Rationale: Variables influencing real-life functioning have repeatedly been modeled in schizophrenia subjects but not systematically investigated in their unaffected first-degree relatives (SRs), in whom milder forms of deficits reported in schizophrenia have been observed, but confounders of clinical cohorts are not in play. Demonstrating that pathways to functional outcome are similar between patients and SRs would validate structural models de- veloped in schizophrenia subjects. The present multicenter study aimed to explore whether variables associated with real-life functioning are similar in schizophrenia patients and their unaffected relatives. Methods: The study sample included 921 schizophrenia patients, 379 SRs and 780 healthy controls. Structural Equation Models (SEMs) were used in patients and SRs to test associations of psychopathological dimensions, neurocognition, social cognition, resilience, perceived stigma and functional capacity with real-life functioning domains, impaired in both patients and SRs. Results: Interpersonal Relationships and Work Skills were the only functional domains impaired in both patients and SRs. For both domains, functional impairment in patients was found to predict impairment in unaffected relatives, suggesting the involvement of similar illness-related vulnerability factors. In both groups variables significantly associated with Interpersonal Relationships included Social Cognition, Neurocognition, Avolition, Resilience, Disorganization, Perceived Stigma and Gender, and those significantly associated with Work Skills in- cluded Social Cognition, Neurocognition and Disorganization. Conclusions: Pathways to functional outcome for Interpersonal relationships and Work skills are similar between schizophrenia patients and their unaffected first-degree relatives. These findings validate, in the absence of con- founders of clinical cohorts, structural models of determinants of functional outcome in people with schizophrenia.
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