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

Sebastian Guelfi,Sarah A Gagliano Taliun,David Zhang,Karishma D’Sa,Juan A Botía,Andrew Thomason,Daniah Trabzuni,Michael E Weale,Kerrin S Small,Leonardo Collado‐Torres ,Jana Vandrovcová ,John Hardy,Regina H Reynolds ,Colin Smith,Pedro Quijada Leyton,Mike A Nalls,Adaikalavan Ramasamy,Mina Ryten

doi:10.1038/s41467-020-14483-x

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/.

Highlights

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk
As it is reasonable to assume that many causal variants operate by regulating gene expression, several studies have attempted to address this problem through the use of expression quantitative trait loci and allele-specific expression (ASE) analyses in a wide range of human tissues, with the aim of finding eQTL and ASE signals that colocalise with disease risk signals[9,10]
We find that splicing eQTLs are enriched for neuron-specific regulatory information; that ASE analyses, probably by more effectively controlling for cellular heterogeneity, provide highly cell-specific regulatory information; and that incomplete annotation of the brain transcriptome is limiting the interpretation of risk loci for neuropsychiatric disease

Summary

Introduction

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. 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/. We find that splicing eQTLs are enriched for neuron-specific regulatory information; that ASE analyses, probably by more effectively controlling for cellular heterogeneity, provide highly cell-specific regulatory information; and that incomplete annotation of the brain transcriptome is limiting the interpretation of risk loci for neuropsychiatric disease. We release the rich resource of eQTL and ASE data generated in this study through a searchable web server, http://braineacv2.inf.um.es/ (Supplementary Fig. 1)

Methods

Results

Conclusion