The Genetics of Complex and Quantitative Traits
Lead Research Organisation:
MRC Human Genetics Unit
Abstract
People differ from one another for almost any characteristic one looks at. These characteristics include obvious ones such as height and weight as well as less immediately apparent traits such as blood pressure or susceptibility to cancer. This variation between people is usually under the control of a number of different genes and environmental influences. If we could understand and measure the various genetic and environmental factors that contribute to differences between people then we will be in a better position to understand the causes of disease and to design new drugs to treat disease and perhaps to predict who may in future suffer from disease and treat them to reduce the risk. Scientists have only just developed the methods and studies that allow them to analyse variation between people effectively. Many genes have been identified in recent years in these studies and these have allowed new biological processes to be identified and new understanding of disease to be obtained. In this research we are attempting to develop new methods to more effectively analyse the data from such studies. This will lead to improved understanding of disease processes and ultimately to improved treatment and outcome of disease.
Technical Summary
This programme aims to aid development of an understanding of the genetic control of complex traits. For such traits inter-individual variation within and between populations is controlled by variation at a number of genes, by environmental factors and by the complex interactions of these components. Most variation between individuals within and between populations is in the form of complex traits. Consequently variation in complex traits is responsible for most inter-individual variation in susceptibility to disease (both infectious and metabolic) and underlies responses to selection, both natural and artificial. Thus understanding the genetic architecture of complex traits, both in general and for specific traits in particular populations, is essential if we are to understand why and how individuals vary. We can only be really effective in understanding and treating many diseases, in predicting individuals risk of developing particular conditions and in dissecting the causes and consequences of natural selection if we understand the genetic control of variation in complex traits.||The research focuses on developing a general understanding of the control of complex traits illustrated by results from specific examples. It has involved the development of specific experimental studies and the resources necessary to implement these studies together with the development and application of methods and tools capable of analysing and interpreting the data generated by my group and our collaborators. Genome-wide association studies (GWAS) have identified a loci contribution to a number of different traits including both diseases and variation between healthy individuals. This has led to the identification of new loci and pathways that underlie variation. However, for most traits only a very limited proportion of the variation can be explained by the detected loci. These identified loci thus are of limited predictive value if used to identify individuals at risk of developing disease. We are exploring a number of different approaches for identifying additional genetic variation in genome-wide association studies. Current GWAS analyses are aimed at detecting individual loci with common alleles and relatively simple genetic effects. This is implemented in analyses that explore the data for associations between individual marker loci and trait variation. One line of our research is exploring the use of multiple marker loci and marker haplotypes for the identification of trait loci with rarer alleles. In a second series of projects we are analysing data for evidence of genetic interactions between loci that contribute to trait variation. In a final series of projects we are attempting to improve the power to predict disease risk by utilising genome-wide prediction algorithms that utilise information from many loci and not just those that pass stringent significance thresholds. These projects utilise real and simulated data to test the effectiveness of alternative analytical approaches. The real data is generated by collaborators within the Human Genetics Unit and elsewhere.
Organisations
- MRC Human Genetics Unit, United Kingdom (Lead Research Organisation)
- University of Oxford, United Kingdom (Collaboration)
- Jiangxi Agricultural University (Collaboration)
- Justus-Liebig University Giessen, Germany (Collaboration)
- University of Turku, Finland (Collaboration)
- University of Edinburgh, United Kingdom (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- Wageningen University & Research (Collaboration)
- China Agricultural University, China (Collaboration)
- Helmholtz Association of German Research Centres (Collaboration)
- Pharmatics Limited (Collaboration)
- MTT Agrifood Research Finland (Collaboration)
- Aviagen Group (Collaboration)
- Erasmus MC (Collaboration)
- University of Queensland, Australia (Collaboration)
- Massey University, New Zealand (Collaboration)
- Boston University, United States (Collaboration)
- University of Manchester, Manchester, United Kingdom (Collaboration)
Publications

Boulton K
(2011)
QTL affecting morphometric traits and stress response in the gilthead seabream (Sparus aurata)
in Aquaculture

Bown MJ
(2011)
Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1.
in American journal of human genetics

Cabrera C
(2012)
Uncovering Networks from Genome-Wide Association Studies via Circular Genomic Permutation
in G3 Genes|Genomes|Genetics

Cabrera CP
(2012)
Complex traits analysis of chicken growth using targeted genetical genomics.
in Animal genetics

Calus MP
(2010)
Including copy number variation in association studies to predict genotypic values.
in Genetics research

Cousminer DL
(2013)
Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.
in Human molecular genetics


Den Hoed M
(2013)
Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
in Nature genetics

Dupuis J
(2010)
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
in Nature genetics

