Imputed Gene Expression versus Single Nucleotide Polymorphism in Predicting Gray Matter Phenotypes

Genetics plays an important role in psychiatric disorders. A clinically relevant question is whether we can predict psychiatric traits from genetics, which holds promise for early detection and tailored intervention. Imputed gene expression, also known as genetically-regulated expression (GRE), reflects the tissue-specific regulatory effects of multiple single nucleotide polymorphisms (SNPs) on genes. In this work, we explored the utility of GRE for trait association studies and how the GRE-based polygenic risk score (gPRS) compared with SNP-based PRS (sPRS) in predicting psychiatric traits. A total of 13 schizophrenia-related gray matter networks identified in another study served as the target brain phenotypes for assessing genetic associations and prediction accuracies in 34,149 individuals from the UK Biobank cohort. GRE was computed leveraging MetaXcan and GTEx tools for 56,348 genes across 13 available brain tissues. We then estimated the effects of individual SNPs and genes separately on each tested brain phenotype in the training set. The effect sizes were then used to compute gPRS and sPRS in the testing set, whose correlations with the brain phenotypes were used to assess the prediction accuracy. The results showed that, with the testing sample size set to 1,138, for training sample sizes from 1,138 up to 33,011, overall both gPRS and sPRS successfully predicted the brain phenotypes with significant correlations observed in the testing set, and higher accuracies noted for larger training sets. In addition, gPRS outperformed sPRS by showing significantly higher prediction accuracies across 13 brain phenotypes, with greater improvement noted for training sample sizes below [~]15,000. These findings support that GRE may serve as the primary genetic variable in brain phenotype association and prediction studies. Future imaging genetic studies may consider GRE as an option depending on the available sample size.