Table 2.
Functional enhancer studies of GWAS risk loci
| Disease/trait | Reference | Lead SNP | Proposed functional SNP | Gene target | How gene target was selected | Cell type | Data supporting SNP enhancer function |
|---|---|---|---|---|---|---|---|
| Blond hair color | Guenther et al. [33] | rs12821256 | rs12821256 | KITLG | Phenotype in mouse model | Developing hair follicles, HaCaT karatinocyte cell line | Allele-specific luciferase activity, allele-specific ChIP, effect of SNP on mouse phenotype |
| Breast cancer | Cowper-Sal lari et al. [38] | rs4784227 | rs4784227 | TOX3 | 3C | MCF7 | Binding motif disruption, allele-specific ChIP, allele-specific 3C, allele-specific expression, eQTL |
| Colorectal cancer | Pomerantz et al. [34] | rs6983267 | rs6983267 | c-MYC | 3C | Colo205 and LS174T | Allele-specific luciferase activity, allele-specific ChIP |
| Colorectal cancer | Wright et al. [39] | rs6983267 | rs6983267 | c-MYC | 3C | DLD1 and HCT116 | Allele-specific ChIP, allele-specific expression |
| Colorectal cancer | Tuupanen et al. [36] | rs67491583 | rs67491583 | c-MYC | Nearest gene | HeLa | Binding motif disruption, allele-specific ChIP, allele-specific luciferase activity |
| Prostate cancer | Wasserman et al. [35] | rs6983267 | rs6983267 | c-MYC | Nearest gene | Prostate tissue (mouse) | Allele-specific activity, LacZ enhancer assay (mouse) |
| Coronary artery disease | Harismendy et al. [31] | rs10757278 | rs10811656/ rs10757278 | CDKN2B, CDKN2BAS, IFNA21, MTAP | 3C and FISH (IFNA21) | HUVEC | Binding motif disruption, allele-specific ChIP |
| Coronary heart disease | Miller et al. [29] | rs12190287 | rs12190287 | TCF21 | Nearest gene, eQTL gene | HCASMC | Binding motif disruption, allele-specific luciferase activity, EMSA, allele-specific ChIP and allele-specific expression |
| Fetal hemoglobin level | Bauer et al. [28] | rs1427407, rs7606173 | rs1427407, rs7606173 | BCL11A | 3C | Primary human erythroblasts | Binding motif disruption, allele-specific ChIP, allele-specific expression, LacZ enhancer assay (mouse), deletion by TALEN |
| Multiple sclerosis | Alcina et al. [27] | rs658115 | rs10877013 | FAM119B, AVIL, TSFM, TSPAN31 | eQTL | LCLs and monocytes | Allele-specific luciferase activity, eQTL |
| Obesity | Smemo et al. [30] | rs9930506 | NA | IRX3 | 4C-seq, 3C, ChIA-PET, Hi-C | Whole mouse embryo and adult mouse brain | eQTL mapping |
| Prostate cancer | Hazelett et al. [6] | rs5945619 | rs4907792 | NUDT1 | Nearest gene, eQTL gene | LNCaP | Allele-specific luciferase activity, eQTL |
| Prostate cancer | Hazelett et al. [6] | rs10486567 | rs10486567 | JAZF1 | Nearest gene | LNCaP | Allele-specific luciferase activity, binding motif disruption |
| QT interval | Kapoor et al. [32] | rs12143842 | rs7539120 | NOS1AP | eQTL gene, genetic association | Cardiac tissues | Allele-specific luciferase activity, eQTL, enhancer assay (zebrafish embryos) |
| Restless leg syndrome | Spieler et al. [37] | rs12469063 | rs13469063 | MEIS1 | PreSTIGE prediction method, ChIA-PET, Hi-C | Telencephalon | Allele-specific expression of reporter gene in zebrafish, Allele-specific LacZ (mouse), EMSA, binding motif disruption, effect of decreased gene expression on phenotype |
| Systemic lupus erythematosus | Wang et al. [40] | rs2230926 | rs148314165, rs200820567 | TNFAIP3 | 3C | LCLs | EMSA, allele-specific luciferase activity, allele-specific 3C |
| Type 2 diabetes | Gaulton et al. [76] | rs7903146 | rs7903146 | TCF7L2 | Nearest gene | Pancreatic islet cells | Allele-specific luciferase activity, allele-specific FAIRE |
3C, chromosome conformation capture; 4C-seq, circular chromosome conformation capture followed by sequencing; ChIA-PET, chromatin interaction analysis by paired-end tag sequencing; ChIP, chromatin immunoprecipitation; EMSA, electrophoretic mobility shift assay; eQTL, expression quantitative trait loci; FAIRE, formaldehyde-assisted isolation of regulatory elements; FISH, fluorescence in situ hybridization; LCLs, lymphoblastoid cell lines; NA, not applicable; SNP, single nucleotide polymorphism.