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.

Publications

10 25 50
 
Description BBSRC Response mode
Amount £261,150 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2012 
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 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 06/2012 
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 University of Wageningen
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 Academic/University 
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 Public 
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 Public 
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 University Medical Center
Country Netherlands 
Sector Academic/University 
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
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/