Genetic Effects Shared Between Schizophrenia and Cognition: Changes Across Age of Risk

Neurodevelopmental models seeking to explain schizophrenia’s peak age of onset in the twenties may be heuristically divided into “early” and “late” models1, with “early” models proposing that... [ view full abstract ]

Neurodevelopmental models seeking to explain schizophrenia’s peak age of onset in the twenties may be heuristically divided into “early” and “late” models¹, with “early” models proposing that schizophrenia-specific brain effects occur perinatally but remain clinically latent until they are revealed by normative brain changes during young adulthood² and “late” models hypothesizing that schizophrenia-specific brain effects, such as excessive synaptic pruning, occur during young adulthood³.  Given schizophrenia’s high heritability (h²=.80)⁴, early neurodevelopmental models thus predict that schizophrenia genetic effects should be present during childhood², whereas late neurodevelopmental models suggest that schizophrenia genetic effects should increase during adulthood nearer to the peak age of onset³.  Cognition is genetically correlated with schizophrenia and thus this correlation may serve as a proxy index of some schizophrenia genetic effects among non-schizophrenia individuals.  The present study thus sought to examine whether the genetic correlation between schizophrenia and cognition increases from ages prior to the peak age of onset of schizophrenia to ages after the peak, as predicted by “late” developmental hypotheses.   To address this question, 636 relatives from 43 multiplex, extended pedigrees (15-87 years old) and 135 unrelated controls underwent diagnostic interview and cognition assessment.  Epidemiological studies of population incidences identify the peak age of schizophrenia onset at approximately 23 years⁵. Therefore, non-schizophrenia relatives and control participants were stratified into two risk groups based on their ages relative to the putative trajectory of schizophrenia genetic risk effects: pre-peak (younger than 23 years) and post-peak (older than 23 years). Quantitative genetic analyses were conducted using maximum-likelihood variance decomposition methods in SOLAR⁶.  Exploratory factor analysis conducted on the eleven cognitive assessments (Penn Computerized Neurocognitive Battery, Trail Making Test, and California Verbal Learning Test) yielded a single general cognition factor.  General cognition was heritable in both the pre-peak (h²=1.00, p=.008) and the post-peak periods (h²=0.49,p<.001) and the genetic correlation between the risk periods was high (R_G=1.00,p=.002), suggesting that similar overall genetic factors influence general cognition across risk periods.  The genetic correlations between schizophrenia and general cognition for was moderate and not significant (R_G=-0.32, p=.070) in the pre-peak period.  Importantly, the genetic correlation between schizophrenia and cognition was significant and significantly higher in the post-peak (R_G=-0.58, p<.001) than in the pre-peak period (Fisher’s z=2.62, p=.004), suggesting that pleiotropic effects between schizophrenia and cognition increase during and continue after the peak age of onset of schizophrenia.  These findings are consistent with late neurodevelopmental models of schizophrenia in which schizophrenia peak age of onset arises at least partly due to the late expression during young adulthood of schizophrenia risk variants and suggest the importance of examining whether specific schizophrenia genetic risk variants modulate their effects across development.

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