Figure 6.
Using Regional Specificity of sQTL Signals to Prioritize Causal sQTL cis Variants and trans Regulators
(A) Top: Gene structure and six isoforms of human MAPT (tau) gene. Exons −1 and 14 are in the untranslated regions (UTRs). Primary transcript of human MAPT contains 13 exons (exons 4A, 6, and 8 are not transcribed in human brain). Among the 13 exons, exons 2, 3, and 10 are alternatively spliced, generating six mRNA isoforms. Bottom: Functional domains of the longest full-length MAPT protein isoform (including exons 2, 3, and 10).
(B) Plots showing distribution of all SNPs within 200 kb (upper) and all significant SNPs within 300 bp (lower) of MAPT exon 3 in cerebellum. Window is extended 30 kb (upper) and 30 bp (lower). Each dot represents one SNP, color-coded according to its LD with the top sQTL SNP (rs62055489). y axis shows the significance of association (−log10(p value)) between each SNP and the sQTL exon. Horizontal line indicates the significance cutoff (p = 10−5). Genes in the UCSC Genome Browser (see Web Resources) are shown in panels below plots.
(C) Bubble plot showing effects of six SNPs on RBP-RNA binding, as predicted by DeepBind. Axes show RBP binding scores of sequences with reference allele (x axis) or alternative allele (y axis) for each RBP. Bubble size is proportional to the difference in DeepBind scores between the two alleles.
(D) DeepBind variant map for SNP rs17651213 with the RBFOX binding site. Star indicates the position of the SNP.
(E) Radar plots showing significance (−log10(p value)) of the sQTL (MAPT exon 3 and rs17651213) and mean gene expression level (TPM) of the RBP (RBFOX2) in each brain region.
(F) LD plot showing SNP rs17651213 (blue) in high LD with the top sQTL SNP (rs62055489; purple), 11 PD GWAS SNPs (GWAS p values ranging from 2 × 10−118 to 2 × 10−6, green), and 1 AD GWAS SNP (GWAS p value = 6 × 10−6, green).
(G) Diagram illustrating a mechanistic model for tissue-/cell-type-specific sQTLs.