The relationship between age of onset and clinical severity, community functioning, and cognitive functioning in schizophrenia: A multiplex extended pedigree study

Schizophrenia is associated with substantial heterogeneity in symptom severity, course of illness, and overall functioning. Earlier age of onset is a consistent predictor of poor outcomes in multiple domains, but the causes of this association are still unknown. We used a multiplex, extended pedigree study (N=773) to determine the heritability of age of onset, to replicate its association with measures of symptom severity and functioning, and to determine the degree to which the genetic effects that influence age of onset are shared with those that influence outcome. We also assessed the degree to which the genetic effects on age of onset might influence functioning in relatives with major depression or those with no psychiatric diagnosis, thus assessing whether or not those genetic factors are transdiagnostic. The current sample consisted of 43 multigenerational families (N=635 relatives) with at least two first-degree relatives diagnosed with schizophrenia (N=103) and 135 matched controls. All participants completed a demographic and symptom interview as well as a cognitive battery with 11 tasks. Although age of onset of schizophrenia was modestly heritable, it was not significant (h2 = 0.198, p = 0.277). However, age of onset was still significantly correlated phenotypically with negative symptoms, positive symptoms, community functioning, and cognitive functioning. The genetic correlation between age of onset of schizophrenia and negative symptoms was significant, while the genetic relationships between age of onset and positive symptoms, community functioning, and cognitive functioning were non-significant. There was no significant genetic correlation between age of onset in schizophrenia and community or cognitive functioning in depressed relatives, or community and cognitive functioning in relatives with no psychiatric diagnoses, which is consistent with the proposal that any genetic effects on age of onset in schizophrenia are not transdiagnostic. This study was, to the best of our knowledge, the first of its kind to assess the potential shared genetic effects linking age of onset to relevant outcome measures and to examine their diagnostic specificity. These findings illustrate the potential of such approaches and support further research elucidating the potential causes of heterogeneity within schizophrenia