MOLECULAR GENETICS OF BIPOLAR AFFECTIVE DISORDER

Lead Research Organisation: University College London
Department Name: Infection and Population Health

Abstract

The research project aims to contribute to the understanding of the basic genetic causes of bipolar disorder and genetically related unipolar disorder. These disorders are strongly associated with alcoholism and other drugs of abuse. Therefore the understanding of the genetic cases of bipolar and related unipolar affective disorders will also contribute to the understanding of one of the many causes of alcoholism. The finding of genes increasing susceptibility to bipolar disorder is not an academic exercise because the science can point to new approaches for designing drugs for depression and mania. Preventive measures are also possible once it is possible to understand the underlying causes.

Technical Summary

A case control sample of 2,000 bipolar affective disorder cases and 2,000 controls will be used for further research into the genetic variation causing susceptibility to bipolar and genetically related unipolar affective disorders. The aim is to use the genetic information to understand the molecular pathology in the brain and to design better treatment and preventive strategies. We have already identified several susceptibility genes in the UCL sample and have partially sequenced the DNA of the ANKYRIN3, GRM7, SLC1A2, TRPM2, SLYNAR and IGF1 genes. We now wish to carry out further exploration of potential aetiological base pair variants found in these genes by genotyping them in the whole enlarged case control sample. In the case of the SYNE1, ANKYRIN3, GRM7 and SLC1A2 genes we wish to extend this sequencing using high through put methods in a greater number of cases as well as to continue sequencing several further genes which are strongly associated with bipolar disorder in the UCL sample. In addition we now wish to make further use of the family lineality and sex of parent transmission data we have in order to find subgroups of cases showing major gene transmission and susceptibility genes which have methylation patterns that correlate with parental sex of transmission. We also wish to explore the genetic role of afective disorder genes in a case control sample of the alcohol dependence syndrome. Lastly we wish to continue to contribute to international collaborations that are generating large enough sample sizes to fully explore the relationship between genetic effects and clinical variables such as prognosis and response to treatment.

Publications

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Al Eissa MM (2019) Genetic association and functional characterization of MCPH1 gene variation in bipolar disorder and schizophrenia. in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

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Belmonte Mahon P (2011) Genome-wide association analysis of age at onset and psychotic symptoms in bipolar disorder. in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

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Bigdeli TB (2016) Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness. in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

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Dedman A (2012) Sequencing of the ANKYRIN 3 gene (ANK3) encoding ankyrin G in bipolar disorder reveals a non-conservative amino acid change in a short isoform of ankyrin G. in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

 
Title DNA from bipolar affective disorder cases 
Description DNA has been extracted from blood sample from 1,400 bipolar affective disorder cases and has been quantified and stored. 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact There have been three collaborations resulting from DNA being sent to other laboratories. These are described in the details about collaborations. 
 
Description Bipolar Sequencing Consortium 
Organisation Icahn School of Medicine at Mount Sinai
Country United States 
Sector Academic/University 
PI Contribution We have provided bipolar disorder whole genome sequence data to this consortium
Collaborator Contribution The other members of this consortium have also contributed pre publication bipolar disorder whole genome and/or whole exome sequence data
Impact None yet
Start Year 2014
 
Description Bipolar Sequencing Consortium 
Organisation Johns Hopkins University
Department Department of Epidemiology
Country United States 
Sector Academic/University 
PI Contribution We have provided bipolar disorder whole genome sequence data to this consortium
Collaborator Contribution The other members of this consortium have also contributed pre publication bipolar disorder whole genome and/or whole exome sequence data
Impact None yet
Start Year 2014
 
Description Bipolar Sequencing Consortium 
Organisation National Institutes of Health (NIH)
Department National Institute of Mental Health (NIMH)
Country United States 
Sector Public 
PI Contribution We have provided bipolar disorder whole genome sequence data to this consortium
Collaborator Contribution The other members of this consortium have also contributed pre publication bipolar disorder whole genome and/or whole exome sequence data
Impact None yet
Start Year 2014
 