Eijgelsheim M
(2010)
Genome-wide association analysis identifies multiple loci related to resting heart rate.
in Human molecular genetics
Description | BBSRC Response mode |
Amount | £261,150 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2012 |
End | 04/2015 |
Description | BBSRC Response mode |
Amount | £577,000 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2012 |
End | 04/2015 |
Description | Exploiting large-scale exome sequence data to determine the genetic control of healthy aging |
Amount | £72,000 (GBP) |
Funding ID | 2274606 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2019 |
End | 08/2023 |
Description | Exploiting large-scale exome sequence data to determine the genetic control of healthy aging-BBSRC NATIONAL PRODUCTIVITY INVESTMENT FUND (NPIF) STUDENTSHIPS |
Amount | £72,000 (GBP) |
Funding ID | BB/S508032/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2019 |
End | 08/2023 |
Description | Gene-by-environment interactions in depression |
Amount | £80,000 (GBP) |
Funding ID | 2096818 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2018 |
End | 02/2022 |
Description | Investigating the genetic architecture of complex traits in Soay sheep |
Amount | £72,000 (GBP) |
Funding ID | 2278106 |
Organisation | Natural Environment Research Council |
Sector | Public |
Country | United Kingdom |
Start | 07/2019 |
End | 08/2023 |
Description | Investigating the mechanisms underlying disease using multiOmics data |
Amount | £72,000 (GBP) |
Funding ID | 2259226 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2019 |
End | 02/2023 |
Description | PI ISIS travel fund to Wenhua Wei |
Amount | £1,400 (GBP) |
Funding ID | BB/K004964/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 05/2012 |
End | 07/2012 |
Description | Tools and Resources Development Fund |
Amount | £107,308 (GBP) |
Funding ID | BB/H024484/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2010 |
End | 05/2012 |
Title | BiForce |
Description | CPU based analysis of epistasis in genome-wide association studies |
Type Of Material | Technology assay or reagent |
Year Produced | 2012 |
Provided To Others? | Yes |
Impact | unknown |
Title | EpiGPU |
Description | Provision of past GPU based analysis software for detection of epistasis in genome-wide association studies. |
Type Of Material | Technology assay or reagent |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | unknown |
Title | GridQTL |
Description | GridQTL is an online resource for data analysis allowing mapping of QTL (www.gridqtl.org.uk). This has developed over a number of years including during the course of this project by myself and a member of my group. Our particular contribution in recent past has been theimplementation of methods fr mapping epistatic interactions in structured experimental populations. |
Type Of Material | Technology assay or reagent |
Year Produced | 2009 |
Provided To Others? | Yes |
Impact | The development of the software has allowed analyses of epistasis fr the first time in a number of populations. This has resulted in somenew collaborations and a resulting publication. |
URL | http://www.gridqtl.org.uk |
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 | Aquafirst |
Organisation | Wageningen University & Research |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | Joint supervision of student analysing genomic data |
Collaborator Contribution | Supported joint studentship |
Impact | Trained student, PhD thessis, publications (listed separately), meeting presentations |
Start Year | 2006 |
Description | Aviagen studentship |
Organisation | Aviagen Group |
Country | United States |
Sector | Private |
PI Contribution | Supervised student |
Collaborator Contribution | Sponsored one PhD student |
Impact | Trained student, meeting presentations, PhE Thesis, papers in preparation. |
Start Year | 2006 |
Description | BBSRC Toolbox prediction project |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | We are performing research to develop computational prediction of health and disease outcomes utlising genomics and life style data funded by the BBSRC |
Collaborator Contribution | Provide access to large population data and advice |
Impact | Publications |
Start Year | 2012 |
Description | BBSRC Toolbox prediction project |
Organisation | Pharmatics Limited |
Country | United Kingdom |
Sector | Private |
PI Contribution | We are performing research to develop computational prediction of health and disease outcomes utlising genomics and life style data funded by the BBSRC |
Collaborator Contribution | Provide access to large population data and advice |
Impact | Publications |
Start Year | 2012 |
Description | DIAGRAM |
Organisation | University of Oxford |
Department | Wellcome Trust Centre for Human Genetics |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | Data analysis |
Collaborator Contribution | Participation in large consortium for T2D meta-analysis and related subprojects, including 1000Genomes imputation group |
Impact | 1 Publication in Nature and 1 in Nature Genetics. Further 2 manuscripts in preparation. |
Start Year | 2008 |
Description | EC funded Integrated Project SABRE |
Organisation | Jiangxi Agricultural University |
Department | Key Laboratory for Animal Biotechnology |
Country | China |
Sector | Academic/University |
PI Contribution | We developed a GridQTL module to allow high thoughput epistasis analysis for linkage mapping populations derived from structured crosses. Wenhua developed the collaboration project and won an award of 5000 Euros from SABRE. Wenhua visited the collaborator, host a return visit, performed data analyses, drafted and published a paper. |
