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Open Access Publications from the University of California

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

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

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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.

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