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, Leonardo 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

May 06, 2019

Received Date: 5th April 19

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,

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature