PT  - JOURNAL ARTICLE
AU  - Nicole Mariani
AU  - Alessandra Borsini
AU  - Charlotte A.M. Cecil
AU  - Janine F. Felix
AU  - Sylvain Sebert
AU  - Annamaria Cattaneo
AU  - Esther Walton
AU  - Yuri Milaneschi
AU  - Guy Cochrane
AU  - Clara Amid
AU  - Jeena Rajan
AU  - Juliette Giacobbe
AU  - Yolanda Sanz
AU  - Ana Agustí
AU  - Tania Sorg
AU  - Yann Herault
AU  - Jouko Miettunen
AU  - Priyanka Parmar
AU  - Nadia Cattane
AU  - Vincent Jaddoe
AU  - Jyrki Lötjönen
AU  - Carme Buisan
AU  - Miguel A. González Ballester
AU  - Gemma Piella
AU  - Josep L. Gelpi
AU  - Femke Lamers
AU  - Brenda WJH Penninx
AU  - Henning Tiemeier
AU  - Malte von Tottleben
AU  - Rainer Thiel
AU  - Katharina F. Heil
AU  - Marjo-Riitta Järvelin
AU  - Carmine Pariante
AU  - Isabelle M. Mansuy
AU  - Karim Lekadir
TI  - Identifying Causative Mechanisms Linking Early-Life Stress to Psycho-Cardio-Metabolic Multi-Morbidity: The EarlyCause Project
AID  - 10.1101/2020.07.08.181958
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.08.181958
4099  - http://biorxiv.org/content/early/2020/07/09/2020.07.08.181958.short
4100  - http://biorxiv.org/content/early/2020/07/09/2020.07.08.181958.full
AB  - Introduction Depression, cardiovascular diseases and diabetes are among the major non-communicable diseases, leading to significant disability and mortality worldwide. These diseases may share environmental and genetic determinants associated with multimorbid patterns. Stressful early-life events are among the primary factors associated with the development of mental and physical diseases. However, possible causative mechanisms linking early life stress (ELS) with psycho-cardio-metabolic (PCM) multi-morbidity are not well understood. This prevents a full understanding of causal pathways towards shared risk of these diseases and the development of coordinated preventive and therapeutic interventions.Methods and analysis This paper describes the study protocol for EarlyCause, a large-scale and inter-disciplinary research project funded by the European Union’s Horizon 2020 research and innovation programme. The project takes advantage of human longitudinal birth cohort data, animal studies and cellular models to test the hypothesis of shared mechanisms and molecular pathways by which ELS shape an individual’s physical and mental health in adulthood. The study will research in detail how ELS converts into biological signals embedded simultaneously or sequentially in the brain, the cardiovascular and metabolic systems. The research will mainly focus on four biological processes including possible alterations of the epigenome, neuroendocrine system, inflammatome, and the gut microbiome. Life course models will integrate the role of modifying factors as sex, socioeconomics, and lifestyle with the goal to better identify groups at risk as well as inform promising strategies to reverse the possible mechanisms and/or reduce the impact of ELS on multi-morbidity development in high-risk individuals. These strategies will help better manage the impact of multi-morbidity on human health and the associated risk.Ethics and dissemination The study has been approved by the Ethics Board of the European Commission. The results will be published in peer-reviewed academic journals, and disseminated to and communicated with clinicians, patient organisations and media.Competing Interest StatementThe authors have declared no competing interest.