Description Bipolar Sequencing Consortium 
Organisation University of Michigan
Department School of Public Health
Country United States 
Sector Academic/University 
PI Contribution We have provided bipolar disorder whole genome sequence data to this consortium
Collaborator Contribution The other members of this consortium have also contributed pre publication bipolar disorder whole genome and/or whole exome sequence data
Impact None yet
Start Year 2014
 
Description Genetic analysis of bipolar disorder 
Organisation Cardiff University
Department Division of Psychological Medicine and Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of genome wide association data on bipolar affective disorder
Impact Collaborative Paper Polygenic dissection of the bipolar phenotype PUBMED ID 21972277 Both clinicians and molecular geneticists are collaborating,
Start Year 2011
 
Description International Case Control Consortium on the Genetics of Bipolar Disorder 
Organisation Broad Institute
Department Stanley Center for Psychiatric Research
Country United States 
Sector Academic/University 
PI Contribution The UCL bipolar case control sample has been subjected to genome wide association analysis and combined with data from Harvard, Cardiff, Edinburgh and Sweden to analyse genetic effects on bipolar affective disorder.
Collaborator Contribution Carrying out genotyping for tests of genome wide association using Affymetrix arrays. Providing support for two research assistants to collect interview data and blood samples for DNA extraction.
Impact See publications for research in Nature Genetic and Molecular Psychiatry published with Sklar, Smoller, Owen, and Blackwood. This research was multidisciplinary with clinical and molecular genetic expertise. The collaboration resulted in several genes being implicated in susceptibility to bipolar disorder for the first time. For example the finding of the CACNA1C calcium channel subunit as a cause of bipolar disorder has reinvigorated interest in calcium channel antagonists as a treatment for bipolar mania.
Start Year 2008
 
Description NIHR Mental Health Research Network (MHRN) Bipolar arm of DPIM 
Organisation National Institute for Health Research
Department INVOLVE
Country United Kingdom 
Sector Public 
PI Contribution Hugh Gurling is the principal investigator of a national programme of sample collection of bipolar affective cases. The project is called DNA polymorphism in mental illness (DPIM). The aim is for the MHRN to collect DNA and diagnostic data from 2,000 more cases of bipolar disorder to add to the previous collection of 1,400 cases. This is to help resolve the statistical challenges of heterogeneity for bipolar affective disorder and to enhance international efforts for genetic analysis of bipolar disorder.
Collaborator Contribution Enabled a collection of a larger sample of bipolar affective disorder cases. Providing diagnostic data and blood samples.
Impact So far 147 bipolar cases have been collected. The work is a collaboration between clinicians and molecular geneticists.
Start Year 2011
 
Description NIHR Primary Care Research Network 
Organisation National Institute for Health Research
Department School for Primary Care Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Creating data collection methods and directing the network activities
Collaborator Contribution Has been helping develop a national network of GP commissioning groups and PCTs and GP practices that are willing to collect DNA and diagnostic data on cases of bipolar affective disorder to enhance MRC funded research.
Impact This is in an early stage. 500 GP practices have been asked to join in the network.
Start Year 2011
 
Description Psych Chip Consortium 
Organisation Broad Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution We are contributing DNA samples from over 4,000 research subjects
Collaborator Contribution Project partners are providing additional DNA samples, genotyping consumables and expertise and analyis
Impact None Yet
Start Year 2013
 
Description Psych Chip Consortium 
Organisation Icahn School of Medicine at Mount Sinai
Country United States 
Sector Academic/University 
PI Contribution We are contributing DNA samples from over 4,000 research subjects
Collaborator Contribution Project partners are providing additional DNA samples, genotyping consumables and expertise and analyis
Impact None Yet
Start Year 2013
 
Description Psychiatric Genomics Consortium (PGC) 
Organisation Psychiatric Genomics Consortium (PGC)
Country Global 
Sector Learned Society 
PI Contribution UCL collected and sent DNA from two cohorts (500 cases then 600 cases) of bipolar affective disorder to contribute to a worldwide genome wide association analysis. UCL has carried out genetic analyses on age of onset, frequency of manias and other clinical variables that may have specific genetic associations.
Collaborator Contribution Genetic analysis to which UCL has contributed sub-phenotype analyses for genome wide data.
Impact Papers recently published include "Psychiatric GWAS Consortium" Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4 in Nature Genetics. PUBMED ID 21926972. A genome-wide association study of attempted suicide PUBMED ID 21423239, Genome-wide association analysis of age at onset and psychotic symptoms in bipolar disorder PUBMED ID 21305692
Start Year 2010
 
