Mapping the genetic architecture of global gene and exon expression in the human brain to understand common diseases

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Diseases affecting the brain are common and often devastating. Unfortunately, we know relatively little about why certain people suffer from psychiatric conditions like schizophrenia, or neurological conditions like Alzheimer?s and Parkinson?s disease. However, in the past 3 years scientists have been able to show that some individuals inherit risk factors in their DNA, which make them more likely to develop these conditions. Although this has been an amazing step forward, because most of the inherited risk factors are not within the part of the DNA that codes for proteins we still do not understand how these risk factors change the way cells in the brain behave to cause disease. Without this type of information we cannot begin to develop new and more effective treatments.
The aim of our work is to fill this gap in knowledge by investigating how inherited risk factors influence gene expression in the human brain so that we can better understand the causes of neurological and psychiatric disease. We hope to identify genetic variants in the DNA which not only increase the risk of having a disease of the brain, but also affect gene expression in brain regions already known to be important in disease. In this way we can start to pinpoint the systems or pathways in brain cells, which are causing the problem and hopefully provide the basic information that will lead to new treatments.
In this study we will use human brain tissue that has been donated for research by the deceased?s family to study the effect of inherited risk factors on the quantity and type of gene expression in different areas of the brain. We will use microarray technology to obtain detailed genetic and gene expression information about human brain tissue. The huge amount of information generated will be carefully analysed. The information this study will produce is likely to be of use to many researchers investigating a wide range of different diseases of the brain. Therefore, we will make sure that the results are made publicly available as soon as possible, while at the same time ensuring that information that could be used to identify individuals is protected.
Thus, we hope to be able to improve the understanding of the molecules and pathways that cause diseases of the brain and provide the basis for new treatments for diseases like Parkinson?s or schizophrenia.

Technical Summary

The aim of this project is to translate newly discovered genetic risk traits for complex neurological and psychiatric conditions into an understanding of pathogenesis. Until recently there seemed little hope of developing a genetic understanding of common diseases of the central nervous system (CNS). However, whole genome association studies of human disease are revolutionising our understanding of the aetiology of complex diseases, from psychiatric conditions such as drug addiction and schizophrenia on the one hand, to neurological conditions like Parkinson?s and Alzheimer?s disease on the other. These studies have demonstrated what has long been suspected, that common ?normal? variability contributes to the risk of common neurological and psychiatric disease. While some of the risk loci identified have been assigned to coding changes in genes, the majority have not, and many have not even mapped to recognisable genes.

Thus, knowing genetic risk variants for common diseases has not provided an automatic understanding of pathogenesis or obvious therapies. In order to address this problem we will study the genetic variability of gene expression within the human brain. The basis of our approach is the hypothesis that genetic differences in transcriptional regulation, which are present and measurable in control populations, are important drivers of pathology in the human CNS. If common genetic differences in transcriptional regulation can drive pathology in the human CNS, then we would expect to find strong associations between the risk SNPs identified in GWAs for neurological and psychiatric diseases and specific mRNA expression phenotypes of functional significance in control human brain.

We intend to use post-mortem control human brain tissue to collect samples from well-defined brain regions known to be particularly affected in the most common neurological and psychiatric diseases. Since risk-associated SNPs will be present in the control as well as the case population, using control brain tissue we can study downstream affects on gene expression without the complications of neuronal death, glial response and symptomatic treatments. Using microarray technology, we will produce high quality, genome-wide paired SNP and exon-specific expression data. Data analysis will be focused on identifying downstream gene expression changes associated with individual SNPs known to increase the risk of developing a neurological or psychiatric disease.

Thus, we will bridge the gap between genetic risk and pathophysiology. In this way, we will be able to point towards new therapeutic strategies for the early and effective treatment of human diseases of the CNS.

Publications

10 25 50
 
Description Project grant
Amount £100,000 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 12/2010
 
Title Human genome expression database 
Description Gene expression database. http://caprica.genetics.kcl.ac.uk:51519/BRAINEAC/ 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2010 
Provided To Others? Yes  
Impact It has been accessed several thousand times and data from it incorporated into at least 100 publications 
URL http://smarturl.it/braineac
 
Title Mouseac 
Description Database of gene expression in pathological mouse brain 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2014 
Provided To Others? Yes  
Impact This web resource of mouse gene expression is accessed 50 times per week and has referred to about 300 further publications 
URL http://www.mouseac.org/
 
Title Braineac - The Brain eQTL Almanac 
Description The Brain eQTL Almanac (Braineac) is a web-based resource to access the UK Brain Expression Consortium (UKBEC) dataset. The aim of Braineac is to release to the scientific community a valid instrument to investigate the genes and SNPs associated with neurological disorders. What is possible with BRAINEAC? - Visualise gene expression across the brain - SNP acting as cis-eQTL on a selected gene and know where it's located - Find if a one or more risk SNPs are operating as a eQTL and in which brain region - Download the expression data by genes or tissue to develop new methods 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact http://www.nature.com/neuro/journal/v17/n10/full/nn.3801.html 
URL http://www.braineac.org/
 
