Genetic Architecture Of Sex Steroid-related Psychiatric Disorders

Project Information

GASSP

Grant agreement ID: 947763

DOI

10.3030/947763

EC signature date 18 January 2021

Start date 1 December 2021

End date 30 November 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 499 961,00

EU contribution

€ 1 499 961,00

Coordinated by

CARDIFF UNIVERSITY
United Kingdom

Periodic Reporting for period 2 - GASSP (Genetic Architecture Of Sex Steroid-related Psychiatric Disorders)

Reporting period: 2023-06-01 to 2024-11-30

Summary of the context and overall objectives of the project

Psychiatric disorders associated with changes in female sex hormones are a major public health issue and represent a unique opportunity to study the complex interplay between gender, sex and mental states. The Genetic Architecture Of Sex Steroid-related Psychiatric Disorders (GASSP) study aims to understand how genetic and environmental markers can help identify women at risk of psychiatric disorders in relation to the menstrual cycle, childbirth and transition to menopause and improve the current approach to diagnosis, prevention and treatment. It takes a ground-breaking approach across diagnoses and life stages, rather than focusing on the current diagnostic labels that have limited clinical and biological validity. It seeks to characterise the largest cohort to date of women with psychiatric disorders temporally related with changes in sex hormones by leveraging new technologies a) to identify and reach sufferers, making it easier for them to participate in research b) to conduct sophisticated analyses, integrating detailed longitudinal clinical and psycho-social information with aggregated genome-wide data and functional annotations.
GASSP is the first molecular genetic study of the psychiatric sensitivity to sex hormone changes. It has the potential to contribute to the de-stigmatization of mental disorders related to female reproduction by providing evidence-based, easy-to-understand information to the public, and addressing the gender gap in psychiatry highlighted by the European Commission and the World Health Organization.
We have 3 research questions that we are hoping to address: 1) How much do genetic variants, environmental and clinical factors affect the psychiatric vulnerability to reproductive events? 2) How much does the genetic architecture of each reproductive psychiatric disorder differ from that of disorders with similar presentation or other reproductive psychiatric disorders? 3) Is there any genetic evidence that this vulnerability reflects perturbations in sex steroid signaling pathways or in systems regulated by sex steroids? To begin answering these questions, our first objective is to recruit and characterise a sample of 3,000 women with psychiatric disorders related to changes in reproductive hormones (the GASSP cohort). The second objective is to conduct analyses integrating both genetic and clinical information.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

To address objective one, we have established two sub-cohorts of participants, one for postpartum psychosis and one for premenstrual dysphoric disorder. So far, 1133 participants have been recruited and screened for inclusion. For the postpartum psychosis project, out of 104 participants meeting the inclusion criteria, 30 completed the study, including the provision of samples for genetic analyses. For the premenstrual dysphoric disorder (PMDD) project, out of the 342 participants meeting the inclusion criteria, 127 completed the study. To improve uptake, we have developed a new mobile phone application for the assessment of PMDD
For objective two, we have made progress in three main areas:
1) Before we are able to explore how genetics affects psychiatric vulnerability to reproductive events, we must first isolate the effect of genetics on females with relevant psychiatric disorders i.e. bipolar disorder. We have therefore run genetic analyses of bipolar disorder separately in males and females.
2) We are exploring how the inclusion of people who have experienced postpartum psychosis affects clinical sex differences in bipolar disorder using previously collected data. We are also conducting genetic studies of postpartum psychosis. We are cleaning and quality controlling the data to collate the largest ever genetic study of postpartum psychosis. As part of this, we have been collaborating with other researchers who have agreed to contribute data. From this data, we have shown for the first time that the genetic architecture between bipolar disorder and postpartum psychosis differ by their genetic risk for pre-eclampsia, a hypertensive disorder that affects people during pregnancy. This suggests subtle differences in the biological underpinning between these two conditions of similar presentation.
3) Analyses of the UK Biobank database have been run to test the association between menopause and psychiatric disorders. This study investigated whether the perimenopause (i.e. the years around the final menstrual period) is associated with increased risk of developing psychiatric disorders compared to the late reproductive stage (part of this is funded by a further grant from the Medical Research Council). Incidence rates of psychiatric disorders during the perimenopause (4 years surrounding the final menstrual period) were compared with the reference premenopausal period (6 to 10 years before the final menstrual period). Compared to the reference reproductive period, incidence rates of psychiatric disorders significantly increased during the perimenopause and decreased back down to that observed in the premenopausal period in the postmenopause. The effect was primarily driven by increased incidence of major depressive disorder, but the largest risk increase was observed for mania.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We have prioritised co-production in our work, with people with lived experience being involved in the design of both the PMDD and perimenopause studies. For example, Dr Clare Dolman, a researcher with lived experience and co-author on the publication on perimenopause mental illness, provided expertise and voiced the issues experienced by people affected by severe mental illness, in her roles within the charities Bipolar UK and Action on Postpartum Psychosis. The design of the perimenopause study was informed by a Bipolar UK survey which received over 1,000 responses. We had the opportunity to collaborate with Bipolar UK on a project on hypersexuality, which has already resulted in a publication and will lead to a research paper by the end of the year.
Additionally, we collaborated with the International Association of Premenstrual Disorders (IAPMD) to produce educational and recruitment materials such as a leaflet and animation. We have held webinars and panels with IAPMD and met with the Fair Treatment of Women in Wales group to discuss how we can contribute to policy change. We have two research champions who are people with lived experience that have taken part in our study, who advocate for our project and contribute to outreach. Outreach remains an important area of our work, with regular webinars, blogs and contributions to social media across all of our research areas.
Focus groups with participants to discuss obstacles to study completion has led to a collaboration with the School of Computer Science to develop an application for daily mood ratings on Android devices. We are now adapting this for iOS. The application will be tested by a small number of people with lived experience and then offered to all participants of the premenstrual dysphoric disorder study. The long-term goal is to apply to further funding to make it available to NHS patients.
Genetic analyses into postpartum psychosis will continue to better understand the biology of this condition. This will inform future grants to fund research into this area, which will focus on biological pathways which facilitate early identification and treatment and potentially inform our understanding of other forms of psychotic illness.

GASSP Hypothesis Model