Age of onset and clinical severity, cognitive functioning, and community functioning in schizophrenia: A multiplex extended pedigree study

Schizophrenia has substantial variation in symptom severity, cognitive deficits, and overall functioning. Age of onset is a consistent predictor of this variation and yet the causes of this association are still unknown. We... [ view full abstract ]

Schizophrenia has substantial variation in symptom severity, cognitive deficits, and overall functioning. Age of onset is a consistent predictor of this variation and yet the causes of this association are still unknown. We employed a multiplex, extended pedigree study to examine within schizophrenia the heritability of age of onset and its prediction of symptom severity, cognition, and functioning. Our primary aim was to determine the causes of this relationship—specifically, to assess whether genetic effects on age of onset are shared with those that influence outcome. We also examined the degree to which genetic effects on age of onset in schizophrenia might influence functioning in relatives with major depression or those with no psychiatric diagnosis, thus assessing whether or not those genetic factors are diagnostically specific or transdiagnostic. This study is, to the best of our knowledge, the first to examine the potential shared genetic effects between age of onset and relevant outcome measures and to examine their diagnostic specificity. The sample (total N=771) consisted of 43 extended pedigrees (N=636 relatives, including N=110 with major depression, N=256 with no psychiatric diagnosis) 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. Factor analyses were conducted separately on the 11 cognitive measures and the four community functioning measures and single factor solutions were considered appropriate for both cognition and community functioning. Within schizophrenia, earlier age of onset significantly predicted increased severity of negative (r = -0.196, p = .003) and positive (r = -0.228, p = .045) symptoms, poorer cognition (r = 0.295, p = .030), and poorer community functioning (r = 0.318, p = .008).  Age of onset of schizophrenia was modestly heritable, although not significant (h² = 0.198, p = 0.277). Negative symptoms (h² = 0.977, p < 0.001), positive symptoms (h² = 0.853, p = 0.003), and cognition (h² = 0.835, p = 0.013) were all significantly heritable, and community functioning was not (h² = 0.320, p = 0.182). Notably, the genetic correlation between age of onset of schizophrenia and negative symptoms was significant (R_G = -1.0, p = .007), indicating pleiotropy, while the genetic correlations between age of onset and positive symptoms, community functioning, and cognitive functioning were high (i.e., R_Gs = 1.0 or -1.0) but not statistically significant (ps = 0.139 – 0.590). Genetic correlations between age of onset in schizophrenia and community or cognitive functioning in depressed or non-diagnosed relatives were not significant, thus not supporting transdiagnostic age of onset genetic effects.