European Partnership Brain Health: CaSMS: Causal pathways linking substance use, major depressive disorder, and stroke
Verweij K., Bergstedt J., Grove J., Gerring Z., Laisk T., Næss O., et al.
TÜBİTAK Uluslararası Çoklu İşbirliği Projesi , ERA.NET Projesi , 2027 - 2030
- Proje Türü: TÜBİTAK Uluslararası Çoklu İşbirliği Projesi
- Destek Programı: ERA.NET Projesi
- Başlama Tarihi: Haziran 2027
- Bitiş Tarihi: Haziran 2030
Proje Özeti
Scientific abstract of the project
Stroke is one of the leading causes of death and disability worldwide, while major depressive
disorder (MDD) and substance use disorders (SUD) are highly prevalent and frequently co-occur
with stroke. Although epidemiological studies consistently report associations between these
conditions, it remains unclear whether the relationships are causal, which biological mechanisms
underlie them, and why they differ between women and men. This knowledge gap limits the
development of effective prevention strategies and precision medicine approaches.
CaSMS (Causal links between Substance use, Major depressive disorder, and Stroke) is
aimed at bridging chasms, both conceptually (between mental and cerebrovascular health,
between men and women) and methodologically (by combining data levels and multidisciplinary
research designs). CaSMS will investigate the causal pathways linking substance use, MDD, and stroke by integrating
nationwide electronic health records, large population-based cohorts, biobanks, and genome-wide genetic data from
millions of individuals across Europe. The consortium will combine complementary epidemiological, family-based,
genetic, and multi-omic approaches, allowing causal conclusions to be supported by converging evidence rather than a
single study design.
The project consists of five interconnected work packages. WP1 will characterise sex- and age-specific genetic
architecture of MDD and assess disease trajectories linking substance use, MDD, and stroke. WP2 will determine
whether these relationships are causal using quasi-experimental designs (within-family studies and Mendelian
randomisation). WP3 will identify inflammatory and metabolic pathways that mediate these effects and assess whether
they differ between women and men. WP4 will integrate genetic and functional genomic evidence to identify sex-specific
druggable targets and opportunities for drug repurposing. Throughout the project, WP5 will ensure responsible and
inclusive research through ethical analysis, stakeholder and patient involvement, and implementation planning.
CaSMS is innovative because it integrates large-scale longitudinal data, multiple complementary causal
inference methods, metabolomics, functional genomics, and drug target prioritisation within a single framework. Rather
than treating sex as a covariate, sex differences are modelled as a central biological question throughout the project.
By identifying causal mechanisms linking substance use, MDD and stroke, CaSMS will provide a foundation for
improved risk prediction, targeted prevention, sex-specific intervention strategies, and future precision medicine, while
ensuring that translation into healthcare is ethically responsible and socially inclusive.
Lay abstract
Stroke is one of the leading causes of death and disability worldwide. People with depression and substance use
problems are more likely to have a stroke, but we do not know whether these conditions actually cause stroke or simply
occur alongside it. Women and men also differ in their risk of depression, substance use, and stroke, yet the reasons
remain poorly understood. Without this knowledge, it is hard to identify who is most at risk, how stroke can best be
prevented, and whether women and men might benefit from different prevention or treatment strategies. We aim to
answer these questions by bringing together genetic information, national health records, blood biomarker data, and
large population studies involving millions of people across Europe. By combining different research methods, we will
test whether depression and substance use truly raise stroke risk, identify the biological pathways involved, and
investigate why these pathways differ between women and men.
CaSMS (Causal links between Substance use, Major depressive disorder, and Stroke) sets out to bridge
chasms, such as those between mental and vascular health and between males and females. We also bridge gaps
between methods, combining different kinds of data and research approaches from several fields. The project is
organised into five closely connected work packages. We will first study how depression, substance use, and stroke
develop across the lifespan and identify genetic differences between women and men, then test whether these
relationships are causal. Next, we will investigate which biological processes explain the effects and search for existing
and novel medications to target them. Throughout, biomedical ethicists, patient representatives, and clinicians will work
alongside the researchers to ensure the work is conducted responsibly, addresses questions that matter to patients,
and can be translated into healthcare.
CaSMS is primarily a fundamental research project, so it will not produce a new treatment immediately. Instead,
it will provide the scientific foundation needed to improve prevention, identify those at highest risk, support more
personalised and sex-specific care, and guide future therapies. Where medicines already exist that act on the pathways
we identify, drug repurposing may speed clinical translation.
The project places patients at its centre. Patient organisations representing people with depression, stroke, and
substance use disorders have already shaped the study design and will stay involved by helping interpret results,
prioritise the research agenda, and develop accessible materials. Most of the research uses existing health and genetic
data, so no new hospital visits, treatments, or tests are required from participants. All analyses use de-identified data in
secure systems that comply with European data protection law, and ethical oversight ensures careful attention to
privacy, fairness, stigma, and equal access to future innovations.
Ultimately, CaSMS aims to generate knowledge that helps prevent stroke before it occurs, improves care for
people with depression and substance use disorders, and lays the foundation for more effective, personalised, and
equitable healthcare for both women and men.