentations of the FAS Passive Surveillance Study 2010-2014 and The Ayrshire and Arran Pilot Project, to the Fourth European Conference on FASD September 12-15th at the Royal Holloway, University of London (Organised by the European FASD Alliance (www.eufasd.org) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentations of the FAS Passive Surveillance Study 2010-2014 and The Ayrshire and Arran Pilot Project, to the Fourth European Conference on FASD September 12-15th at the Royal Holloway, University of London (Organised by the European FASD Alliance (www.eufasd.org)
Year(s) Of Engagement Activity 2016
 
Description Farr Institute Case Study 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The activity was preparation and publishing a case study on the Farr Institute website, part of the series "100 ways of using data to make lives better"
Year(s) Of Engagement Activity 2016
URL http://www.farrinstitute.org/public-engagement-involvement/100-ways-of-using-data-to-make-lives-bett...
 
Description Fieldwork Consultancy 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Consultancy on fieldwork and sample handling standard operating procedures, provided by Dr Caroline Hayward to the World health organisation
Year(s) Of Engagement Activity 2013,2014
 
Description Genetic Ancestry Testing 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Prof Jim Wilson is a member of the American Society of Human Genetics Round Table on Genetic Ancestry Testing, white paper in preparation.
Year(s) Of Engagement Activity 2016,2017
 
Description IGMM Open Day 
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 The IGMM Open Day was part of the Edinburgh Doors Open Day event and attracted over 200 visitors. A range of activities was offered, including a poster about the work of the QTL Group
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/igmm/news-and-events/news-2017/over-200-visitors-igmm-open-day
 
Description MRC Festival of Medical Research 
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 As part of the MRC Festival of Medical Research, the MRC Institute of Genetics and Molecular Medicine organised a day of hands-on activities at Ocean Terminal, one of Europe's largest shopping and leisure centres. Shoppers were engaged with the DNA research happening at the Institute, through colourful hands-on activities, thought-provoking conversation and presentation of posters, under the overall theme of "People-powered DNA Research".
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/igmm/news-and-events/news-2017/people-powered-dna-research