Alternative polyadenylation (APA) is emerging as a widespread regulatory layer since the majority of human protein-coding genes contain several polyadenylation (p(A)) sites in their 3’UTRs. By generating isoforms with different 3’UTR length, APA potentially affects mRNA stability, translation efficiency, nuclear export, and cellular localization. Polyadenylation sites are regulated by adjacent RNA cis-regulatory elements, the principals among them are the polyadenylation signal (PAS) AAUAAA and its main variant AUUAAA, typically located ~20-nt upstream of the p(A) site. Mutations in PAS and other auxiliary poly(A) cis-elements in the 3’UTR of several genes have been shown to cause human Mendelian diseases, and to date, only a few common SNPs that regulate APA were associated with complex diseases. Here, we systematically searched for SNPs that affect gene expression and human traits by modulation of 3’UTR APA. First, focusing on the variants most likely to exert the strongest effect, we identified 2,305 SNPs that interrupt the canonical PAS or its main variant. Implementing pA-QTL tests using GTEx RNA-seq data, we identified 330 PAS SNPs (called PAS pA-QTLs) that were significantly associated with the usage of their p(A) site. As expected, PAS-interrupting alleles were mostly linked with decreased cleavage at their p(A) site and the consequential 3’UTR lengthening. However, interestingly, in ~10% of the cases, the PAS-interrupting allele was associated with increased usage of an upstream p(A) site and 3’UTR shortening. As an indication of the functional effects of these PAS pA-QTLs on gene expression and complex human traits, we observed for few dozens of them marked colocalization with eQTL and/or GWAS signals. The PAS-interrupting alleles linked with 3’UTR lengthening were also strongly associated with decreased gene expression, indicating that shorter isoforms generated by APA are generally more stable than longer ones. Last, we carried out an extended, genome-wide analysis of 3’UTR variants and detected thousands of additional pA-QTLs having weaker effects compared to the PAS pA-QTLs.

由于大多数人类蛋白质编码基因在其3'UTR中均包含多个聚腺苷酸化（p（A））位点，因此，替代性聚腺苷酸化（APA）逐渐成为一种广泛的调控层。通过生成具有不同3'UTR长度的同工型，APA可能会影响mRNA的稳定性，翻译效率，核输出和细胞定位。聚腺苷酸化位点由相邻的RNA顺式调控元件调控，其中的主要成分是聚腺苷酸化信号（PAS）AAUAAA及其主要变异体AUUAAA，通常位于p（A）位点上游〜20-nt。已显示几种基因3'UTR中PAS和其他辅助多聚（A）顺式元件的突变会导致人类孟德尔疾病，迄今为止，仅少数调节APA的常见SNP与复杂疾病有关。这里，我们系统地搜索了通过调节3'UTR APA影响基因表达和人类特征的SNP。首先，我们着眼于最有可能发挥最强作用的变体，我们确定了2,305个SNP干扰了经典的PAS或其主要变体。使用GTEx RNA-seq数据实施pA-QTL测试，我们确定了330个PAS SNP（称为PAS pA-QTL），它们与p（A）位点的使用显着相关。如预期的那样，中断PAS的等位基因主要与p（A）位点的切割减少和相应的3'UTR延长有关。然而，有趣的是，在约10％的病例中，中断PAS的等位基因与上游p（A）位点的使用增加和3'UTR缩短有关。为了说明这些PAS pA-QTL对基因表达和复杂人类特征的功能影响，我们观察到其中数十个标记与eQTL和/或GWAS信号共定位。与3'UTR延长相关的PAS中断等位基因也与基因表达下降密切相关，这表明APA产生的较短同工型通常比较长的同工型稳定。最后，我们对3'UTR变体进行了扩展的全基因组分析，并检测了成千上万个与PAS pA-QTL相比作用更弱的pA-QTL。