Abstract

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/.

International Parkinson’s Disease Genomics Consortium (IPDGC) Alastair J. Noyce1,14, Aude Nicolas8, Mark R. Cookson8, Sara Bandres-Ciga8, J. Raphael Gibbs8, Dena G. Hernandez8, Andrew B. Singleton8, Xylena Reed8, Hampton Leonard8, Cornelis Blauwendraat8,14, Faraz Faghri3,15,16, Jose Bras10, Rita Guerreiro17, Arianna Tucci17, Demis A. Kia17, Henry Houlden17, Helene Plun-Favreau17, Kin Y Mok17, Nicholas W. Wood17, Ruth Lovering17, Lea R’Bibo17, Mie Rizig17, Viorica Chelban17, Manuela Tan12, Huw R. Morris18, Ben Middlehurst19, John Quinn19, Kimberley Billingsley19, Peter Holmans20, Kerri J. Kinghorn21, Patrick Lewis22, Valentina Escott-Price23, Nigel Williams23, Thomas Foltynie24, Alexis Brice25, Fabrice Danjou25, Suzanne Lesage25, Jean-Christophe Corvol25, Maria Martinez25,26, Anamika Giri27,28, Claudia Schulte27,28, Kathrin Brockmann27,28, Javier Simón-Sánchez27,28, Peter Heutink27,28, Thomas Gasser27,28, Patrizia Rizzu28, Manu Sharma29, Joshua M. Shulman30,31, Laurie Robak30, Steven Lubbe32, Niccolo E. Mencacci33, Steven Finkbeiner34,35, Codrin Lungu36, Sonja W. Scholz37, Ziv Gan-Or38, Guy A. Rouleau39, Lynne Krohan40, Jacobus J. van Hilten41, Johan Marinus41, Astrid D. Adarmes-Gómez42, Inmaculada Bernal-Bernal42, Marta Bonilla-Toribio42, Dolores Buiza-Rueda42, Fátima Carrillo42, Mario Carrión-Claro42, Pablo Mir42, Pilar Gómez-Garre42, Silvia Jesús42, Miguel A. Labrador-Espinosa42, Daniel Macias42, Laura Vargas-González42, Carlota Méndez-del-Barrio42, Teresa Periñán-Tocino42, Cristina Tejera-Parrado42, Monica Diez-Fairen43, Miquel Aguilar43, Ignacio Alvarez43, María Teresa Boungiorno43, Maria Carcel43, Pau Pastor43, Juan Pablo Tartari43, Victoria Alvarez44, Manuel Menéndez González44, Marta Blazquez44, Ciara Garcia44, Esther Suarez-Sanmartin44, Francisco Javier Barrero45, Elisabet Mondragon Rezola46, Jesús Alberto Bergareche Yarza47, Ana Gorostidi Pagola47, Adolfo López de Munain Arregui47, Javier Ruiz-Martínez47, Debora Cerdan48, Jacinto Duarte49, Jordi Clarimón50,51, Oriol Dols-Icardo50,51, Jon Infante51,52,53, Juan Marín51,54, Jaime Kulisevsky51,54, Javier Pagonabarraga51,54, Isabel Gonzalez-Aramburu52, Antonio Sanchez Rodriguez52, María Sierra52, Raquel Duran55, Clara Ruz55, Francisco Vives55, Francisco Escamilla-Sevilla56, Adolfo Mínguez56, Ana Cámara57, Yaroslau Compta57, Mario Ezquerra57, Maria Jose Marti57, Manel Fernández57, Esteban Muñoz57, Rubén Fernández-Santiago57, Eduard Tolosa57, Francesc Valldeoriola57, Pedro García-Ruiz58, Maria Jose Gomez Heredia59, Francisco Perez Errazquin59, Janet Hoenicka60, Adriano Jimenez-Escrig60, Juan Carlos Martínez-Castrillo60, Jose Luis Lopez-Sendon60, Irene Martínez Torres61, Cesar Tabernero61, Lydia Vela61, Alexander Zimprich62, Lasse Pihlstrom63, Sulev Koks64,65,66, Pille Taba67, Kari Majamaa68,69, Ari Siitonen68,69, Njideka U. Okubadejo70 & Oluwadamilola O. Ojo70 14Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, QMUL, London, UK. 15National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. 16Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA. 17Department of Molecular Neuroscience, UCL, London, UK. 18Department of Clinical Neuroscience, University College London, London, UK. 19Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 20Biostatistics & Bioinformatics Unit, Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff, UK. 21Institute of Healthy Ageing, University College London, London, UK. 22University of Reading, Reading, UK. 23MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK. 24UCL Institute of Neurology, London, UK. 25Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, AP-HP, Pitié-Salpêtrière Hospital, Paris, France. 26Paul Sabatier University, Toulouse, France. 27Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 28DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany. 29Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tübingen, Germany. 30Departments of Neurology, Neuroscience, and Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA. 31Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA. 32Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 33Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 34Departments of Neurology and Physiology, University of California, San Francisco, CA, USA. 35Gladstone Institute of Neurological Disease; Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA, USA. 36National Institutes of Health Division of Clinical Research, NINDS, National Institutes of Health, Bethesda, MD, USA. 37Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. 38Montreal Neurological Institute and Hospital, Department of Neurology & Neurosurgery, Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada. 39Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada. 40Department of Neurology, Leiden University Medical Center, Leiden, Netherlands. 41Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. 42Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain. 43Hospital Universitario Central de Asturias, Oviedo, Spain. 44Hospital Universitario Parque Tecnologico de la Salud, Granada, Spain. 45Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain. 46Hospital General de Segovia, Segovia, Spain. 47Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 48Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. 49Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain. 50University of Cantabria, Santander, Spain. 51Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 52Centro de Investigacion Biomedica, Universidad de Granada, Granada, Spain. 53Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria de Granada, Granada, Spain. 54Hospital Clinic de Barcelona, Barcelona, Spain. 55Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain. 56Hospital Universitario Virgen de la Victoria, Malaga, Spain. 57Institut de Recerca Sant Joan de Déu, Barcelona, Spain. 58Hospital Universitario Ramón y Cajal, Madrid, Spain. 59Department of Neurology, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain. 60Hospital General de Segovia, Segovia, Spain. 61Department of Neurology, Hospital Universitario Fundación Alcorcón, Madrid, Spain. 62Department of Neurology, Medical University of Vienna, Vienna, Austria. 63Department of Neurology, Oslo University Hospital, Oslo, Norway. 64Department of Pathophysiology, University of Tartu, Tartu, Estonia. 65Department of Reproductive Biology, Estonian University of Life Sciences, Tartu, Estonia. 66Perron Institute for Neurological and Translational Science, Perth, WA, Australia. 67Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia. 68Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland. 69Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. 70University of Lago, Lagos State, Nigeria UK Brain Expression Consortium (UKBEC) Paola Forabosco71 & Robert Walker11 71Istituto di Ricerca Genetica e Biomedica, Cittadella Universitaria di Cagliari, 09042 Monserrato, Sardinia, Italy