Abstract
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.
Competing Interest Statement
In the past year, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from, Akili, Arbor, Genomind, Ironshore, Ondosis, Otsuka, Rhodes, Shire/Takeda, Sunovion, Supernus, Tris, and Vallon. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received support from: Alcobra, CogCubed, Eli Lilly, Enzymotec, Janssen, KemPharm, Lundbeck/Takeda, McNeil, Neurolifesciences, Neurovance, Novartis, Pfizer, and Vaya. Dr. Faraone also receives royalties from books published by Guilford Press: Straight Talk about Your Childs Mental Health; Oxford University Press: Schizophrenia: The Facts; and Elsevier: ADHD: Non-Pharmacologic Interventions. He is also principal investigator of www.adhdinadults.com. In the past year, Dr. Glatt has received royalties from a book published by Oxford University Press: Schizophrenia: The Facts, and consulting fees from Cohen Veterans Bioscience. Dr. Cairns is supported by NHMRC project grants (1147644 and 1188493) and an NHMRC Senior Research Fellowship (1121474), and a University of Newcastle College of Health Medicine and Wellbeing, Gladys M Brawn Senior Fellowship.
Footnotes
↵† See Appendix
In this revised version of the manuscript, data from the Religious Order Study and Memory and Aging Project (ROSMAP) was integrated as an external test dataset to evaluate the generalizability of our trained BrainGENIE models for the prefrontal cortex and caudate. We included corresponding analyses of the ROSMAP dataset in which we evaluated the concordance of imputed and observed disease-, age-, and sex-related effects on gene expression levels.