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A genome-wide association study for shared risk across major psychiatric disorders in a nation-wide birth cohort implicates fetal neurodevelopment as a key mediator

By Andrew J Schork, Hyejung Won, Vivek Appadurai, Ron Nudel, Mike Gandal, Olivier Delaneau, David M Hougaard, Marie Bækved-Hansen, Jonas Byberg-Grauholm, Marianne Gioertz Pedersen, Esben Agerbo, Carsten Boecker Pedersen, Benjamin Neale, Mark J. Daly, Merete Nordentoft, Ole Mors, Anders D Børglum, Preben B Mortensen, Alfonso Buil, Wesley K Thompson, Daniel Geschwind, Thomas M Werge

Posted 29 Dec 2017
bioRxiv DOI: 10.1101/240911 (published DOI: 10.1038/s41593-018-0320-0)

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 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 SNP-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 midgestation. This epoch is supported by partitioning cross-disorder SNP-heritability which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings indicate that dysregulation of genes that direct neurodevelopment by common genetic variants results in general liability for many later psychiatric outcomes.

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