Alternative tandem transcription initiation links noncoding variants to human disease through translational control

Here, we systematically quantified genetic regulation of ATI across 25,859 samples from 49 human normal tissues and 33 tumor tissues. We identified ~0.4 million 5′ UTR ATI quantitative trait loci (5′aQTLs) in 5,295 genes, with 32% operating independently of gene expression.

Moreover, we discovered 2,238 multi-tissue ATI outliers enriched for rare deleterious promoter and 5′ UTR variants, demonstrating that both common and rare variants modulate transcription initiation. Strikingly, 74% of disease variants that colocalize with 5′aQTLs cannot be identified by eQTLs. Transcriptome-wide association studies identified 614 ATI-mediated disease susceptibility genes, including known cancer drivers such as MAFF and MLLT10.