Translating gene-environment interaction from aetiology to personalised medicine for anxiety and depression.
Lead Research Organisation:
Queen Mary University of London
Department Name: Sch of Biological and Chemical Sciences
Abstract
Anxiety and depression are the most common of all mental illnesses affecting as many as one in five people at some point in their lives. They are also amongst the earliest to emerge, with the majority of adult cases of both disorders beginning in childhood or adolescence. Anxiety and depression are extremely costly for afflicted individuals and society as a whole resulting in reduced over-all educational level, increased usage of sick leave and benefits and increased risk of substance dependence and suicide.
Cognitive Behavioural Therapy (CBT) has been shown to be a safe, effective treatment for both depression and anxiety in children and adults. Nevertheless, at least two in five patients do not respond to CBT and may need to switch to a different treatment such as medication. Finding predictors of response is extremely important as it will allow doctors to pick the right treatment for the right person from the start, cutting costs and speeding up their recovery.
Recent research suggests that 'plasticity' genes might make some individuals more sensitive to their environment than others. These 'plasticity' genes may therefore be important predictors of response to CBT. Dr Robert Keers will test this proposition at the institute of Psychiatry in London and Emory University, Atlanta. Dr Keers will attempt to identify new plasticity genes using a novel twin based method and then test these genes as predictors of response to CBT in patients with anxiety and depression.
Cognitive Behavioural Therapy (CBT) has been shown to be a safe, effective treatment for both depression and anxiety in children and adults. Nevertheless, at least two in five patients do not respond to CBT and may need to switch to a different treatment such as medication. Finding predictors of response is extremely important as it will allow doctors to pick the right treatment for the right person from the start, cutting costs and speeding up their recovery.
Recent research suggests that 'plasticity' genes might make some individuals more sensitive to their environment than others. These 'plasticity' genes may therefore be important predictors of response to CBT. Dr Robert Keers will test this proposition at the institute of Psychiatry in London and Emory University, Atlanta. Dr Keers will attempt to identify new plasticity genes using a novel twin based method and then test these genes as predictors of response to CBT in patients with anxiety and depression.
Technical Summary
Aim: To investigate whether genes that moderate the effects of the environment on the development of depression and anxiety may also predict response to psychological treatment.
Objectives
1. Examine the extent to which genes moderate the effects of the environment on anxiety and depression.
2. Identify the genetic variants involved.
3. Test these variants as predictors of response to CBT.
Methods
Objective 1
Sample: 10,301 twin and sibling pairs.
Analyses: An established quantitative-genetic model to test for gene-environment interaction will be used to examine the extent to which genes moderate the effects of positive and negative environments on depression and anxiety.
Objective 2
Sample: 1,183 monozygotic twin pairs.
Analyses: A novel extension of the monozygotic twin differences design, which examines within-pair discordance as a function of genotype, will be used to identify genetic variants that moderate the effects of the environment on depression and anxiety.
Objective 3
Sample: 2,000 anxious children treated with CBT and 400 depressed adults treated with either CBT or medication.
Analyses: Genotypes detected in Objective 2 will be tested as predictors of change and remission of symptoms.
Scientific and medical opportunities: The results of this research may have far reaching implications for understanding the aetiology of depression and anxiety and their prevention and treatment. Variants suggestive of increased environmental sensitivity may enable targeted interventions for individuals at a high-risk of developing these disorders. These same genotypes may also be used to select the most effective treatment for a given patient. Given their prevalence, and their substantial social and economic costs, advancing the prevention and treatment of depression and anxiety would lead to improved mental health and well-being for a significant proportion of the population and ultimately benefit society as a whole.
Objectives
1. Examine the extent to which genes moderate the effects of the environment on anxiety and depression.
2. Identify the genetic variants involved.
3. Test these variants as predictors of response to CBT.
Methods
Objective 1
Sample: 10,301 twin and sibling pairs.
Analyses: An established quantitative-genetic model to test for gene-environment interaction will be used to examine the extent to which genes moderate the effects of positive and negative environments on depression and anxiety.
Objective 2
Sample: 1,183 monozygotic twin pairs.
Analyses: A novel extension of the monozygotic twin differences design, which examines within-pair discordance as a function of genotype, will be used to identify genetic variants that moderate the effects of the environment on depression and anxiety.
Objective 3
Sample: 2,000 anxious children treated with CBT and 400 depressed adults treated with either CBT or medication.
Analyses: Genotypes detected in Objective 2 will be tested as predictors of change and remission of symptoms.
Scientific and medical opportunities: The results of this research may have far reaching implications for understanding the aetiology of depression and anxiety and their prevention and treatment. Variants suggestive of increased environmental sensitivity may enable targeted interventions for individuals at a high-risk of developing these disorders. These same genotypes may also be used to select the most effective treatment for a given patient. Given their prevalence, and their substantial social and economic costs, advancing the prevention and treatment of depression and anxiety would lead to improved mental health and well-being for a significant proportion of the population and ultimately benefit society as a whole.
Planned Impact
Who will benefit?
