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Regulatory sites for known and novel splicing in human basal ganglia are enriched for disease-relevant information

Sebastian Guelfi, Karishma D’Sa, Juan Botía, Jana Vandrovcova, Regina H. Reynolds, David Zhang, Daniah Trabzuni, Leonoardo Collado-Torres, Andrew Thomason, Pedro Quijada Leyton, Sarah A. Gagliano, Mike A. Nalls, UK Brain Expression Consortium, Kerrin S. Small, Colin Smith, Adaikalavan Ramasamy, John Hardy, Michael E. Weale, Mina Ryten
doi: https://doi.org/10.1101/591156
Sebastian Guelfi
1Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK
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Karishma D’Sa
1Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK
2Department of Medical & Molecular Genetics, School of Medical Sciences, King’s College London, Guy’s Hospital, London, UK
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Juan Botía
1Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK
3Departamento de Ingeniería de la Información y las Comunicaciones. Universidad de Murcia, Murcia, Spain
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Jana Vandrovcova
1Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK
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Regina H. Reynolds
1Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK
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David Zhang
1Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK
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Daniah Trabzuni
1Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK
4Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Leonoardo Collado-Torres
5Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD, United States
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Andrew Thomason
6Goldsmiths, University of London, New Cross, London, UK
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Pedro Quijada Leyton
6Goldsmiths, University of London, New Cross, London, UK
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Sarah A. Gagliano
7Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
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Mike A. Nalls
8Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA
9Data Tecnica International, Glen Echo, Maryland, USA
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Kerrin S. Small
10Department of Twin Research and Genetic Epidemiology, King’s College London, UK
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Colin Smith
11Department of Neuropathology, MRC Sudden Death Brain Bank Project, University of Edinburgh, Edinburgh, UK
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Adaikalavan Ramasamy
1Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK
2Department of Medical & Molecular Genetics, School of Medical Sciences, King’s College London, Guy’s Hospital, London, UK
12Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore
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John Hardy
1Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK
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Michael E. Weale
2Department of Medical & Molecular Genetics, School of Medical Sciences, King’s College London, Guy’s Hospital, London, UK
13Genomics plc, Oxford, UK
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Mina Ryten
1Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK
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  • For correspondence: mina.ryten@ucl.ac.uk
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Abstract

Genome-wide association studies have generated an increasing number of common genetic variants that affect neurological and psychiatric disease risk. Given that many causal variants are likely to operate by regulating gene expression, an improved understanding of the genetic control of gene expression in human brain is vital. However, the difficulties of sampling human brain, and its complexity, has meant that brain-related expression quantitative trait loci (eQTL) and allele specific expression (ASE) signals have been more limited in their explanatory power than might otherwise be expected. To address this, we use paired genomic and transcriptomic data from putamen and substantia nigra dissected from 117 brains, combined with a comprehensive set of analyses, to interrogate regulation at different stages of RNA processing and uncover novel transcripts. We identify disease-relevant regulatory loci and reveal the types of analyses and regulatory positions yielding the most disease-specific information. We find that splicing eQTLs are enriched for neuron-specific regulatory information; that ASE analyses provide highly cell-specific regulatory information; and that incomplete annotation of the brain transcriptome limits the interpretation of risk loci for neuropsychiatric disease. We release this rich resource of regulatory data through a searchable webserver, http://braineacv2.inf.um.es/.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 28, 2019.
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Regulatory sites for known and novel splicing in human basal ganglia are enriched for disease-relevant information
Sebastian Guelfi, Karishma D’Sa, Juan Botía, Jana Vandrovcova, Regina H. Reynolds, David Zhang, Daniah Trabzuni, Leonoardo Collado-Torres, Andrew Thomason, Pedro Quijada Leyton, Sarah A. Gagliano, Mike A. Nalls, UK Brain Expression Consortium, Kerrin S. Small, Colin Smith, Adaikalavan Ramasamy, John Hardy, Michael E. Weale, Mina Ryten
bioRxiv 591156; doi: https://doi.org/10.1101/591156
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Regulatory sites for known and novel splicing in human basal ganglia are enriched for disease-relevant information
Sebastian Guelfi, Karishma D’Sa, Juan Botía, Jana Vandrovcova, Regina H. Reynolds, David Zhang, Daniah Trabzuni, Leonoardo Collado-Torres, Andrew Thomason, Pedro Quijada Leyton, Sarah A. Gagliano, Mike A. Nalls, UK Brain Expression Consortium, Kerrin S. Small, Colin Smith, Adaikalavan Ramasamy, John Hardy, Michael E. Weale, Mina Ryten
bioRxiv 591156; doi: https://doi.org/10.1101/591156

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