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

CommonMind Consortium, The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium, iPSYCH-GEMS Schizophrenia Working Group

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

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
StatePublished - 1 Apr 2019
Externally publishedYes

Funding

FundersFunder number
Stanley Medical Research Institute
Takeda Pharmaceuticals U.S.A.
University Hospitals
CIRRAU Center
National Human Genome Research Institute
National Institute of Neurological Disorders and Stroke
Illinois Department of Public Health
European Commission
Translational Genomics Research Institute
National Cancer Institute
National Institute on Drug Abuse
F. Hoffmann-La Roche
Strategiske Forskningsråd
National Heart, Lung, and Blood Institute
European Research Council
Novo Nordisk Fonden
National Institute on AgingU01AG032984, R01AG036836, P30AG010161, R01AG017917, R01AG030146, U01AG046152, P01AG002219, R01AG015819, P50AG005138
National Institute of Mental HealthRC2MH089929, R01MH093725, R01MH085542, RC2MH089921, U01MH109536, R01MH118278, R37MH057881, R01MH080405, R01MH097276, P50MH066392, R01MH107666, P50MH084053, R01MH075916, RC2MH090047
Seventh Framework Programme294838
Medical Research CouncilMR/L010305/1
UK Research and Innovation90029
LundbeckfondenR155-2014-1724, R102-A9118
National Institutes of HealthMH06692, HHSN271201300031C, P50M096891

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