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

• Published in: Nature communications Vol. 11; no. 1; p. 1041
• Main 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., Small, Kerrin S., Smith, Colin, Ramasamy, Adaikalavan, Hardy, John, Weale, Michael E., Ryten, Mina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-02-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38/23; 38/39; 38/43; 38/91; 45/90; 631/208/1792; 631/208/200; 631/208/514/1949; 631/378/2583; Alleles; Annotations; Basal ganglia; Brain; Disease control; Enrichment; Ganglia; Gene expression; Gene Expression Regulation; Gene mapping; Genetic control; Genetic diversity; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Health risks; Humanities and Social Sciences; Humans; Internet; Mental disorders; multidisciplinary; Nervous System Diseases - genetics; Neurons - physiology; Parkinson Disease - genetics; Polymorphism, Single Nucleotide; Putamen; Putamen - physiology; Quantitative Trait Loci; Reproducibility of Results; RNA processing; RNA Splicing; Schizophrenia - genetics; Science; Science (multidisciplinary); Servers; Splicing; Substantia nigra; Substantia Nigra - physiology; Transcriptome; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-14483-x

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/
.
Regulation of gene expression and splicing are thought to be tissue-specific. Here, the authors obtain genomic and transcriptomic data from putamen and substantia nigra of 117 neurologically healthy human brains and find that splicing eQTLs are enriched for neuron-specific regulatory information.