Genome-wide association study of colorectal cancer in Hispanics

Abstract

Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10(-8) Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10(-6)) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47-2.36); P = 2.5×10(-7)], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21-1.55); P = 4.0×10(-7)), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36-2.01); P = 4.1×10(-7)) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37-2.08); P=7.8×10(-7)]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10(-5)) and 11q12.2 (P = 6.8×10(-5)), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations.

Figure 1.

Comparison of association effect sizes for previously published CRC risk SNPs (n = 57) in the original GWAS population and in Hispanic/Latinos. Red shading denotes P < 0.05 in the HL study. GWAS = genome-wide association study. OR = odds ratio. Pearson correlation coefficient = 0.13.

Figure 2.

LocusZoom regional plots (±500kb from the index SNP and/or the region’s most strongly associated variant in LD (r ² ≥ 0.2) with the index) for 2q32.3, 3q26.2 and 11q12.2 based on analyses using best genotype calls. A–C represent association results from logistic regression adjusted for age, sex and global ancestry. D–F represent association results from logistic regression adjusted for age, sex, global ancestry and allelic dosage of the known region’s lead variant. Linkage disequilibrium shading is based on 1000 Genomes Project Phase 3 AMR samples. Diamond-shaped points in purple represent these regions’ lead variants.