Regional Variation of Splicing QTLs in Human Brain

Am J Hum Genet. 2020 Aug 6;107(2):196-210. doi: 10.1016/j.ajhg.2020.06.002. Epub 2020 Jun 25.


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.

Keywords: RNA-seq; alternative splicing; genetic variation; single-nucleotide polymorphism; splicing quantitative trait loc; transcriptome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain / metabolism*
  • Exons / genetics
  • Humans
  • Polymorphism, Single Nucleotide / genetics*
  • Proteomics / methods
  • Quantitative Trait Loci / genetics*
  • RNA Splicing / genetics*
  • RNA-Binding Proteins / genetics
  • Transcriptome / genetics


  • RNA-Binding Proteins