Functional annotation of four SNPs with high level of evidence for CRC susceptibility
| No. | Locus | Mapped gene | SNP | Allele | MAF | Risk allele (OR) | Promoter (P) or enhancer (E)* | DNase I cluster† | Protein(s) bound (cell lines)‡ | Motif(s) altered‡ | meQTL (risk allele association, p) | eQTL (risk allele, association, p) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 5q21.3 | APC | rs1801155 | A/T | 0.068 | T (1.96) | None | Yes | None | CCNT2, GATA, HDAC2 | None | None |
| 2 | 20q11.21 | DNMT3B | rs1569686 | G/T | 0.170 | T (0.57) | P | Yes | None | GR, Gfi1, Gfi1b, LBP-1, NF-κB | cg13636640 (increase, 3.28×10−10) | None |
| 3 | 3q22.2 | MLH1 | rs1800734 | G/A | 0.211 | A (1.51) | P | Yes | NFKB, ELF1 (HCT116, etc) | BHLHE40 | cg03901257, cg14751544, cg02279071, cg16764580, cg19132762, cg04841293, cg00893636, cg21490561, cg11600697. (increase, p<1×10−5) | MLH1 (decrease, 1.37×10−8) |
| 4 | 5p15.33 | TERT | rs2736100 | T/G | 0.485 | G (1.07) | None | Yes | None | FOXA | cg01603247 (increase, 0.023) | None |
*The term ‘Promoter (P) refers to an active or flanking promoter region, while Enhancer (E) refers to an active, poised or weak enhancer or enhancer-like region as defined by the 25 states of HMM (http://www.broadinstitute.org/mammals/haploreg/documentation_v2.html).
†DNase I hypersensitivity clusters were assigned by DNase I hypersensitive assay in 125 cell types, ENCODE (http://genome.ucsc.edu/ENCODE/).
‡Protein interactions defined by chromatin immunoprecipitation sequencing for 161 factors were obtained from ENCODE (http://genome.ucsc.edu/ENCODE/) and transcription factor DNA binding motifs represented as position weight matrices in HaploRegV.2 and RegulomeDB (http://www.regulomedb.org/).
CRC, colorectal cancer; MAF, minor allele frequency; meQTL, methylation quantitative trait loci; SNPs, single nucleotide polymorphisms.