BrainGENIE: The Brain Gene Expression and Network Imputation Engine

In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. We developed a novel method called the Brain Gene Expression and Network Imputation Engine ( BrainGENIE ) that uses peripheral-blood transcriptomes to predict brain-tissue-specific gene-expression levels. BrainGENIE reliably predicted brain-tissue-specific expression levels for 1,733 – 11,569 genes (false-discovery rate-adjusted p <0.05), including many transcripts that cannot be predicted reliably by a transcriptome imputation method such as PrediXcan . We tested the generalizability of BrainGENIE in external within-individual data from ex vivo peripheral blood and postmortem brain samples from the Religious Orders Study and Memory and Aging Project, wherein we validated 39% of predicted gene expression levels as concordant with observed expression levels in dorsolateral prefrontal cortex and 23% in caudate. BrainGENIE recapitulated diagnosis-related gene expression changes in brain better than direct correlations from blood and predictions from PrediXcan. BrainGENIE complements and, in some ways, outperforms existing transcriptome-imputation tools, providing biologically meaningful predictions and opening new research avenues.