Research Programme
Work Package 2 - Functional Enviromics
WP-Leaders: Craig Morgan (IoP) and Robin Murray (IoP)
Our primary objective is to investigate the relationship between exposure to candidate environmental risk factors (i.e., migration and ethnicity, urbanicity, cannabis and other substance use, and developmental adversity including childhood trauma) and the onset of schizophrenia spectrum disorders.
Our specific aims are:
- To develop and apply methods for the detailed assessment of candidate environmental exposures, at both individual and area levels, for use in this and other work packages
- To investigate the impact of hypothesised environmental exposures, measured at individual and area levels, on: a) risk of schizophrenia spectrum disorders; and b) high rates of disorder in urban centres and in migrant and ethnic minority groups
- To examine evidence for a) hypothesized gene x environment interactions; and b) hypothesized environment x environment interactions across the life course
- To develop a translational environmental risk assessment chart
We will meet these aims by conducting, over a three-year period, directly comparable population based incidence and case-control studies of schizophrenia spectrum disorders in 12 centres across 5 countries (see Figure.), yielding (from approximately 2,410,000 persons at risk, or 7,230,000 person years) a sample of around 1,200 incident cases, 600 siblings and 1,200 controls. This sample will be further bolstered by the addition of a site in Ribeirão Preto, Brasil (Lead: Dr. Paulo Menezes), which will contribute around an additional 300 cases, 150 siblings and 300 controls. We will collect extensive data from cases, siblings and controls across a number of domains, including genetic (e.g., DNA, family histories of mental illness), socio-environmental (e.g., childhood and adult adversity, characteristics of neighbourhoods), social cognition (e.g., cognitive schema and biases) and clinical (e.g., nature and duration of symptoms).
Our analyses of these extensive data will enable us to more fully understand how environmental, genetic and other factors interact to increase risk of schizophrenia spectrum disorders, particularly in urban areas and in migrant and minority ethnic populations. This will have important implications both for prevention and for treatment.
Lead and participating researchers in each site:
Spain Miguel Bernardo (Barcelon); Ailicia Valiente (Bareclona); Julio Bobes (Oviedo); Pilar Saiz (Oviedo); Celso Arango (Madrid); Julio Sanjuan (Valencia); France Andrei Szoke (Creteil); Marion Leboyer (Creteil); Jeanne Vilain (Creteil); Pierre-Michel Llorca (Clermont-Ferrand); Jordane Durand-Roger (Clermont-Ferrand); Anne-Marie Tronche (Clermont-Ferrand); The Netherlands Lieuwe de Haan (Amsterdam); Jean-Paul
For a map with the locations of the partners, click HERE
Work Package 3 - Discovery Genetics
WP-Leaders: Michael O'Donovan (CU) and Mike Owen (CU)
The genetics work package will contribute to the goals of the EU-GEI by identifying and measuring specific genetic variants to be tested for interaction with the environmental measures being collected by the consortium. To this end, we will adopt a number of strategies, some currently planned, others based upon new approaches are emerging in this fast moving field.
A main goal will be to identify risk variants with already strong evidence for their involvement in schizophrenia as these are also most likely to show variable effects that depend upon environmental exposure. A small number of genetic risk variants for schizophrenia have already been identified by EU-GEI members through genome-wide association studies (GWAS). GWAS simultaneously extract information about the possible involvement in disease of nearly every human gene without having to guess in advance which are most likely to be involved. This is useful because researchers have not been good at predicting genes that are relevant to most diseases, indeed in less that 1 year, GWAS have identified many more genetic risk factors for common disorders than all the research in the proceeding 20 years.
Those with strong evidence for association will be drawn from a synthesis of the publically available GWAS data, which we expect during the first year will include approximately 20,000 cases and 20,000 controls. Additional targets will be taken from updated meta-analyses across the world datasets.
It is possible, some would say likely, that many variants that do not show observable effects on their own may do so when aspects of the environment are allowed for, indeed there may be genetic variants that are in some circumstances beneficial, in others detrimental, to health. Aiming to identify these, in collaboration with the statistics work package (WP8), we will generate GWAS data in several thousand EU-GEI subjects to facilitate genome-wide GxE studies that will test virtually every gene for evidence for interaction with aspects of the environment.
As a complement to the above tests that are not based upon particular functional hypotheses, we will also conduct a wide ranging series of hypotheses based tests. As an example we will identify and test individually or in groups, candidate genetic variants based upon knowledge of their functions, the hypothesis being that variants that influence the function of particular genes that might be predicted to interact with particular aspects of the environment. One example would be to test for interaction with psychosocial adversity, variants that regulate genes involved in the stress response
Overall, it is expected that by identifying genes and interacting aspects of the environment, we will understand better how the genes exert their effects in people with schizophrenia, identify ways to minimise risk in those for whom it is particularly high, and obtain targets for novel treatments for people in whom disease is already manifest.
