Why does age of onset predict clinical severity in schizophrenia? A multiplex extended pedigree study

Abstract

Schizophrenia has substantial variation in symptom severity, course of illness, and overall functioning. Earlier age of onset (AOO) is consistently associated with negative outcomes and yet the causes of this association are still unknown. We used a multiplex, extended pedigree design (total N = 771; 636 relatives from 43 multigenerational families with at least 2 relatives diagnosed with schizophrenia and 135 matched controls) to examine among the schizophrenia relatives (N = 103) the relationship between AOO and negative and positive symptom severity, cognition, and community functioning. Most importantly, we assessed whether there are shared genetic effects between AOO and negative symptoms, positive symptoms, cognition, and community functioning. As expected, earlier AOO was significantly correlated with increased severity of negative and positive symptoms and poorer cognition and community functioning among schizophrenia patients. Notably, the genetic correlation between AOO of schizophrenia and negative symptoms was significant (Rg = −1.00, p = .007). Although the genetic correlations between AOO and positive symptoms, cognition, and community functioning were estimated at maximum and in the predicted direction, they were not statistically significant. AOO of schizophrenia itself was modestly heritable, although not significant and negative symptoms, positive symptoms, and cognition were all strongly and significantly heritable. In sum, we replicated prior findings indicating that earlier AOO is associated with increased symptom severity and extended the literature by detecting shared genetic effects between AOO and negative symptoms, suggestive of pleiotropy.

The Role of Premorbid IQ and Age of Onset as Useful Predictors of Clinical, Functional Outcomes, and Recovery of Individuals with a First Episode of Psychosis

“…Musket et al [40] also identified shared genetic effects between age at onset and negative symptom severity in patients with schizophrenia. Additional evidence supports the idea that early onset of schizophrenia is moderately heritable [39,40] and that a familial component exists in the relationship between cognitive performance and psychosis [41,42]. Thus, the presence of an early age of onset and a low pIQ may reflect a specific neurodevelopmental course within psychotic disorders [43].…”

“…Lack of insight has been a variable with state and trait characteristics (these latter ones associated with schizophrenia and particularly early onset) that could have a role in the persistence of negative symptoms [75,76]. Musket et al [40] also identified shared genetic effects between age at onset and negative symptom severity in patients with schizophrenia. Additional evidence supports the idea that early onset of schizophrenia is moderately heritable [39,40] and that a familial component exists in the relationship between cognitive performance and psychosis [41,42].…”

Study of Early Onset Schizophrenia: Associations of GRIN2A and GRIN2B Polymorphisms

“…Earlier onset is often associated with a poorer outcome [37]. Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes [38].…”

"Predictors of Negative Symptom Domains in Outpatients with Schizophrenia: A Cross-Sectional Study"

“…To our knowledge this is the first study aiming to identify predictive factors of negative symptoms dimensions separately. Previous studies have reported a young age of onset, early onset of illness, cognitive symptoms, general psychopathology as predictors of the broad domain of negative symptoms (Fujimaki et al, 2018, Cuesta et al, 2020, Musket et al, 2020.…”