Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, UK.
Department of Medical & Molecular Genetics, School of Medical Sciences, King's College London, Guy's Hospital, London, UK.
Nat Commun. 2020 Feb 25;11(1):1041. 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/.
全基因组关联研究产生了越来越多与神经和精神疾病风险相关的常见遗传变异。考虑到许多因果变异可能就是通过这种方式起作用的，因此，深入了解人类大脑中基因表达的遗传控制至关重要。然而，人脑样本的复杂性限制了与大脑相关的表达数量性状基因座 (eQTL) 和等位基因特异性表达 (ASE) 信号的解释能力。我们通过来自 117 个人脑的壳核和黑质的配对基因组和转录组数据来解决这个问题，研究了不同 RNA 处理阶段的调控情况，并揭示了新的转录本。我们确定了与疾病相关的调节基因座，发现剪接 eQTL 富含神经元特异性基因的调节信息，ASE 提供了具有细胞特异性证据的细胞特异性调节信息，并且大脑转录组的不完全注释限制了对神经精神疾病风险基因座的解释。该调控数据资源可通过我们的网络服务器 http://braineacv2.inf.um.es/ 访问。