Work Package 4 - Experimental GxE
WP-Leaders: Andreas Meyer-Lindenberg (CIMH) and Marcus Leweke (CIMH)
Work Package 5 - GxE Prodrome
WP-Leaders: Philip McGuire (IoP) and Lucia Valmaggia (IoP)
Work Package 6 - GxE Vulnerability & Severity
WP-Leaders: Cem Atbasoglu (AU) and Meram Can Saka (AU)
Work Package 7 - GxE Course
WP-Leaders: Inez Myin-Germeijs (UM) and Richard Bruggeman (UM)
G*E in the course of psychosis
Workpackage 7 is designed to improve our understanting of the course of clinical and subclinical psychosis over time and the role of G*E interactions herein. The objectives are:
- To assess the 6-year course of illness and cognition in a sample of patients with recent-onset illness and course of schizotypy and cognition in their siblings (assessed at 3 time points: T0, three years later (T1) and 6 years later (T2))
- To assess the clinical, environmental and genetic determinants of course and outcome in these two groups
- To examine gene-environment interactions underlying course and outcome
Workpackage 7 is closely linked to the Dutch National Group Study (Genetic Risk and Outcome of Psychosis Study), a joint effort between 4 Universities (AMC Amsterdam; MUMC Maastricht, UMC Groningen, UMC Utrecht) and several mental health care institutions all over the Netherlands and Flanders, Belgium. The baseline assessment has already been conducted including 1120 patients with psychosis, 1057 of their siblings, 919 of their parents, and 590 controls. The second assessment (T1) is well on its way and will be ended by the end of 2010, with the start of T2 in the beginning of 2011.
This workpackage also includes a user-led stigma project, with a focus on the impact of stigma on the course of schizophrenia, as well as on the coping strategies that may be important in treatment and psycho-education.
Finally, this workpackage also aims to develop two translational tools that can be used in clinical practice. First, we aim to develop a Risk Assessment Chart indexing clinical, environmental and genetic determinants of course and outcome as well as their interactions, to be used for predicting outcome and guiding treatment. Second, we aim to further develop a sensitive momentary assessment tool, the Psymate, predicting course of positive, negative, and affective symptoms in schizophrenia.
Work Package 8 - GxE Data & Statistics
WP-Leaders: Pak Sham (UHK) and Peter Holmans (CU)
Work Package 9 - Ethics
WP-Leaders: Carlos Romeo (UPV/EHU) and Aitziber Emaldi (UPV/EHU)
WP9 includes the domain of Management, Ethics, Impact and Training within the EU-GEI project. In relation to these issues WP9 aims to develop an ethical context for translational GxE research in schizophrenia, as well as to detect the specific needs of regulation in this sense, such as informed consent. Furthermore WP9 will perform research on the balance between risk and benefits for subjects in non-therapeutic research and on data protection.
At the same time, the following objectives are articulated around a series of linked tasks to be realized:
- investigate and report on ethical and legal questions and gender aspects
- ethical aspects of schizophrenia research, particularly informed consent
- the balance between risks and benefits for subjects in non-therapeutic research
- data protection issues - ethical and legal aspects of schizophrenia research
- gender issues within (1) the consortium and (2) research results
- develop (in collaboration with SERMAS) a dissemination plan on the implementation of the research on health and policy makers, also via IC-LHG contacts at European level and other stakeholders
A small field study (likely to be conducted in Spain) studying ethical aspects of schizophrenia research will be set up.
Work Package 10 - Dissemination
WP-Leaders: Celso Arrango (SERMAS) and Mara Parellada (SERMAS)
The aim of the dissemination workpage is to facilitate the flow of new knowledge on the benefits for the scientific community in deploying new findings, experimental protocols and data gathering standards, applicable not only within EU-GEI but also across schizophrenia research and across human genomics (genetics) and epidemiology (environment) more generally.
Our two major goals to reach regarding these objectives are:
- Dissemination of scientific information within the relevant scientific community to spread state-of-the-art and new knowledge. This task is closely allied with, and complements, the training activities, which disseminate new practical skills.
- Communication of EU-GEI findings and their implications to stakeholder groups who will be able to influence the patient beneficially as regards schizophrenia control/prevention (medical professionals, industry, etc.). This task is closely allied with, and complements, the ethical activities, which disseminate the ethical implications of the research conducted.
The dissemination WP working in close relation with other workpagages such as training and ethics will ensure a good communication between the different groups comprising the EU-GEI project and between researchers and relevant stakeholders such as family and users associations, European Commission, researchers in the field of schizophrenia, genetics and epidemiology and the media.
Work Package 11 - Training
WP-Leaders: Lieuwe de Haan (AMC) and Don Linszen (AMC)
Training of researchers in EU-GEI
Training in the EU-GEI is supported by an interactive website. The name of the training website is GET-THERE (an acronym of Gene Environment Tools - Training Home Education Reliability Europe).
The training website is restricted to members of the research group. The reason for this restriction is that material is available in which patients are interviewed.
This website is intended to provide researchers with information and training for the instruments to be assessed in the EU-GEI project. Besides training documentation, manuals, score sheets and different translations, we will present audiovisual material for the most advanced instruments.
Because different countries will work together to create one substantial dataset, we believe that inter-rater reliability is a top priority of EU-GEI. To this end we created GET-THERE, a joint virtual 'practice, training and reliability area. In order to achieve good reliability, researcher will find practice tapes (with feedback options) and tapes to determine inter-rated reliability. In addition, various online presentations are presented and will be regularly updated.
