Behavioural and neurophysiological effects of schizophrenia risk genes: a multi-locus, pathway based approach

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

Schizophrenia is a major mental disorder, which affects between 0.5 and 1% of the population and has substantial impact on patients' wellbeing and life expectancy. Although medical and psychosocial interventions can bring some relief, the causes of the disease are poorly understood and no causal treatments are available. Because schizophrenia is highly heritable one hope is that identification of genes that contribute to disease risk will help elucidate the causal mechanisms and thus enable the development of new treatments. Over the last years, large scale genetic studies, many of which were led by investigators from Cardiff, have identified hitherto unknown genetic variants associated with schizophrenia. It has emerged from this work that most patients with schizophrenia probably carry many risk variants, each of which only contributes a small amount to disease risk, and different genes and thus different aspects of the brain's biology may be affected in different patient groups. Understanding the effects of these genes on the brain will likely reveal more about the causal mechanisms of schizophrenia and also whether subgroups of patients need to be diagnosed and treated in different ways ("stratification"). However, very little is yet known about the effects of these variants on brain and behaviour and how they contribute to clinical symptoms. We therefore plan to investigate these effects, bringing together expertise in the molecular genetics of schizophrenia and in the investigation of brain substrates of cognition and psychological symptoms.
In order to fulfil our aim of elucidating the effects of schizophrenia risk variants, alone and in combination, we will conduct brain scanning with magnetic resonance imaging (providing high spatial resolution) and magnetoencephalography (providing high temporal resolution) on 200 healthy individuals. The reason for investigating healthy individuals rather than patients in the first place is that these genetic variants are common in the healthy population as well, and here they can be studied without the confounding effects of medication and other consequences of suffering from an illness. We will recruit participants from an existing cohort of 10000 young adults in the Bristol area (the ALSPAC cohort) who are representative of the general population and have been followed up from birth. Genetic information is already available from this cohort, and we can thus recruit 100 individuals each with high and low genetic risk for schizophrenia. We will investigate imaging measures that have previously been associated with abnormal brain processes in schizophrenia and tap into core cognitive functions such as learning and memory. We will also obtain detailed cognitive profiles of these individuals. Our expectation is that individuals with high genetic risk scores for schizophrenia will show similar abnormalities to patients on these measures. We also expect to see genes that affect specific biological pathways, for example brain development, to be associated with particular imaging measures, for example those probing the connections between brain areas. This information would help us identified biological subtypes of schizophrenia. The next step would be to validate these measures in patient groups, for which we have lined up collaborations with groups who already have relevant data from patient studies.
Potential applications of this work include the stratification of patients with schizophrenia into different biological groups, which could be tested for different responses to particular drugs in clinical trials. This could improve the targeting of existing medication. Another application, based on the better understanding of the biological pathways affected by the genetic risk variants would be to suggest brain mechanisms that might be targeted by new drugs.

Technical Summary

Our research is based on the recent discovery of several genetic risk variants for schizophrenia and the observation that most cases of schizophrenia carry several (and only partly overlapping) common variants that each only contribute a small amount to disease risk. Because little is know about the downstream effects of these variants, we combine neuroimaging, neuropsychology and molecular genetics to elucidate their effects on brain and behaviour. Because power has been an issue in previous studies in this area, we have developed a new approach using healthy participant groups pre-selected for their polygenic risk scores from an existing genotyped cohort (ALSPAC). We will compare high and low genetic risk individuals on imaging and behavioural measures that have been proposed as candidate markers for schizophrenia. Examples include measures of reward sensitivity, associative learning, oscillatory brain activity, cognitive inhibition and maturation of white matter. We hypothesise that high risk individuals will show changes similar to those observed in schizophrenia patients on these measures. More specifically, though, we expect risk variants that cluster along specific biological pathways, for example those of synaptic plasticity or myelination, to be associated with some of these intermediate phenotypes but not with others. Our study is powered to detect these associations. We will also probe, in an exploratory fashion, the effects of single risk variants on the full range of neural and behavioural phenotypes acquired. Our research will provide an answer to the question whether intermediate phenotypes proposed by the current biological models can index genetic risk of schizophrenia, and whether they provide evidence for different neural effects of genes on different pathways. If the expected results are obtained, this could pave the way for a future biological stratification of schizophrenia, and for the identification of new pathways for drug development.

Planned Impact

In addition to the academic beneficiaries, which include basic and clinical researchers in the wider fields of neuropsychiatric genetics, bioinformatics, psychiatric neuroimaging and biological models of schizophrenia, we expect interest into our research and its further application to patient populations from
a) drug companies working on the translation of genetic findings into biological models for the discovery and screening of new compounds for psychotic disorders
b) clinicians and policy makers working on new classification systems and diagnostic guidelines (especially with a view towards incorporating biological/ aetiological criteria) for psychiatric disorders
c) clinicians and clinical researchers seeking biomarkers for treatment prediction and stratification for clinical trials.
Any association between risk variants/ polygenic scores confirmed in our study can be taken into patient research, and, if replicated, will yield biomarkers that can tap into different components of biological risk and thus contribute to the identification of disease pathways. Specifically, future patient studies can use these biomarkers to test for their diagnostic value in comparison between patients and controls, for their prognostic value in high-risk individuals (combining genetic and clinical risk according to present prodromal criteria), and for their value in treatment prediction in stratification studies. Ultimately, our findings can thus contribute to drug development (a), and provide a basis for biological classification (b) or stratification (c). In addition to these downstream impacts on industry and health services, we will also make immediate contributions to the UK's skills base in biomedical research, by developing novel bioinformatics tools (e.g. for polygenic genetic imaging and behavioural genetics analysis) and training a new generation of investigators in their use.

