Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Laura M. Huckins, Amanda Dobbyn, Douglas M. Ruderfer, Gabriel Hoffman, Weiqing Wang, Antonio F. Pardiñas, Veera M. Rajagopal, Thomas D. Als, Hoang t. Nguyen, Kiran Girdhar, James Boocock, Panos Roussos, Menachem Fromer, Robin Kramer, Enrico Domenici, Eric R. Gamazon, Shaun Purcell, CommonMind Consortium, The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium, iPSYCH-GEMS Schizophrenia Working GroupDitte Demontis, Anders D. Børglum, James T. R. Walters, Michael C. O’Donovan, Patrick Sullivan, Michael J. Owen, Bernie Devlin, Solveig K. Sieberts, Nancy J. Cox, Hae Kyung Im, Pamela Sklar, Eli A. Stahl

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.
Original languageEnglish
Pages (from-to)659-674
Number of pages16
JournalNature Genetics
Volume51
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

Cite this

Huckins, L. M., Dobbyn, A., Ruderfer, D. M., Hoffman, G., Wang, W., Pardiñas, A. F., ... Stahl, E. A. (2019). Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nature Genetics, 51(4), 659-674. https://doi.org/10.1038/s41588-019-0364-4