The results from this program of research may have far reaching implications for improving the prevention and treatment of affective disorders. Given the prevalence of these disorders, these improvements will therefore have a profound impact on the mental health and well-being of a large proportion of the population. The social and economic cost of anxiety and depression means that ultimately society as a whole could benefit from this research.
How will they benefit?
This research will feed into three key areas aimed at reducing mental health problems in the population: Targeted intervention, personalised medicine and the development of novel treatments.
1) Targeted intervention: A growing body of research suggests that early intervention with cognitive behavioural prevention can limit the onset of emotional disorders in children. By identifying genetic variants suggestive of increased sensitivity to the environment or response to psychological treatments, the current research may allow for these prevention programmes to be targeted at those at a high-risk of anxiety or depression and those who will reap the most benefit from these preventative measures.
2) Personalised medicine: Cognitive Behavioural Therapy (CBT) is currently being rolled out in the UK as the first line treatment for depression and anxiety in adults and children as part of the Improving Access to Therapy (IAPT) initiative. However, at least two in five individuals do not respond to CBT and may require additional or alternative treatments. Genetic predictors of treatment response would allow for a personalised approach to CBT. This means that clinicians will be able to select the most effective treatment for a given patient prior right from the start, cutting costs and speeding up recovery times.
3) New treatments: Current treatment options for anxiety and depression are ineffective for a substantial proportion of sufferers. By identifying genetic factors involved in the aetiology of depression and anxiety, natural resilience to these disorders and response to treatment the current study may provide novel targets for pharmacological and non-pharmacological treatments.
The results from this program of research may have far reaching implications for improving the prevention and treatment of affective disorders. Given the prevalence of these disorders, these improvements will therefore have a profound impact on the mental health and well-being of a large proportion of the population. The social and economic cost of anxiety and depression means that ultimately society as a whole could benefit from this research.
How will they benefit?
This research will feed into three key areas aimed at reducing mental health problems in the population: Targeted intervention, personalised medicine and the development of novel treatments.
1) Targeted intervention: A growing body of research suggests that early intervention with cognitive behavioural prevention can limit the onset of emotional disorders in children. By identifying genetic variants suggestive of increased sensitivity to the environment or response to psychological treatments, the current research may allow for these prevention programmes to be targeted at those at a high-risk of anxiety or depression and those who will reap the most benefit from these preventative measures.
2) Personalised medicine: Cognitive Behavioural Therapy (CBT) is currently being rolled out in the UK as the first line treatment for depression and anxiety in adults and children as part of the Improving Access to Therapy (IAPT) initiative. However, at least two in five individuals do not respond to CBT and may require additional or alternative treatments. Genetic predictors of treatment response would allow for a personalised approach to CBT. This means that clinicians will be able to select the most effective treatment for a given patient prior right from the start, cutting costs and speeding up recovery times.
3) New treatments: Current treatment options for anxiety and depression are ineffective for a substantial proportion of sufferers. By identifying genetic factors involved in the aetiology of depression and anxiety, natural resilience to these disorders and response to treatment the current study may provide novel targets for pharmacological and non-pharmacological treatments.
People |
ORCID iD |
Robert Keers (Principal Investigator / Fellow) |
Publications
Lester KJ
(2017)
Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders.
in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
Coleman JRI
(2017)
Genome-wide association study of facial emotion recognition in children and association with polygenic risk for mental health disorders.
in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
Booth C
(2017)
The CogBIAS longitudinal study protocol: cognitive and genetic factors influencing psychological functioning in adolescence
in BMC Psychology
González RA
(2016)
Childhood maltreatment and violence: mediation through psychiatric morbidity.
in Child abuse & neglect
Keers R
(2017)
Childhood quality influences genetic sensitivity to environmental influences across adulthood: A life-course Gene × Environment interaction study.
in Development and psychopathology
Coleman Jonathan
(2017)
COMBINING GENETIC AND GENE EXPRESSION METHODS TO IDENTIFY BIOLOGICAL PREDICTORS OF RESPONSE TO COGNITIVE BEHAVIOURAL THERAPY FOR ANXIETY DISORDERS
in EUROPEAN NEUROPSYCHOPHARMACOLOGY
Eley T
(2017)
Polygenic Scores for Differential Susceptibility to Emotional Symptoms Predict Response to Cbt in Child Anxiety
in European Neuropsychopharmacology
McKinnon A
(2018)
The impact of treatment delivery format on response to cognitive behaviour therapy for preadolescent children with anxiety disorders.
in Journal of child psychology and psychiatry, and allied disciplines
Reardon T
(2019)
The utility of the SCAS-C/P to detect specific anxiety disorders among clinically anxious children.
in Psychological assessment
Keers R
(2016)
A Genome-Wide Test of the Differential Susceptibility Hypothesis Reveals a Genetic Predictor of Differential Response to Psychological Treatments for Child Anxiety Disorders.
in Psychotherapy and psychosomatics
Coid JW
(2016)
Paranoid Ideation and Violence: Meta-analysis of Individual Subject Data of 7 Population Surveys.
in Schizophrenia bulletin
Assary E
(2018)
Gene-environment interaction and psychiatric disorders: Review and future directions.
