A major question in human genetics is how sequence variants of broadly expressed genes produce tissue- and cell type-specific molecular phenotypes. Genetic variation of alternative splicing is a prevalent source of transcriptomic and proteomic diversity in human populations. We investigated splicing quantitative trait loci (sQTLs) in 1,209 samples from 13 human brain regions, using RNA sequencing (RNA-seq) and genotype data from the Genotype-Tissue Expression (GTEx) project. Hundreds of sQTLs were identified in each brain region. Some sQTLs were shared across brain regions, whereas others displayed regional specificity. These “regionally ubiquitous” and “regionally specific” sQTLs showed distinct positional distributions of single-nucleotide polymorphisms (SNPs) within and outside essential splice sites, respectively, suggesting their regulation by distinct molecular mechanisms. Integrating the binding motifs and expression patterns of RNA binding proteins with exon splicing profiles, we uncovered likely causal variants underlying brain region-specific sQTLs. Notably, SNP rs17651213 created a putative binding site for the splicing factor RBFOX2 and was associated with increased splicing of MAPT exon 3 in cerebellar tissues, where RBFOX2 was highly expressed. Overall, our study reveals a more comprehensive spectrum and regional variation of sQTLs in human brain and demonstrates that such regional variation can be used to fine map potential causal variants of sQTLs and their associated neurological diseases.

人类遗传学中的一个主要问题是广泛表达的基因的序列变异体如何产生组织和细胞类型特异性的分子表型。选择性剪接的遗传变异是人类转录组和蛋白质组多样性的普遍来源。我们使用RNA测序（RNA-seq）和基因型组织表达（GTEx）项目的基因型数据，研究了来自13个人脑区域的1,209个样品中的剪接定量性状基因座（sQTL）。在每个大脑区域中识别出数百个sQTL。一些sQTL在大脑区域之间共享，而其他sQTL显示区域特异性。这些“区域普遍存在的”和“区域特定的” sQTL分别显示了基本剪接位点之内和之外的单核苷酸多态性（SNP）的不同位置分布，通过不同的分子机制提示它们的调控。整合具有外显子剪接图谱的RNA结合蛋白的结合基序和表达模式，我们发现了潜在的因果变异，是大脑区域特异性sQTL的基础。值得注意的是，SNP rs17651213为剪接因子RBFOX2创建了一个假定的结合位点，并且与SNP rs17651213的剪接增加有关。小脑组织中的MAPT外显子3，其中RBBFX2高表达。总体而言，我们的研究揭示了人脑中sQTL的更全面的频谱和区域变化，并证明了这种区域变化可用于精细绘制sQTL及其相关神经疾病的潜在因果变异图。