To Örebro University

Background: Schizophrenia (SCZ) is highly heterogenous and no subtypes have been established to have good clinical utility in characterizing treatment response or longitudinal course. Cognitive impairment is one of the core clinical features of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive ability is complex, with limited studies of comprehensive epidemiological and genomic evidence.

Methods: To comprehensively examine the relation between SCZ and three cognitive traits, educational attainment (EDU), premorbid cognitive ability, and intellectual disability (ID), we used two samples from Sweden: a national cohort (13 738 SCZ cases and 3 677 172 controls) and a subsample with comprehensive genetic data (4 992 cases and 6 009 controls).

Results: Population-based analyses showed worse cognition as risk factors for SCZ, and the pedigree genetic correlations between them were comparable with estimations from common genetic variants. In the genotyped subsample, premorbid cognitive ability and EDU were associated positively with their genetic risk score (GRS) and negatively with total number of rare exonic variants. The total size of copy number variants (CNV) deletions was associated with premorbid cognitive ability in controls. Finally, by applying an empirical clustering method, we dissect SCZ cases into four subgroups, defined by sex and ID. In particular, female cases with ID showed higher suicide-related events in the population cohort, and male-ID cases in genetic subsample had higher CNV and rare exonic burdens.

Discussion: In conclusion, we found extensive evidence of a robust relation between cognitive ability and SCZ, underscoring the importance of cognition in dissecting the heterogeneity of SCZ.