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Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights

Alexander Gusev, Nick Mancuso, Hilary K Finucane, Yakir Reshef, Lingyun Song, Alexias Safi, Edwin Oh, SCZ Working Group of the Psychiatric Genomics Cons, Steven McCaroll, Benjamin Neale, Roel Ophoff, Michael C O'Donovan, Nicholas Katsanis, Gregory E Crawford, Patrick F Sullivan, Bogdan Pasaniuc, Alkes L Price
doi: https://doi.org/10.1101/067355
Alexander Gusev
Harvard TH Chan School of Public Health;
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  • For correspondence: agusev@hsph.harvard.edu
Nick Mancuso
University of California, Los Angeles;
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Hilary K Finucane
Harvard TH Chan School of Public Health;
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Yakir Reshef
Harvard University;
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Lingyun Song
Duke University;
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Alexias Safi
Duke University;
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Edwin Oh
Duke University;
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Steven McCaroll
Harvard Medical School;
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Benjamin Neale
Broad Institute of MIT and Harvard;
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Roel Ophoff
University of California, Los Angeles;
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Michael C O'Donovan
Cardiff University;
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Nicholas Katsanis
Duke University;
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Gregory E Crawford
Duke University;
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Patrick F Sullivan
University of North Carolina, Chapel Hill
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Bogdan Pasaniuc
University of California, Los Angeles;
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Alkes L Price
Harvard TH Chan School of Public Health;
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Abstract

Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating expression data from brain, blood, and adipose tissues across 3,693 individuals with schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium. We identified 157 genes with a transcriptome-wide significant association, of which 35 did not overlap a known GWAS locus; the largest number involved alternative splicing in brain. 42/157 genes were also associated to specific chromatin phenotypes measured in 121 independent samples (a 4-fold enrichment over background genes). This high-throughput connection of GWAS findings to specific genes, tissues, and regulatory mechanisms is an essential step toward understanding the biology of schizophrenia and moving towards therapeutic interventions.

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The copyright holder for this preprint is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
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  • Posted August 2, 2016.

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Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights
Alexander Gusev, Nick Mancuso, Hilary K Finucane, Yakir Reshef, Lingyun Song, Alexias Safi, Edwin Oh, SCZ Working Group of the Psychiatric Genomics Cons, Steven McCaroll, Benjamin Neale, Roel Ophoff, Michael C O'Donovan, Nicholas Katsanis, Gregory E Crawford, Patrick F Sullivan, Bogdan Pasaniuc, Alkes L Price
bioRxiv 067355; doi: https://doi.org/10.1101/067355
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Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights
Alexander Gusev, Nick Mancuso, Hilary K Finucane, Yakir Reshef, Lingyun Song, Alexias Safi, Edwin Oh, SCZ Working Group of the Psychiatric Genomics Cons, Steven McCaroll, Benjamin Neale, Roel Ophoff, Michael C O'Donovan, Nicholas Katsanis, Gregory E Crawford, Patrick F Sullivan, Bogdan Pasaniuc, Alkes L Price
bioRxiv 067355; doi: https://doi.org/10.1101/067355

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