Complex clinical, neurobiological, and molecular signatures of the longitudinal course of psychosis: leveraging comprehensive phenotyping, novel machine learning, and (epi)genomic approaches

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The overall goal of the PC1 project of PsyCourse is the identification of clinical, neurobiological, and molecular genetic signatures of the longitudinal course of major psychiatric disorders. As it is based upon the successful work of the Clinical Research Group 241 (KFO 241), a major focus will lie on schizophrenia (SZ) and bipolar disorder (BD). To better account for the etiological overlap between psychiatric phenotypes, we will now also include major depressive disorder (MDD). Over the course of 3 years, we will establish a deep-phenotyped cohort of 1,700 patients (700 SZ, 700 BD, 300 MDD) and 500 controls, for whom extensive phenotyping and biobanking (blood, DNA, RNA, plasma, serum) at at least 4 time points (0,6,12,18 months) will be available. This unique resource that has been made possible through KFO 241`s German-wide recruitment infrastructure will thus constitute the core resource for human-centered research across PsyCourse. We will apply advanced machine learning methods to the baseline and longitudinal phenotypic information in these cohorts to define novel target phenotypes of course and outcome for further molecular and statistical analyses. We will assess the feasibility of an individualized diagnostic classification and outcome prediction. A vast array of data will inform these novel analyses, such as socio-demographic, psychopathological, neurocognitive and genomic data. The machine-learning part of our project will also help define patients at the extreme ends of the course of disorder (worst vs. very favorable course). We will interrogate the complete genomic background of these two groups by whole-genomic sequencing to establish a potential involvement of rare variants determining course and outcome. Finally, using cutting-edge microRNAnome sequencing, we propose to establish regulatory elements as novel biomarkers for course in SZ. Thus, in its entirety, our project is one of the core projects within PsyCourse as it lays the foundation for the clinical research of the consortium and as it delineates novel, data-driven course phenotypes feeding into molecular analyses within PC1 and others within PsyCourse.