Title Mouseac - Web server for data from the Mouse Dementia Network 
Description Gene expression data from the Mouse Dementia Network (Mouse DemNet). The aim of Mouseac is to provide to the scientific community an easy to use tool to investigate gene expression changes in a number of mouse models of dementia across their lifespan relating to neurodegenerative disorders such as Alzheimer's disease. Mouseac is an interface that provides access to the dataset presented in Matarin et al [http://dx.doi.org/10.1016/j.celrep.2014.12.041]. The aim of Mouseac is to provide a tool with which to explore the dataset resulting from a genome-wide microarray of genes expressed in 3 brain regions across 4 ages in 5 transgenic mouse models of dementia and their wild-type counterparts. Detailed methodology can be found in the main manuscript. All procedures were performed in agreement with the UK Animals (Scientific Procedures) Act, 1988, under HO PPL licence 70/7279 with local ethical agreement and following the GlaxoSmithKline statement on the use of animals. 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact Open access research paper published in Cell Reports: Matarin M, Salih DA, Yasvoina M, Cummings DM, Guelfi S, Liu W, Nahaboo Solim MA, Moens TG, Paublete RM, Ali SS, Perona M, Desai R, Smith KJ, Latcham J, Fulleylove M, Richardson JC, Hardy J, Edwards FA. A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. Cell Rep. 2015 Feb;10(4) 633-644. doi:10.1016/j.celrep.2014.12.041. PMID: 25620700. By creating the website at http://www.mouseac.org/, all the data has been made freely available for scientists and the general public to use. 
URL http://www.mouseac.org/
 
Description Whole genome expression database 
Organisation National Institute on Aging
Department Laboratory of Neurogenetics
Country United States 
Sector Public 
PI Contribution We are just abouhttp://bit.ly/braineac (ignore certificate warning) username: UKBEC password: BraineacNOW t to relase this database to the general public
Collaborator Contribution We worked with our Us collaborators on this project (Singleton/Cookson): about half the work each
Impact Just search Ryten plus Singleton on pubmed These are the current PMID 23223016, 23177596, 22892372 , 22777693, 22723018, 22433082, 21738488 , 21292315
Start Year 2009
 
Description 2nd international Taiwanese Congress of Neurology and 2017 Annual meeting of Taiwan Neurological Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited speaker - talk title: Next Generation Sequence in Neurological Diseases: Clinical-Molecular Associations and Therapeutic Perspectives
Year(s) Of Engagement Activity 2017
 
Description 5th Venusberg Meeting, Bonn 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited speaker to the meeting talk title: "The genomics of neurodegeneration"
Year(s) Of Engagement Activity 2017
 
Description EMBL-EBI Industry Workshop on "Informatics Resources to Support Neurodegenerative Research - Dr Effie Mutasa-Gottgens, Senior Scientific Officer 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Genomic data integration to help with the target identification disease diagnosis in neurodegenerative disease research
Year(s) Of Engagement Activity 2017
 
Description Faculty of Medicine, University of Iceland Vatnsmyrarvegur 16 101 Reykjavik - Iceland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Distinguished speakers series
Year(s) Of Engagement Activity 2017
 
Description Genomic analysis of neurodegenerative disease 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk given at the following events:

- Nuffield Department of Clinical Neurosciences monthly seminar series, John Radcliffe Hospital, Oxford, 26/03/2015
- Federation of European Neuroscience Societies (FENS) Summer School, Bologna, Italy, 07/06/2015
- Annual Symposium of the Korean Academy of Science and Technology (KAST), Seoul, South Korea, 12/11/2015

In-depth discussion following the talks. Approached by potential collaborators.
Year(s) Of Engagement Activity 2015
 
Description Invitation from Hilary Evans Chief Executive Alzheimer's Research UK to participate in Roundtable talks 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact roundtable to consider 'where now for Alzheimer's disease research? Learning from clinical trials Solanezumab and planning for the future'
Year(s) Of Engagement Activity 2017
 
Description Meeting EMBO - Basal Life 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Plenary session 4 Genes to disease and therapies - René Bernards, Botond Roska, Christine Petit, John Hardy
Year(s) Of Engagement Activity 2017
 
Description Methusalem Lecture, Leuven, Belgium: The genetics of neurodegenerative disorders 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was two lectures, one to professionals and one to care-givers on the molecular biology of neurodegenerative diseases.
Year(s) Of Engagement Activity 2016
URL http://www.vib.be/en/research/scientists/Pages/John-Hardy-public-lecture.aspx
 
Description Pan-London regional teaching day for all the neurology registrars in London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Pan-London regional teaching day for all the neurology registrars in London - talk - Genomics and neurology
Year(s) Of Engagement Activity 2017
 
Description Visit and seminar Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taiwan 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker - Talk title: Genomic clues as to the reasons for selective vulnerability in neurodegenerative disease
Year(s) Of Engagement Activity 2017
 
Description World Congress of Brain, Behavior and Emotions, Porto Alegre, Brazil 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk entitled "The amyloid hypothesis for Alzheimer's disease: a critical reappraisal". Deep discussion ensued following talk.

Exchange of in-depth emails regarding Prof Hardy's presentation and key ideas.
Year(s) Of Engagement Activity 2015