Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information
Authors: Guelfi Sebastian , D’Sa Karishma , Botía Juan A. , Vandrovcova Jana , Reynolds Regina H. , Zhang David , Trabzuni Daniah , Collado-Torres Leonardo , Thomason Andrew , Quijada Leyton Pedro , Gagliano Taliun Sarah A. , Nalls Mike A. ,   International Parkinson’s Disease Genomics Consortium (IPDGC), Noyce Alastair J. , Nicolas Aude , Cookson Mark R. , Bandres-Ciga Sara , Gibbs J. Raphael , Hernandez Dena G. , Singleton Andrew B. , Reed Xylena , Leonard Hampton , Blauwendraat Cornelis , Faghri Faraz , Bras Jose , Guerreiro Rita , Tucci Arianna , Kia Demis A. , Houlden Henry , Plun-Favreau Helene , Mok Kin Y , Wood Nicholas W. , Lovering Ruth , R’Bibo Lea , Rizig Mie , Chelban Viorica , Tan Manuela , Morris Huw R. , Middlehurst Ben , Quinn John , Billingsley Kimberley , Holmans Peter , Kinghorn Kerri J. , Lewis Patrick , Escott-Price Valentina , Williams Nigel , Foltynie Thomas , Brice Alexis , Danjou Fabrice , Lesage Suzanne , Corvol Jean-Christophe , Martinez Maria , Giri Anamika , Schulte Claudia , Brockmann Kathrin , Simón-Sánchez Javier , Heutink Peter , Gasser Thomas , Rizzu Patrizia , Sharma Manu , Shulman Joshua M. , Robak Laurie , Lubbe Steven , Mencacci Niccolo E. , Finkbeiner Steven , Lungu Codrin , Scholz Sonja W. , Gan-Or Ziv , Rouleau Guy A. , Krohan Lynne , van Hilten Jacobus J. , Marinus Johan , Adarmes-Gómez Astrid D. , Bernal-Bernal Inmaculada , Bonilla-Toribio Marta , Buiza-Rueda Dolores , Carrillo Fátima , Carrión-Claro Mario , Mir Pablo , Gómez-Garre Pilar , Jesús Silvia , Labrador-Espinosa Miguel A. , Macias Daniel , Vargas-González Laura , Méndez-del-Barrio Carlota , Periñán-Tocino Teresa , Tejera-Parrado Cristina , Diez-Fairen Monica , Aguilar Miquel , Alvarez Ignacio , Boungiorno María Teresa , Carcel Maria , Pastor Pau , Tartari Juan Pablo , Alvarez Victoria , González Manuel Menéndez , Blazquez Marta , Garcia Ciara , Suarez-Sanmartin Esther , Barrero Francisco Javier , Rezola Elisabet Mondragon , Yarza Jesús Alberto Bergareche , Pagola Ana Gorostidi , Arregui Adolfo López de Munain , Ruiz-Martínez Javier , Cerdan Debora , Duarte Jacinto , Clarimón Jordi , Dols-Icardo Oriol , Infante Jon , Marín Juan , Kulisevsky Jaime , Pagonabarraga Javier , Gonzalez-Aramburu Isabel , Rodriguez Antonio Sanchez , Sierra María , Duran Raquel , Ruz Clara , Vives Francisco , Escamilla-Sevilla Francisco , Mínguez Adolfo , Cámara Ana , Compta Yaroslau , Ezquerra Mario , Marti Maria Jose , Fernández Manel , Muñoz Esteban , Fernández-Santiago Rubén , Tolosa Eduard , Valldeoriola Francesc , García-Ruiz Pedro , Heredia Maria Jose Gomez , Errazquin Francisco Perez , Hoenicka Janet , Jimenez-Escrig Adriano , Martínez-Castrillo Juan Carlos , Lopez-Sendon Jose Luis , Torres Irene Martínez , Tabernero Cesar , Vela Lydia , Zimprich Alexander , Pihlstrom Lasse , Koks Sulev , Taba Pille , Majamaa Kari , Siitonen Ari , Okubadejo Njideka U. , Ojo Oluwadamilola O. ,   UK Brain Expression Consortium (UKBEC), Forabosco Paola , Walker Robert , Small Kerrin S. , Smith Colin , Ramasamy Adaikalavan , Hardy John , Weale Michael E. , Ryten Mina 
Published: February 2020

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/.