An atlas of alternative polyadenylation quantitative trait loci contributing to complex trait and disease heritability

Abstract

Highlights− The first atlas of human 3'QTLs: ~0.4 million genetic variants associated with alternative polyadenylation of target genes across 46 tissues from 467 individuals − 3'QTLs could alter polyA motifs and RNA-binding protein binding sites − 3'QTLs can be used to interpret ~16.1% of trait-associated variants − Many disease-associated 3'QTLs contribute to phenotype independent of gene expression .

3′aQTL-atlas: an atlas of 3′UTR alternative polyadenylation quantitative trait loci across human normal tissues

“…3′aQTL analysis was performed separately for each tissue, using the genotype and normalized PDUI values as previously described (Figure 1A ) ( 22 ). Briefly, we split the VCF data for each tissue with BCFtools ( 25 ) and further transformed them into genotype matrix files using BioAlcidae v.2.27.1 ( 30 ).…”

“…Increasing evidence suggests that genetic variants impacting APA usage play crucial roles in human diseases and traits ( 22 , 39 , 40 ). Here, we comprehensively evaluated the effects of genetic variants on 3′UTR usage across 49 human normal tissue types from the GTEx project and provide a user-friendly database, 3′aQTL-atlas, for users to query, browse, visualize, and download the 3′aQTLs.…”

“…Similarly, rs10954213 at the IRF5 3′UTR locus can shorten the 3′UTR of IRF5 , which alters mRNA stability and further results in high systemic lupus erythematosus susceptibility ( 17 ). Taking the advantage of large-scale transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project (version 7), our recent study established the concept of 3′UTR APA quantitative trait loci (3′aQTLs), which can be used to interpret ∼16.1% of GWAS SNPs and are largely distinct from eQTLs and sQTLs ( 22 ). 3′aQTLs provide consequential supplements to the functional interpretation of non-coding variants.…”

“…3′aQTL-atlas contains ∼1.49 million SNPs associated with the APA of target genes, based on 15,201 RNA-seq samples across 49 human GTEx (version 8) tissues isolated from 838 individuals. The 3′aQTL-atlas not only provides a ∼2-fold increase in sample size compared with our published study ( 22 ) but also includes 3′aQTL searches by Gene/SNP across tissues, a 3′aQTL genome browser, 3′aQTL boxplots, and GWAS-3′aQTL colocalization event visualization. The 3′aQTL-atlas aims to establish APA as an emerging and important molecular phenotype to explain a large fraction of GWAS risk SNPs, leading to significant novel biological insights into the genetic basis of APA and APA-linked susceptibility genes in a wide spectrum of human traits and diseases.…”

Methyl-lysine readers PHF20 and PHF20L1 define two distinct gene expression–regulating NSL complexes

“…The samples were prepared as described previously ( 49 ). Briefly, the agarose bead-bound proteins were washed several times with 50 mM triethylammonium bicarbonate (TEAB) at pH 7.1, before being solubilized with 40 ml of 5% SDS, 50 mM TEAB, pH 7.55 followed by a room temperature incubation for 30 min.…”