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.
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.
Organisations
- University of Edinburgh, United Kingdom (Collaboration, Lead Research Organisation)
- Global Lipids Genetic Consortium (GLGC) (Collaboration)
- ReproGen Consortium (Collaboration)
- CKDGen Consortium (Collaboration)
- Global Urate Genetics Consortium (GUGC) (Collaboration)
- High Glycans (Collaboration)
- University of Glasgow, United Kingdom (Collaboration)
- Broad Institute (Collaboration)
- Regeneron Pharmaceuticals, Inc. (Collaboration)
- Consortium for Refractive Error and Myopia (Collaboration)
- University of Dundee, United Kingdom (Collaboration)
- Generation Scotland (Collaboration)
- University of Aberdeen, United Kingdom (Collaboration)
- Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE) (Collaboration)
- MaGIC (Collaboration)
- European Consortium of Urinary Traits (Collaboration)
- Diabetes Genetics Replication and Meta-Analysis (DIAGRAM) Consortium (Collaboration)
- SpiroMeta Consortium (Collaboration)
- European Commission, Belgium (Collaboration)
- International Consortia of Blood Pressure (ICBP-GWAS) (Collaboration)
- Cortisol Network (CORNET) (Collaboration)
Publications
Zoldoš V
(2012)
Epigenetic silencing of HNF1A associates with changes in the composition of the human plasma N-glycome.
in Epigenetics
Miljkovic A
(2012)
Heritability analysis suggests comparable genetic component of mechanical pain threshold and tolerance.
in Pain medicine (Malden, Mass.)
Pattaro C
(2012)
Genome-wide association and functional follow-up reveals new loci for kidney function.
in PLoS genetics
Verhoeven VJ
(2012)
Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium.
in Human genetics
Demirkan A
(2012)
Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations.
in PLoS genetics
Murabito JM
(2012)
Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.
in Circulation. Cardiovascular genetics
Cipriani V
(2012)
Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3.
in Human molecular genetics
Scott RA
(2012)
Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.
in Nature genetics
Okada Y
(2012)
Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations.
in Nature genetics
Stolk L
(2012)
Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.
in Nature genetics
Girotto G
(2011)
Hearing function and thresholds: a genome-wide association study in European isolated populations identifies new loci and pathways.
in Journal of medical genetics
Kornfeld JW
(2011)
Variants in STAT5B associate with serum TC and LDL-C levels.
in The Journal of clinical endocrinology and metabolism
Bakija-Konsuo A
(2011)
Leprosy epidemics during history increased protective allele frequency of PARK2/PACRG genes in the population of the Mljet Island, Croatia.
in European journal of medical genetics
Dehghan A
(2011)
Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.
in Circulation
Obeidat M
(2011)
A comprehensive evaluation of potential lung function associated genes in the SpiroMeta general population sample.
in PloS one
Smith NL
(2011)
Genetic predictors of fibrin D-dimer levels in healthy adults.
in Circulation
Zhu H
(2011)
The Lin28/let-7 axis regulates glucose metabolism.
in Cell
Facheris MF
(2011)
Variation in the uric acid transporter gene SLC2A9 and its association with AAO of Parkinson's disease.
in Journal of molecular neuroscience : MN
Polašek O
(2011)
Does inbreeding affect N-glycosylation of human plasma proteins?
in Molecular genetics and genomics : MGG
McKay GJ
(2011)
Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies.
in Human mutation
Pucic M
(2011)
High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG glycome in three isolated human populations.
in Molecular & cellular proteomics : MCP
Wain LV
(2011)
Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
in Nature genetics
Oexle K
(2011)
Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels
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 | 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, 29093028, 28586769, 27915449, 26966016 |
| 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 | Academic/University |
| 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 | Lothian Birth Cohorts |
| Organisation | University of Edinburgh |
| Department | MRC Centre for Cognitive Ageing and Cognitive Epidemiology |
| Country | United Kingdom |
| Sector | Academic/University |
| 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 LBC 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 LBC 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 | 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. PMID: 24929828, 30804561, 30175238, 28082375, 26404118, 26395457, 21625484, 20010834 |
| 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 |
| 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 | No |
| 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 |