@article{890e1e270c1043e1bde31a26d8661101,
title = "Gene expression imputation across multiple brain regions provides insights into schizophrenia risk",
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.",
keywords = "ACUTE INTERMITTENT PORPHYRIA, COGNITIVE DEFICITS, ASSOCIATION, MOUSE, TRANSCRIPTOME, CHILDHOOD, TRAITS, PSYCHOSIS, DISORDER, VARIANTS",
author = "Huckins, {Laura M.} and Amanda Dobbyn and Ruderfer, {Douglas M.} and Gabriel Hoffman and Weiqing Wang and Pardinas, {Antonio F.} and Rajagopal, {Veera M.} and Als, {Thomas D.} and Nguyen, {Hoang T.} and Kiran Girdhar and James Boocock and Panos Roussos and Menachem Fromer and Robin Kramer and Enrico Domenici and Gamazon, {Eric R.} and Shaun Purcell and Ditte Demontis and Borglum, {Anders D.} and Walters, {James T. R.} and O'Donovan, {Michael C.} and Patrick Sullivan and Owen, {Michael J.} and Bernie Devlin and Sieberts, {Solveig K.} and Cox, {Nancy J.} and Im, {Hae Kyung} and Pamela Sklar and Stahl, {Eli A.} and Johnson, {Jessica S.} and Shah, {Hardik R.} and Klein, {Lambertus L.} and Dang, {Kristen K.} and Logsdon, {Benjamin A.} and Mahajan, {Milind C.} and Mangravite, {Lara M.} and Hiroyoshi Toyoshiba and Gur, {Raquel E.} and Chang-Gyu Hahn and Eric Schadt and Lewis, {David A.} and Vahram Haroutunian and Peters, {Mette A.} and Lipska, {Barbara K.} and Buxbaum, {Joseph D.} and Keisuke Hirai and Perumal, {Thanneer M.} and Richard Bruggeman and Inez Myin-Germeys and {Van Os}, Jim and {CommonMind Consortium} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium} and {iPSYCH-GEMS Schizophrenia Working Group}",
note = "Funding Information: We dedicate this manuscript to the memory of Pamela Sklar, whose guidance and wisdom we miss daily. We strive to continue her legacy of thoughtful, innovative, and collaborative science. Data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer{\textquoteright}s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC Leadership: P. Sklar, J. Buxbaum (Icahn School of Medicine at Mount Sinai), B. Devlin, D. Lewis (University of Pittsburgh), R. Gur, C.-G. Hahn (University of Pennsylvania), K. Hirai, H. Toyoshiba (Takeda Pharmaceuticals Company Limited), E. Domenici, L. Essioux (F. Hoffman-La Roche Ltd), L. Mangravite, M. Peters (Sage Bionetworks), T. Lehner, B. Lipska (NIMH). ROSMAP study data were provided by the Rush Alzheimer{\textquoteright}s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute. The iPSYCH-GEMS team acknowledges funding from the Lundbeck Foundation (grant no. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no. 294838), the Danish Strategic Research Council the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on September 5, 2016. BrainSpan: Atlas of the Developing Human Brain (Internet). Funded by ARRA Awards 1RC2MH089921-01, 1RC2MH090047-01, and 1RC2MH089929-01. H.K.I. was supported by R01 MH107666-01. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = apr,
doi = "10.1038/s41588-019-0364-4",
language = "English",
volume = "51",
pages = "659--674",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "4",
}