Positive and negative symptoms are prominent but heterogeneous characteristics of schizophrenia spectrum disorder (SSD). Within the framework of the Genetic Risk and Outcome of Psychosis (GROUP) longitudinal cohort study, we aimed to distinguish and identify the genetic and non-genetics predictors of homogenous subgroups of the long-term course of positive and negative symptoms in SSD patients (n = 1119) and their unaffected siblings (n = 1059) in comparison to controls (n = 586). Data were collected at baseline, and after 3- and 6-year follow-ups. Group-based trajectory modeling was applied to identify latent subgroups using positive and negative symptoms or schizotypy scores. A multinomial random-effects logistic regression model was used to identify predictors of latent subgroups. Patients had decreasing, increasing, and relapsing symptoms course. Unaffected siblings and healthy controls had three to four subgroups characterized by stable, decreasing, or increasing schizotypy. PRSSCZ did not predict the latent subgroups. Baseline symptoms severity in patients, premorbid adjustment, depressive symptoms, and quality of life in siblings predicted long-term trajectories while were nonsignificant in controls. In conclusion, up to four homogenous latent subgroups of symptom course can be distinguished within patients, siblings, and controls, while non-genetic factors are the main factors associated with the latent subgroups.