Collaborator Contribution | Provide data of a large F2 mapping population for high throughput epistasis analyses |
Impact | One paper published in Animal Genetics. Another paper is in preparation by the collaborator. This is a multi-disciplinary collaboration involving animal genetics, statistical genetics and computing. |
Start Year | 2008 |
Description | Epicluster project collaborator |
Organisation | University of Turku |
Department | Finnish DNA Microarray Centre |
Country | Finland |
Sector | Academic/University |
PI Contribution | We put together a research grant proposal to develop a fast tool for high-throughput epistasis analysis. We also developed statatistical analysis methodology. |
Collaborator Contribution | Dr Attila Gyenesei will provide bi-clustering algorithm and a prototype (in Java) to select SNPs for epistasis testing. He will also consult and host visits to train the project postholder. In addition, he will directly involve in the tool development and data analyses. |
Impact | A grant awarded by BBSRC Tools and Resources Development Fund A computational biologist recurited. This is a multi-disciplinary collaboration involving stastistical genetics, bioinformatics and computing. Several publications resulted |
Start Year | 2009 |
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 | GridQTL eggshell epistasis analysis |
Organisation | MTT Agrifood Research Finland |
Country | Finland |
Sector | Academic/University |
PI Contribution | Helped with data analyses using GridQTL automated software and paper editing |
Collaborator Contribution | Data for analysis |
Impact | A paper is published in Animal Genetics. This collaboration helped algorithm development and testing. This is a multi-disciplinary collaboration invovling animal genetics, statistical genetics and computing. |
Start Year | 2008 |
Description | GridQTL normal mapping analysis |
Organisation | China Agricultural University (CAU) |
Department | State Key Laboratory for Agrobiotechnology |
Country | China |
Sector | Academic/University |
PI Contribution | Helped with QTL linkage analysis using GridQTL automated software and edited the manuscript |
Collaborator Contribution | Data for analysis |
Impact | A paper published in Animal Genetics. This is not a multi-disciplinary collaboration |
Start Year | 2009 |
Description | Haplotype analysis |
Organisation | University of Edinburgh |
Department | Institute of Evolutionary Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Joint supervision of three PhD Students |
Collaborator Contribution | Supported two studentships on haplotype analysis |
Impact | two PhD theses so far, two trained post graduate sudents, presentations at meetings, papers in preparation. |
Start Year | 2006 |
Description | MAGIC |
Organisation | Boston University |
Department | Department of Biostatistics |
Country | United States |
Sector | Academic/University |
PI Contribution | Data analysis |
Collaborator Contribution | Paticipation in fasting glucose, insuline and related traits large consortium meta-analysis and related subprojects |
Impact | 1 Publication in Nature Genetics. Further 2 manuscripts in preparation. |
Start Year | 2008 |
Description | QTGEN |
Organisation | Helmholtz Association of German Research Centres |
Country | Germany |
Sector | Academic/University |
PI Contribution | Data analysis |
Collaborator Contribution | Participation in large consortium and meta-analysis for ECG traits |
Impact | Manuscript in preparation |
Start Year | 2009 |
Description | RRGEN |
Organisation | Erasmus MC |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | Data analysis |
Collaborator Contribution | Participation in large consortium and meta-analysis for ECG traits |
Impact | Publication in Human Molecular Genetics |
Start Year | 2008 |
Description | Roslin Institute |
Organisation | University of Edinburgh |
Department | The Roslin Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Joint supervision of students, involvement in projects on gene networks, genetic diversity, disease resistance, genomic analysis tools |
Collaborator Contribution | Contribution to joint research projects and publications |
Impact | A number of collaborative papers listed under publications, trained post graduate students, PhD theses, meeting presentations |
Description | Selenium rich green tea work |
Organisation | Massey University |
Department | Institute of Food, Nutrition and Human Health |
Country | New Zealand |
Sector | Academic/University |
PI Contribution | Initiated the collaboration to investigate potential synergistic effiects of a green tea rich in selenium. Contributed to problem formulation, experiment design and paper editing. |
Collaborator Contribution | Intellectual input and experimentation |
Impact | Two papers and one book chaper published (one with MRC address). A few more to come. This is a multi-disciplinary collaboration involving animal genetics, human genetics, microbiology, biochemistry, nutrition. |
Description | WW Manchester |
Organisation | University of Manchester |
Department | Arthritis Research UK Centre for Epidemiology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Review of epistasis |
Collaborator Contribution | Review of epistasis |
Impact | Nature Review Genetics Publication |
Start Year | 2013 |
Description | WW Manchester |
Organisation | University of Queensland |
Department | University of Queensland Diamantina Institute |
Country | Australia |
Sector | Academic/University |
PI Contribution | Review of epistasis |
Collaborator Contribution | Review of epistasis |
