The Genetics of Complex and Quantitative Traits

Lead Research Organisation: University of Edinburgh

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 KTN CASE Studentship
Amount £80,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2016 
End 08/2021
 
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 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 Establishing causal relationships from phenotypic, genotypic, and proteomic data.
Amount £233,584 (GBP)
Funding ID 204979/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2016 
End 07/2019
 
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 MRC response mode
Amount £17,672 (GBP)
Funding ID MR/N003179/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2015 
End 10/2018
 
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 STRADL - Wellcome Trust Programme Grant
Amount £4,787,640 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2019
 
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
 
Description Wellcome Trust ECAT Fellowship
Amount £233,584 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2016 
End 07/2019
 
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
 
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 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 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 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 Discussing careers in Science with S6 pupil 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I discussed careers in biomedicine with an S6 student and his family, as he was deciding which path to take to further his education. The student showed a lot of interest and subsequently I arranged a visit to the institute where he had the opportunity to talk to colleagues working in different areas of research to myself.
Year(s) Of Engagement Activity 2016
 
Description Doors open day 
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 Public/other audiences
Results and Impact Participation in open day at IGMM
Year(s) Of Engagement Activity 2015
 
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 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 2016 activities as part of College-wide exhibition, which sparked questions and discussions.
Year(s) Of Engagement Activity 2016
URL http://www.sciencefestival.co.uk/
 
Description Genomic Prediction workshop 
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 Organised a scientific workshop on the subject of genomic prediction / precision medicine to highlight our own and ongoing research. Around 10 presentations to a largely academic audience
Year(s) Of Engagement Activity 2015
 
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 Press release and wide press coverage for PLoS Genetics 12(2): e1005804 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A press release was issued for Xia et al. PLoS Genetics 12(2): e1005804 (http://www.eurekalert.org/pub_releases/2016-02/uoe-clc022216.php)
The piece was reported in more than 130 English-language media (European, Asian and Australian) and several websites in other languages.
Year(s) Of Engagement Activity 2016
URL https://news.google.com/news/story?cf=all&hl=en&pz=1&ned=uk&q=obesity+edinburgh&scoring=d&cf=all&ncl...
 
Description Press release based on Nature Genetics publication 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A press release was made describing our paper: "Evaluating the contribution of genetic and familial shared environment to common disease using the UK Biobank
Munoz, M., Pong-Wong, R., Canela-Xandri, O., Rawlik, K., Haley, C. & Tenesa, A. Sep 2016 In : Nature Genetics. 48, 9, p. 980-983". This resulted in articles in several daily newspapers in the UK as well as overseas.
Year(s) Of Engagement Activity 2016
 
Description Radio Berkshire Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interview on Anne Diamond show to discuss work on genetic and environmental control of obesity related traits
Year(s) Of Engagement Activity 2016
 
Description Sciennes Science Fair 2015 
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 I co-organised the parent led Science Fair at Sciennes school in 2015. I got in touch and coordinated participation from various researchers from the University of Edinburgh, including Volcanologists, Mineralogists, Computing Scientists, Chemists, Mathematicians and Neuroscientists. Activities were set up in the school and made available to pupils, their families and the general public. The fair was very well attended, and engagement with the activities was very good, sparking lots of questions. The audience was estimated to be in excess of 1000 people.
Year(s) Of Engagement Activity 2015
URL http://sciennesnewsflash.blogspot.co.uk/2015/06/remarkable-parent-led-summer-science.html?spref=fb
 
Description Sciennes Science Fair 2015 
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 In Summer 2015, Pau Navarro organised, together with Aileen Nimmo a Science Fair at Sciennes Primary School. The fair was visited by over 1000 people and greatly successful. Dr Navarro gathered colleagues and collaborators from within the University, organising the science activities within the school and lead the IGMM activities at the event, in which 2 further group members (Richard Oppong and Athina Spiliopoulou) participated, as well as Roslin Institute and IGMM collaborators.
Hundreds of families and children, as well as teachers, participated in our 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 of our interlocutor(s).The feedback from the school, parents, children and teachers was very good, and further editions of such event are planned. The event might occur on a bi-yearly basis in principle.
Year(s) Of Engagement Activity 2015
URL http://sciennesnewsflash.blogspot.co.uk/2015/06/remarkable-parent-led-summer-science.html?spref=fb
 
Description Visit to Cubs and Rainbows groups 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact In 2013-2015, Pau Navarro organised genetics workshops and participated a science -related activities at the 72nd Brownies Girlguiding group and 85th-a Cub Scouts group from Edinburgh. Each activity engaged ~20 children and 4 adults. The workshops were received enthusiastically by both adults and children, and sparked questions and discussions.
Year(s) Of Engagement Activity 2013,2014,2015
 
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
 
Description Visit to Rainbows group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Annual visit to my local Rainbow unit, that is received with lots of enthusiasm by both girls and leaders. We discuss cells and inheritance, and do related crafty activities. This year we built cells in petri dishes with airdough. The visits sparks lots of interest and questions. It is used by the unit leaders as both a science and a "girls can" activity, and to promotes the visibility of women in science in this case.
Year(s) Of Engagement Activity 2016
 
Description Visit to Sciennes Primary School 
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 We have made a series of workshops with P4 pupils talking about science, cells and genetics, that were welcome with a lot of interest by staff and students. The school reports that the visits really enrich the way curricular content is delivered, and that they are valued by staff and students. PhD students in our group (Charley Xia and Richard Oppong) also joined the workshops.
Year(s) Of Engagement Activity 2014,2016