Description The genetic involvement of the NK1R receptor in ADHD and bipolar disorder 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Genetic analysis of the role of TACR1 gene in bipolar affective disorder, alcoholism and ADHD
Collaborator Contribution This has developed into a drug development programme and negotiations are in progress for treatment trials with novel NP1R (TACR1) related drugs.
Impact Publication entitled "NK1 (TACR1) receptor gene 'knockout' mouse phenotype predicts genetic association with ADHD" PUBMED ID 19204064
Start Year 2008
 
Description University College London with University of Aarhus 
Organisation Aarhus University
Country Denmark 
Sector Academic/University 
PI Contribution Genetic analysis of the BRD1 gene in bipolar disorder. We provided DNA from the UCL bipolar case control sample with research diagnostic criteria for genetic analysis in Denmark. The MRC funded research enabled positive replication of a susceptibility gene for bipolar disorder.
Collaborator Contribution They needed to replicate the involvement of a specific gene that had found to be associated with bipolar disorder in Denmark.
Impact Clinicians are involved in both Denmark and London. Academic molecular genetic expertise from UCL and Aarhus has been combined. The research has enable the Aarhus group to have confidence in their initial findings and to target the BRD1 to find aetiological base pair changes within the gene, so that new treatment and preventive strategies can be created.
Start Year 2010
 
Title NK1R animal model of ADHD 
Description Genetic effects on ADHD in mouse and man from the NK1R (TACR1) gene. Therefore a mouse animal model based on positive human genetic research was created for novel drug testing. 
IP Reference EP2114130 
Protection Patent granted
Year Protection Granted 2011
Licensed Yes
Impact Charles River (Cerebricon) have a non exclusive licence to use the knockout animal line for drug development. This has meant that new drugs have been synthesised and tested. Human trials are being negotiated.
 
Title New drugs for ADHD and bipolar affective disorder 
Description Two new treatments for ADHD and bipolar disorder have been tested in the mouse model. One of these is a novel compound synthesised by the MRC technology group. The other is a repositioned existing drug (Captopril) which acts on the NK1R/TACR1 pathway. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2011
Development Status Actively seeking support
Impact UCL developed the first genetically validated animal model for drug treatment of ADHD and bipolar affective disorder. Several drug companies have expressed an interest in funding trials based on drugs that affect ADHD and bipolar symptoms in the animal model. 
 
Description Bipolar affective disorder genetics research 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Research on the genetics of bipolar disorder has been carried out with help of the bipolar affective disorder charity EQUILIBRIUM. UCL contributed information to the charity website and has been recruiting cases through the web site.

Further charitable support for research at UCL was obtained.
Year(s) Of Engagement Activity 2011
 
Description Cheshire and Wirral NHS PT (DPIM talk) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact I was approached afterwards by a number of members of the audience with questions about the research

The was an interest in greater recruitment for our study.
Year(s) Of Engagement Activity 2014
 
Description New genes involved in bipolar affective disorder 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact News articles appeared worldwide describing the PGC collaborative research on finding new genes (eg ODZ4) involved in the aetiology of bipolar affective disorder.

Feedback received from new volunteers for bipolar sample collection that there had been widespread dissemination of knowledge of advances in the discovery of the causes of bipolar affective disorder.
Year(s) Of Engagement Activity 2011
 
Description Public Health Teaching 
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 The talk prompted a number of questions and a lively debate

The workshop stimulated interest in the impact of genomics in public health and was attended by officials from the Welsh Government and by public health professionals.
Year(s) Of Engagement Activity 2013,2014
 
Description User group seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact 20 service users attended

Feedback was very positive and service users reported satisfaction that new drug treatment were beginning to merge.
Year(s) Of Engagement Activity 2011