Preprint open access publication

Gene expression imputation across multiple brain regions reveals schizophrenia risk throughout development

bioRxiv, Cold Spring Harbor Laboratory,

2017

DOI:10.1101/222596, Dimensions: pub.1100764773,

Affiliations

Organisations

  1. (1) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  2. (2) Vanderbilt University Medical Center, grid.412807.8
  3. (3) Cardiff University, grid.5600.3
  4. (4) Aarhus University, grid.7048.b, AU
  5. (5) Lundbeck Foundation, grid.452548.a
  6. (6) University of California, Los Angeles, grid.19006.3e
  7. (7) National Institute of Mental Health, grid.416868.5
  8. (8) University of Trento, grid.11696.39
  9. (9) Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA
  10. (10) Karolinska Institute, grid.4714.6
  11. (11) University of North Carolina at Chapel Hill, grid.10698.36
  12. (12) University of Pittsburgh, grid.21925.3d
  13. (13) Sage Bionetworks, grid.430406.5

Description

Abstract Transcriptomic imputation approaches offer an opportunity to test associations between disease and gene expression in otherwise inaccessible tissues, such as brain, by combining eQTL reference panels with large-scale genotype data. These genic associations could elucidate signals in complex GWAS loci and may disentangle the role of different tissues in disease development. Here, we use the largest eQTL reference panel for the dorso-lateral pre-frontal cortex (DLPFC), collected by the CommonMind Consortium, to create a set of gene expression predictors and demonstrate their utility. We applied these predictors to 40,299 schizophrenia cases and 65,264 matched controls, constituting the largest transcriptomic imputation study of schizophrenia to date. We also computed predicted gene expression levels for 12 additional brain regions, using publicly available predictor models from GTEx. We identified 413 genic associations across 13 brain regions. Stepwise conditioning across the genes and tissues identified 71 associated genes (67 outside the MHC), with the majority of associations found in the DLPFC, and of which 14/67 genes did not fall within previously genome-wide significant loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple pathways associated with porphyric disorders. We investigated developmental expression patterns for all 67 non-MHC associated genes using BRAINSPAN, and identified groups of genes expressed specifically pre-natally or post-natally.

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Dimensions Citation Indicators

Times Cited: 7

Field Citation Ratio (FCR): 1.68

Open Access Info

Green, Published