in Seminars in cell & developmental biology
Coleman JR
(2016)
Genome-wide association study of response to cognitive-behavioural therapy in children with anxiety disorders.
in The British journal of psychiatry : the journal of mental science
Lester KJ
(2016)
Non-replication of the association between 5HTTLPR and response to psychological therapy for child anxiety disorders.
in The British journal of psychiatry : the journal of mental science
Coleman JR
(2017)
Separate and combined effects of genetic variants and pre-treatment whole blood gene expression on response to exposure-based cognitive behavioural therapy for anxiety disorders.
in The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry
Rayner C
(2019)
A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders.
in Translational psychiatry
Roberts S
(2017)
Genome-wide expression and response to exposure-based psychological therapy for anxiety disorders.
in Translational psychiatry
Description | Wellcome Trust Seed Award |
Amount | £90,690 (GBP) |
Funding ID | 208881/Z/17/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2018 |
End | 06/2020 |
Description | Alice Gregory - SLEEPIO study |
Organisation | Goldsmiths, University of London |
Department | Department of Psychology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Dr Gregory consulted me on setting up a study to explore genetic predictors of response to the CBT app for sleep problems (SLEEPIO). I consulted on the design of the study, recruitment of participants and the planned analyses. I will be responsible for the analyses of the genetic data, using the polygenic score generated as part of my MRC fellowship to predict response to SLEEPIO. |
Collaborator Contribution | Dr Gregory conceptualized the study and the initial study design. She also sought ethical approval and funding for the project. |
Impact | The study is multidisciplinary involving a behavior geneticist (Dr Gregory) and statistical geneticist (myself). A protocol paper has been drafted and will be submitted for publication shortly. |
Start Year | 2016 |
Description | Dr Michael Pluess |
Organisation | Queen Mary University of London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I have collaborated with Michael on several projects and co-supervise two PhD students. While Michael has expertise in developmental psychology and gene-environment interaction, I bring expertise in statistical genetics. Most of our work includes investigating gene-environment interaction using candidate gene and whole genome approaches. |
Collaborator Contribution | Michael brings expertise in child psychology and gene environment interaction. |
Impact | We have coauthored a paper together on gene-environment interaction across the life-course. The paper is currently under review at Development and Psychopathology. We are also coauthoring a review article on gene-environment interaction in mental illness which will be submitted at the end of the month. |
Start Year | 2016 |
Description | Elaine Fox - Cogbias project |
Organisation | University of Oxford |
Department | Department of Physics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided support on the genetic aspects of the CogBias project. We co-ordinated DNA extraction, genotyping and quality control of the subsequent data. We will provide continued support in the analysis of candidate gene data and will take the lead in several genome-wide projects using the data. |
Collaborator Contribution | Professor Fox conceptualised, designed and obtained funding for the study. Her team collected the data including biological samples for genotyping. The cogbias team bring expertise in cogntiive bias experiments in relation to depression and anxiety. |
Impact | We are still in the early stages of data cleaning on this project but have drafted a protocol paper and are in the process of registering our research questions and hypothesis prior to analyses. |
Start Year | 2016 |
Description | Jennifer Hudson |
Organisation | Macquarie University |
Country | Australia |
Sector | Academic/University |
PI Contribution | I bring expertise in statistical genetics and analyses of longitudinal treatment response data. |
Collaborator Contribution | Jen brings expertise in child psychology and psychiatry and clinical trial data. |
Impact | This is a multi-disciplinary collaboration combining expertise from child psychiatry and psychology with statistical genetics. I have collaborated with Professor Hudson on a number of projects resulting several high impact publications. 10.1002/ajmg.b.32467 10.1192/bjp.bp.115.168229 10.1159/000444023 10.1002/da.22430 10.1192/bjp.bp.114.154997 10.1016/j.jaac.2015.03.018 We have several further studies planned including a grant submitted to the ARC to examine whether polygenic score I developed as part of the MRC fellowship can be used to stratify patients to low, medium and high intensity CBT. This will be the first study to explore whether a genetic score can be used to personalise CBT and if successful will provide significant impact for the findings from my fellowship. |
Start Year | 2013 |
Description | Marianus van Ijzendoorn |
Organisation | Leiden University |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | Professor Van Ijzendoorn approached us about using our polygenic environmental sensitivity score to investigate genetic moderation of environmental influences in the large and well characterized Generation R study. We provided them with the data and are supporting their analyses and interpretation of the findings. |
Collaborator Contribution | Our partners collected the primary data and provided funding for the data collection, genotyping and analyses. They are leading the analyses with support from us. |
Impact | The collaboration was multidisciplinary involving statistical genetics (us) and a leading child development psychologist. The collaboration has resulted in a draft manuscript |
Start Year | 2016 |
Description | Pint of Science - Unravelling the nature and nurture of mental ilnesses |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | I gave a 30 minute talk at The Pint of Science festival. These talks aim to deliver interesting and relevant information on the latest science research in an accessible format to the public across bars and pubs. The talk provoked a lot of discussion and interest in the causes of mental illness. The organizers have invited me back to update on my work next year. |
Year(s) Of Engagement Activity | 2016 |
URL | https://pintofscience.com/about/ |