Vaughan‐Shaw PG, Timofeeva M, Ooi LY, et al. - Researchers investigated if common genetic variants impacting colorectal cancer (CRC) risk might display topographical disparities on CRC risk via regional differences in impacts on gene expression in the large bowel mucosa. To ascertain if established risk variants have differential impacts on risk of proximal, vs distal CRC, a site‐specific genetic association study (10,630 cases, 31,331 controls) was carried out. From 481 participants, normal colorectal mucosa and blood were obtained, and mucosal gene expression was evaluated employing Illumina HumanHT‐12v4 arrays in relation to germline genotype. Findings revealed that genetic variation at the chr11q23.1 risk locus not only conferred a greater risk of distal instead of proximal CRC but also showed site‐specific variations in expression quantitative trait loci impacts in normal mucosa. Topographical disparities in genomic control over gene expression relevant to CRC risk were suggested to likely underlie site‐specific differences in CRC. These data may inform individualised CRC screening programmes.