Department of Economics and Business Economics

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

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  • Laura M Huckins, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. laura.huckins@mssm.edu.
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  • Amanda Dobbyn, Department of Genetics and Genomic Science, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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  • Douglas M Ruderfer, Department of Hematology, Vanderbilt University Medical Center, Nashville, TN, USA.
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  • Gabriel Hoffman, Department of Psychiatry, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
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  • Weiqing Wang, Department of Genetics and Genomic Science, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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  • Antonio F Pardiñas, National Centre for Mental Health, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine, Cardiff University, Cardiff, UK.
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  • Veera M Rajagopal
  • Thomas D Als
  • Hoang T Nguyen, Department of Genetics and Genomic Science, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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  • Kiran Girdhar, Department of Genetics and Genomic Science, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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  • James Boocock, Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
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  • Panos Roussos, Department of Psychiatry, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
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  • Menachem Fromer, Department of Genetics and Genomic Science, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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  • Robin Kramer, Human Brain Collection Core, National Institute of Mental Health, Bethesda, MD, USA.
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  • Enrico Domenici, Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
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  • Eric R Gamazon, Clare Hall, University of Cambridge, Cambridge, UK.
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  • Shaun Purcell, Department of Psychiatry, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
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  • Ditte Demontis
  • Anders D Børglum
  • James T R Walters, National Centre for Mental Health, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine, Cardiff University, Cardiff, UK.
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  • Michael C O'Donovan, National Centre for Mental Health, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine, Cardiff University, Cardiff, UK.
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  • Patrick Sullivan, Department of Medicine, Clinical Pharmacology Unit, Karolinska Institutet, Stockholm, Sweden ; The Stockholm Regional Ethical Review Board, Karolinska Institutet, Stockholm, Sweden.
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  • Michael J Owen, National Centre for Mental Health, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine, Cardiff University, Cardiff, UK.
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  • Bernie Devlin, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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  • Solveig K Sieberts, Systems Biology, Sage Bionetworks, Seattle, WA, USA.
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  • Nancy J Cox, Department of Hematology, Vanderbilt University Medical Center, Nashville, TN, USA.
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  • Hae Kyung Im, Department of Medicine, Section of Genetic Medicine, The University of Chicago, Chicago, Illinois, USA.
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  • Pamela Sklar, Department of Psychiatry, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
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  • Eli A Stahl, Department of Psychiatry, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
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  • CommonMind Consortium

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
JournalNature Genetics
ISSN1061-4036
DOIs
Publication statusE-pub ahead of print - 25 Mar 2019

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