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A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment

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  • Andrew J Schork, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, DK-2100 Copenhagen, Denmark.
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  • Hyejung Won, UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA.
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  • Vivek Appadurai, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, DK-2100 Copenhagen, Denmark.
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  • Ron Nudel, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, DK-2100 Copenhagen, Denmark.
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  • Mike Gandal, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
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  • Olivier Delaneau, 1] Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland [2] Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland [3] Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.
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  • Malene Revsbech Christiansen, DTU Multi-Assay Core, DTU Bioinformatics, Technical University of Denmark, DK-2800 Lyngby, Denmark.
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  • David M Hougaard, Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
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  • Marie Bækved-Hansen, Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
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  • Jonas Bybjerg-Grauholm, Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
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  • Marianne Giørtz Pedersen
  • Esben Agerbo
  • Carsten Bøcker Pedersen
  • Benjamin M Neale, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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  • Mark J Daly, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
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  • Naomi R Wray, Queensland Brain Institute, University of Queensland, Brisbane, Australia; Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
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  • Merete Nordentoft, d Department of Clinical Medicine , Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.
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  • Ole Mors
  • Anders D Børglum
  • Preben Bo Mortensen
  • Alfonso Buil, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, DK-2100 Copenhagen, Denmark.
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  • Wesley K Thompson, Division of Biostatistics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.
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  • Daniel H Geschwind, Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
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  • Thomas Werge, Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Thomas.Werge@regionh.dk.

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.

Original languageEnglish
JournalNature Neuroscience
ISSN1097-6256
DOIs
Publication statusE-pub ahead of print - 28 Jan 2019

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