rs10849432 (PLEKHG6): Colorectal Cancer Risk Locus

Key takeaways

• rs10849432 is an intergenic variant (located between protein-coding genes) at chromosome 12p13.31, near the ATP5MFP5 and PLEKHG6 genes
• This locus was identified as a novel colorectal cancer risk signal in a four-stage genome-wide study of 14,963 cases and 31,945 controls of East Asian ancestry
• The linkage disequilibrium block containing this variant held no known protein-coding genes at the time of its discovery
• Risk signals were consistent across Chinese, Korean, and Japanese subgroups and by tumor site (colon vs. rectum), with no significant heterogeneity detected
• A 2023 multi-ancestry meta-analysis of more than 254,000 individuals catalogued 205 independent colorectal cancer risk associations, providing broader context for established loci like this one

What the research says rs10849432 is an intergenic single-nucleotide polymorphism (a single-letter DNA change located between genes rather than inside one) on chromosome 12 at the region designated 12p13.31, near the ATP5MFP5 and PLEKHG6 genes; at the time of its discovery, the linkage disequilibrium block (a cluster of nearby variants commonly inherited together) surrounding it contained no known protein-coding genes PMID 25132393. The locus reached genome-wide significance (p < 5 x 10^-8) as one of six novel colorectal cancer (CRC) susceptibility signals in a four-stage GWAS of 14,963 CRC cases and 31,945 controls across China, Japan, and South Korea, with p-values across all six newly identified loci in that analysis ranging from 3.42 x 10^-8 to 9.22 x 10^-21 PMID 25132393. A 2023 multi-ancestry GWAS meta-analysis of 100,204 cases and 154,587 controls of European and East Asian ancestry confirmed 155 previously reported CRC risk loci alongside 50 novel associations using integrative genomic, transcriptomic, and methylomic analyses PMID 36539618.

Reported associations

• Colorectal cancer risk (East Asian GWAS discovery): Identified as a genome-wide-significant susceptibility locus at 12p13.31 among 14,963 CRC cases and 31,945 controls across four independent stages; rs10849432 was the sole sentinel variant at this locus, and p-values for the six new loci in this study ranged from 3.42 x 10^-8 to 9.22 x 10^-21 PMID 25132393
• Colorectal cancer risk (multi-ancestry context): A 2023 integrative meta-analysis of 100,204 CRC cases and 154,587 controls of European and East Asian ancestry catalogued 205 independent CRC risk associations and confirmed 155 previously reported loci, providing replication context for earlier East Asian GWAS findings PMID 36539618

Evidence quality The primary evidence rests on a rigorously staged East Asian GWAS with 14,963 CRC cases and 31,945 controls conducted across four independent stages in multiple research groups in China, Japan, and South Korea, achieving genome-wide significance for rs10849432 PMID 25132393. Stratification by tumor anatomic site (colon vs. rectum), ancestry subgroup (Chinese, Korean, Japanese), and sex did not reveal significant heterogeneity, supporting the robustness of the association signal PMID 25132393. The same study replicated 22 previously reported CRC loci, demonstrating internal consistency of the methodology. A subsequent East Asian GWAS identifying further CRC susceptibility loci PMID 27840040 did not specifically evaluate this locus among its primary reported findings. The 2023 multi-ancestry integrative analysis PMID 36539618 provided broader validation context for the CRC risk landscape but did not report a specific effect size for rs10849432 in the text available. Because this locus is intergenic with no protein-coding genes in its linkage disequilibrium block at the time of discovery, its functional mechanism, whether regulatory, epigenetic, or otherwise, has not been established in the provided studies.

Lifestyle considerations No lifestyle considerations on file for this variant.