Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information
Sebastian Guelfi, Karishma D’Sa, Juan A. Botía, Jana Vandrovcová, Regina H. Reynolds, David Zhang, Daniah Trabzuni, Leonardo Collado‐Torres, Andrew Thomason, Pedro Quijada Leyton, Sarah A. Gagliano Taliun, Mike A. Nalls, Alastair J. Noyce, Aude Nicolas, Mark Cookson, Sara Bandrés‐Ciga, J. Raphael Gibbs, Dena Hernández, Andrew Singleton, Xylena Reed, Hampton L. Leonard, Cornelis Blauwendraat, Faraz Faghri, José Brás, Rita Guerreiro, Arianna Tucci, Demis A. Kia, Henry Houlden, Hélène Plun‐Favreau, Kin Y. Mok, Nicholas Wood, Ruth C. Lovering, Lea R’Bibo, Mie Rizig, Viorica Chelban, Manuela Tan, Huw R. Morris, Ben Middlehurst, John P. Quinn, Kimberley J. Billingsley, Peter Holmans, Kerri J. Kinghorn, Patrick A. Lewis, Valentina Escott‐Price, Nigel Williams, Thomas Foltynie, Alexis Brice, Fabrice Danjou, Suzanne Lesage, Jean‐Christophe Corvol, María Martínez, Anamika Giri, Claudia Schulte, Kathrin Brockmann, Javier Simón‐Sánchez, Peter Heutink, Thomas Gasser, Patrizia Rizzu, Manu Sharma, Joshua Shulman, Laurie Robak, Steven Lubbe, Niccolò E. Mencacci, Steven Finkbeiner, Codrin Lungu, Sonja W. Scholz, Ziv Gan‐Or, Guy A. Rouleau, Lynne Krohan, Jacobus J. van Hilten, Johan Marinus, Astrid Adarmes‐Gómez, Inmaculada Bernal‐Bernal, Marta Bonilla‐Toribio, Dolores Buiza‐Rueda, Fátima Carrillo, Mario Carrión‐Claro, Pablo Mir, Pilar Gómez‐Garre, Silvia Jesús, Miguel A. Labrador‐Espinosa, Daniel Macías, Laura Vargas‐González, Carlota Méndez‐del‐Barrio, María Teresa Periñán, Cristina Tejera‐Parrado, Mónica Díez-Fairén, Miquel Aguilar, Ignacio Álvarez, María Teresa Boungiorno, María Cárcel, Pau Pástor, Juan Pablo Tartari, Victoria Álvarez, Manuel Menéndez‐González, Marta Blazquez, Ciara García, Esther Suárez-Sanmartín, Francisco Javier Barrero, Elisabet Mondragón Rezola
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/.