Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
The polygenic risk score (PRS) is derived from SNPs including both those which are genome-wide significant and also a large number of others more weakly associated with schizophrenia. Such variants are widely dispersed, though concentrated near genes expressed in the brain, and it has been proposed that these SNP associations result from impacts on cell regulatory networks which ultimately affect the expression or function of a modest number of "core" genes. A previous study demonstrated association of some GWAS-significant variants with expression of a number of genes, by examining pair-wise correlations of gene expression with SNP genotypes. The present study used data downloaded from the CommonMind Consortium site, consisting of SNP genotypes and RNAseq expression data from the dorsolateral prefrontal cortex, to examine whether the expression of individual genes or sets of genes correlated with PRS in 207 controls and 209 schizophrenia cases. Although the PRS was significantly associated with phenotype, the correlations with genes and genes sets followed distributions expected by chance. Thus, this analysis failed to demonstrate that the PRS captures a cumulative effect of multiple variants impacting the expression of a small number of genes and it failed to focus attention on a small number of genes of biological relevance. The multiple SNP associations observed in schizophrenia may result from other mechanisms, including effects mediated indirectly through environmental risk factors.