Characterizing Schizophrenia Genetic Risk Variants In Cognition And Brain Structure In The Genus Consortium Collection

Abstract

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to understand the genetic mechanisms of impaired brain function underlying schizophrenia. The consortium is examining the influence of genetic variation on cognitive functions and brain structural measures that are abnormal in schizophrenia using a collection of 4,125 patients, 3,644 controls, and 327 familial high-risk participants from 16 international sites. Data from each site were transferred to a central site for data harmonization and analyses. Genetic risk variants identified by previous well-powered schizophrenia GWAS, including individual SNPs, gene sets, and polygenic risk, were tested for association with cognitive functions and global/regional brain volumes that are altered in patients. Analysis of 108 SNPs from the schizophrenia PGC2 GWAS mega-analysis identified significant associations in all GENUS participants between several SNPs and general cognitive ability (Spearman’s ‘g’), visuospatial ability, and verbal learning/memory (FWE corrected p<2.3x10-5). Analysis of three gene sets identified by the PGC network and pathway analysis (synapse, histone methylation, and immune and neuronal/neurotrophic gene sets) detected nominal association between the synapse gene set and non-verbal learning/memory (p<0.001). The SNPs and gene set each explain 0.5-1% of the variance in the associated cognitive functions. Nonsignificant genetic associations with brain volume measures are in line with previous studies, suggesting a weaker relationship between schizophrenia genetic risk and brain structure, or may be due to reduced sample power compared to the analyses of cognitive functions. Schizophrenia polygenic risk was associated with worse performance in several cognitive functions (verbal learning/memory, nonverbal working memory, visuospatial ability), as well as reduced gray matter volume of frontotemporal regions (inferior frontal, superior temporal gyrus) (p<0.0001; 1-1.5% phenotypic variance explained). These results suggest that schizophrenia polygenic risk may be associated with altered development of frontotemporal regions that mediate cognitive functions and psychotic symptoms central to schizophrenia. Overall, these results support the hypothesis that schizophrenia genetic risk influences brain abnormalities underlying the disorder.