Autozygosity and admixture mapping reveal novel colorectal cancer susceptibility regions in Colombians

Genome-wide association studies (GWAS) have identified several colorectal cancer (CRC) susceptibility loci, although most were discovered in populations of European ancestry. Differences in demographic history, admixture, and linkage disequilibrium structure may influence the contribution of these variants to CRC susceptibility in Latin American populations. We analyzed 955 CRC cases and 968 controls from admixed Colombian populations, genotyped for approximately 1 million SNPs, to investigate the contributions of known CRC susceptibility loci, genetic ancestry, runs of homozygosity (ROH), local ancestry, and admixture mapping to CRC risk. Among 229 established CRC susceptibility variants, 42 were associated with CRC risk after adjustment for ancestry and socioeconomic covariates, including three SMAD7 variants at 18q21.1 that remained significant after correction for multiple testing. European ancestry was associated with increased CRC risk, whereas Native American ancestry was associated with a reduced risk. ROH burden was strongly associated with ancestry composition, with individuals carrying higher Native American ancestry exhibiting greater autozygosity, indicating that differences in ROH between cases and controls reflect ancestry composition rather than CRC susceptibility. These ancestry-associated effects persisted after adjustment for known CRC susceptibility loci, suggesting that currently recognized risk variants explain only part of the genetic architecture underlying CRC susceptibility in this population. Admixture mapping identified a genome-wide significant locus at 6p22.2 encompassing the HIST1 histone gene cluster, along with three additional suggestive loci at 4p13, 4p16.3, and 15q26.3. The peaks of these regions did not coincide with loci identified through conventional GWAS replication analyses, highlighting the complementary value of local ancestry approaches for gene discovery in admixed populations. Together, these findings demonstrate that both global and local ancestry contribute to CRC susceptibility, underscoring the importance of studying admixed populations to identify novel determinants of colorectal cancer risk.