Impact | Nature Review Genetics Publication |
Start Year | 2013 |
Description | BBSRC Showcase for Industry 3/12/12 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Poster Presentation |
Geographic Reach | National |
Primary Audience | Health professionals |
Results and Impact | Presented project work to invited representative from biotech and pharmaceutical industries None as yet |
Year(s) Of Engagement Activity | 2012 |
Description | Edinburgh Alliance for Complex Trait Genetics |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Co-organise a twice-yearly meeting to coordinate complex trait genetic research focussed on Edinburgh but with national participation. |
Year(s) Of Engagement Activity | 2011,2012,2013,2014,2015,2016,2017,2018,2019,2020 |
URL | https://www.wiki.ed.ac.uk/display/eactg/Edinburgh+Alliance+for+Complex+Trait+Genetics |
Description | Edinburgh International Science Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Several members of the group have participated for the last years in the MRC-HGU or IGMM public engagement activities at the Edinburgh Science Festival. Hundreds of families and children participated in various hand-on activities related to genetics. This sparked questions and discussions both from adults and children from different backgrounds, and we engaged with them tailoring our dialogue to the appropriate level according to our interlocutor(s). The feedback from both the public and the organisers has consistently been very good. unknown |
Year(s) Of Engagement Activity | 2011,2012,2013,2014,2015 |
URL | http://www.sciencefestival.co.uk/ |
Description | Participation in an activity, workshop or similar - Visit to CEIP 9 D'OCTUBRE (ALCÀSSER, Spain) Pre-School and Primary School for the 2020 International Day of Women and Girls in Science |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | Main event 30/01/2020, with engagement prior to the visit (sending introductory letter, discussing prior activities with teaching staff) and following-up (ongoing) additional science/genetics related activities. To kick off activities related to the 2020 International Day of Women and Girls in Science, Pau Navarro visited the Pre-School and Primary School CEIP 9 D'OCTUBRE (ALCÀSSER, Spain). She engaged with 250 pupils between the ages of 3 and 7 (2 classes each of 25 pupils for 3, 4 and 5 year-olds (pre-school), and 2 classes each of 6 and 7 year-olds (primary 1 and 2 equivalent)), their teaching and support staff and parent volunteers. The activities were delivered to eight groups of 25 pupils each (3-6 year-olds) and a single group of 50 7 year-olds. The activities were designed to explain to the pupils what being a scientist means, and let them have a go at being a hands-on budding one through observation and description of objects looked at through magnifying glasses, a traditional microscope and a small digital camera and a microscope attached to a phone that allowed recording of images. The activity was tailored to the different age groups and discussions with the primary school groups also involved introducing the concepts of phenotypic variation, inheritance and chromosomes. Engagement with the pupils started prior to the visit through an introductory letter sent to the pupils, and a series of tasks (i.e., collect interesting objects, prepare questions for the visiting scientist), and has continued after, with primary school children continuing activities introduced during the visit (i.e. looking at photos of cells under the microscope and drawing with detail, "colourful chromosomes activity), and preparation of further question list with questions that were sparked by the visit. We are working on preparing a web story jointly with the pupils. |
Year(s) Of Engagement Activity | 2020 |
Description | Visit to IGMM from High School student |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | An S6 pupil trying to decide on his future career visited the IGMM, in a visit that I organised and talked to a series of colleagues about their research. He reported that the visit was really useful and helped him decide on the path he wants to take to further his education. |
Year(s) Of Engagement Activity | 2016 |
Description | Visit to James Gillespies Secondary School to discuss Maths in the workplace |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Albert Tenesa liaised with the maths faculty at James Gillespies High School to organise an afternoon with senior (S4-S6) maths pupils, to discuss the application of maths in the workplace and career options. As part of a team of 8 researchers, I delivered a presentation that included: 1. What my undergraduate studies were, and how maths featured in the curriculum (agricultural engineering) 2. An example of PhD work (animal breeding and gene mapping) 3. An example of ealy Postdoc work (mapping in psychiatric studies) 4. An example of current work (population structure) This was followed bya a Q&A session with stutentd and staff. The school reported that the pupils were very interested having seen the breath of careers maths can be useful in, and the younger pupils found that the talks were helpful in guiding their future academic choices. One of the pupils has gone on to study biology and statistics at St Andrews and was keen to find out more JGHS faculty put her in touch directly and I arrange a vistit for her to talk to colleagues in 2019. The event will in principle run in 2019 as well, and has provided the school with a welcome direct link with quantitative scientists they can get pupils in touch with to discuss carreer options. |
Year(s) Of Engagement Activity | 2018 |