Publications

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Dimitriadis SI (2018) A novel, fast and efficient single-sensor automatic sleep-stage classification based on complementary cross-frequency coupling estimates. in Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology

 
Description Behaviour and neurophysiological effects of schizophrenia risk genes: A multi-locus pathway based approach
Amount £704,571 (GBP)
Organisation Wessex Medical Research 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 03/2017
 
Description CUBRIC 2 - Cardiff University Brain Research Imaging Centre
Amount £1,000,000 (GBP)
Organisation The Wolfson Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2014 
End 11/2017
 
Description DEFINE - Defining endophenotypes from integrated neuroscience
Amount £5,234,843 (GBP)
Funding ID 100202/Z/12/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2018
 
Description EEG nuerofeedback as a treatment method for Parkinson's disease?
Amount £58,974 (GBP)
Funding ID HS-14-20 
Organisation Health and Care Research Wales 
Sector Public
Country United Kingdom
Start 10/2014 
End 09/2017
 
Description Excitatory-inhibitory balance in adolescents at high genetic risk of mental disorder: A study of cortical gamma oscillations and GABA concentrations in 22q11.2 delection syndrome
Amount £307,019 (GBP)
Funding ID 102003/Z/13/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 08/2016
 
Description Neurostimulation Therapy - Review of Business Plan
Amount £765 (GBP)
Organisation Arthurian Life Sciences 
Sector Private
Country United Kingdom
Start 07/2014 
End 07/2014
 
Description Project to dissect the biology of schizophrenia into clusters of intermediate phenotypes
Amount £7,487 (GBP)
Funding ID C0465 
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 08/2013 
End 09/2014
 
Description Ultra-high field MRI: Advancing clinical neuroscientific research in experimental medicine.
Amount £6,700,929 (GBP)
Funding ID MR/M008932/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2015 
End 03/2016
 
Title Schizophrenia polygenic risk scores 
Description We have developed a method for stratification of cohorts according their polygenic risk for schizophrenia based on data from the Psychiatric Genetics Consortium 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact The technique has allowed us to perfrom participant selection for the grant MR/K004360/1. 
 
Description ALSPAC 
Organisation University of Bristol
Department Avon Longitudinal Study of Parents and Children (ALSPAC)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generted polygenic risk scores for participant selection. We have also provided/created all experimental materials and procedures.
Collaborator Contribution ALSPAC have proviede us with access to their cohort of participants for recruitment into the study.
Impact No outputs yet.
Start Year 2013
 
Title NFD 
Description Neurofeedback training, based on real-time functional magnetic resonance imaging signals, for patients with depression 
Type Therapeutic Intervention - Psychological/Behavioural
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Increase in research activities in clinical neurofeedback worldwide 
URL https://clinicaltrials.gov/show/NCT01544205
 
Description Brain control: new developments in neurofeedback and neuromodulation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Delivered a seminar entitled Brain control: new developments in neurofeedback and neuromodulation



unknown
Year(s) Of Engagement Activity 2014
URL https://www.mrc-cbu.cam.ac.uk/?event=chaucer-club-seminar-david-linden-cardiff-university
 
Description Cardiff Science festival 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Groups members also took part in an event as part of Cardiff Science Festival, manning a stand at the Science Festival Exhibition at which families could engage in various hands-on activities designed to illustrate various aspects of psychology and neuroscience.

Increased interest in neuroscience in visitors to the event.
Year(s) Of Engagement Activity 2013
 
Description Joint meeting of the Welsh Psychiatric Society and the Royal College of Psychiatrists in Wales 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Delivered talk entitled - Brain Control: Between manipulation and therapy

unknown
Year(s) Of Engagement Activity 2014
URL http://www.wps.swan.ac.uk/conferences.htm?id=12
 
Description MRC centenary event 
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 Participants in your research and patient groups
Results and Impact Members of the research group took part in a public event hosted by the MRC Centre for Neuropsychaitric Genetics and Genomics to celebrate 100 years of the MRC. Group members manned a stand at which members of the public could try a hands on activity illustrating the princples of neurofeedback as well as being presented with information about ongoing neuroimaging research into psychatric conditions taking place at Cardiff University.


A number of visitors expressed interest in taking part in neuroimaging studies at Cardiff and took away contact details for relevant researchers.
Year(s) Of Engagement Activity 2013
URL http://medicine.cardiff.ac.uk/event/mrc-centenary-event/
 
Description PD Event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact information meeting with PD patients from ongoing research projects to inform design of new research

further engagement with local PD community
Year(s) Of Engagement Activity 2014
 
Description Royal College of Psychiatrists Annual Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Delivered 3 symposium talks at Royal College of Psychiatrists Annual Meeting

unknown
Year(s) Of Engagement Activity 2014
 
Description Talk King's College 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Talk by Dr Thomas Lancaster (Research Associated on the project) on Genetic risk for psychosis and mechanisms of aetiology; evidence from imaging genetics: MRC Social, Genetic & Developmental Psychiatry Centre, King's College London 24/06/2016
Year(s) Of Engagement Activity 2016