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Distinct profiles of four polygenic scores in schizophrenia subgroups defined by cognitive development trajectories
Objective: Different trajectories of cognitive development in schizophrenia may reflect different profiles of neuropsychiatric and cognitive genetic influence. The authors examined subgroups in a schizophrenia sample with different developmental trajectories, and profiled the subgroups across four polygenic scores (PGS).
Method: Demographic, clinical and genetic data were collected for 746 schizophrenia cases, 370 unaffected siblings and 1525 controls at the NIMH Clinical Center. Cognitive trajectory subgroups were derived through cluster analysis using estimates of premorbid and current IQ. PGS were generated for schizophrenia, cognition, educational attainment and ADHD. Associations were tested using general linear models and logistic regression.
Results: Cluster analyses identified 3 cognitive trajectory subgroups in the schizophrenia cases: pre-adolescent cognitive impairment (19%), adolescent disruption of cognitive development (44%), and cognitively stable adolescent development (37%). The four PGS predicted 7.9% of the variance in subgroup membership. Subgroup characteristics converged with genetics. Cognitively stable individuals had the best clinical and functional outcomes in adulthood and only differed from controls on schizophrenia PGS. Those with declining adolescent cognition showed the worst symptoms after diagnosis, and had the highest schizophrenia PGS and disadvantageous cognitive PGS. Individuals showing pre-adolescent impairment in cognitive and academic performance and poor adult outcome, also had the most generalized PGS disadvantage relative to controls and were the only subgroup to differ from controls on education and ADHD PGS.
Conclusions and Relevance: Subgroups derived using estimates of premorbid and current IQ showed different premorbid and clinical characteristics, which converged with genetic findings. Simultaneous analysis of multiple PGS may contribute to clinical stratification in schizophrenia.