Trans-Ancestral Fine-Mapping and Epigenetic Annotation as Tools to Delineate Functionally Relevant Risk Alleles at IKZF1 and IKZF3 in Systemic Lupus Erythematosus
Abstract
:1. Introduction
2. Results
2.1. Defining the Risk Haplotype at IKZF1 in SLE
2.2. Refining the IKZF1 Risk Haplotype Using the 1000 Genomes Super-Populations
2.3. Functional Annotation of IKZF1 Risk Alleles
2.3.1. Determination of Chromatin Status
2.3.2. Chromatin Looping with Risk Alleles
2.3.3. Cell-Type Specificity in DNAse Sensitivity in the IKZF1 Enhancer Region
2.3.4. Discovery of Allele-Specific Transcription Factor Binding Sites
2.3.5. Identification of cis-eQTLs at IKZF1
2.4. Extended IKZF3 Haplotype across Multiple Genes in European SLE GWAS Study
2.5. Fine-Mapping the IKZF3 Risk Haplotype Using the 1000 Genomes Super-Populations
2.6. Trans-Ancestral Exclusion Mapping of IKZF3 using the SLE ImmunoChip Data
2.7. Functional Annotation of Risk Alleles at IKZF3
2.7.1. Analysis of Expression Levels
2.7.2. Determination of Chromatin Looping at IKZF3
2.7.3. Accessibility of the Chromatin across IKZF3
2.7.4. Cell-Type Specificity in DNAse Sensitivity in the IKZF3 Interaction Regions
2.7.5. Discovery of Allele-Specific Transcription Factor Binding Sites
2.7.6. IKZF3 Risk Alleles Lie within a SuperEnhancer in B Cells
3. Discussion
4. Materials and Methods
4.1. Datasets
4.2. Haplotype Analysis of the Genetic Datasets
4.3. Trans-Ancestral Meta-Analysis
4.4. Trans-Ancestral Exclusion Mapping
4.5. Functional Annotation of Risk Alleles
4.6. Allele-Specific Transcription Factor Binding
4.7. Visualisation of Genomic Data
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
Tag-SNPs | Single nucleotide polymorphism tagging a haplotype |
SLE GWAS | Genome-Wide association study in Systemic Lupus Erythematosus |
ASTF | Allele-Specific transcription factor binding site |
eQTL | Expression quantitative trait locus |
GWAS | Genome-Wide association study |
MAF | Minor allele frequency |
PC Hi-C | Promoter Capture Hi-C |
SLE | Systemic Lupus Erythematosus |
TF | Transcription factor |
Appendix A
SNP | Pos (hg19) | African American 2970 Cases, 2452 Controls | European 6748 Cases, 11,516 Controls | Hispanic 1872 Cases and 2016 Controls | ||||||
---|---|---|---|---|---|---|---|---|---|---|
p Value | ORAA (CI) | MAFAA | p Value | OREA (CI) | MAFEA | p Value | ORHisp (CI) | MAFHisp | ||
rs4917014 | 7:50305863 | 1.48 × 10−5 | 0.728 (0.631–0.841) | 0.09 (G) | 3.67 × 10−9 | 0.866 (0.826–0.909) | 0.32 (G) | 0.021 | 0.897 (0.818–0.984) | 0.48 (T) |
rs11185603 | 7:50306810 | 4.29 × 10−5 | 0.742 (0.643–0.856) | 0.09 (G) | 8.99 × 10−9 | 0.870 (0.829–0.912) | 0.32 (G) | 0.021 | 0.898 (0.819–0.984) | 0.48 (C) |
rs4385425 | 7:50307334 | 1.83 × 10−5 | 0.831 (0.771–0.897) | 0.49 (G) | 1.51 × 10−9 | 0.872 (0.832–0.914) | 0.32 (G) | 0.148 | 0.934 (0.852–1.026) | 0.50 (A) |
rs876036 | 7:50307710 | 9.52 × 10−3 | 0.890 (0.815–0.972) | 0.25 (C) | 7.49 × 10−9 | 0.869 (0.829–0.912) | 0.32 (C) | 0.053 | 0.913 (0.833–1.001) | 0.49 (T) |
rs876037 | 7:50308692 | 1.87 × 10−5 | 0.731 (0.633–0.844) | 0.09 (A) | 2.23 × 10−8 | 0.873 (0.832–0.915) | 0.31 (A) | 0.020 | 0.897 (0.818–0.983) | 0.48 (T) |
Locus | Element | Name | Position (hg19) |
---|---|---|---|
IKZF1 | PC Hi-C interaction regions | Enhancer (Enh) | chr7:50305428-50311993 |
Transcriptional Start Site/Promoter (TSS) | chr7:50341186-50347256 | ||
intron 3 (I3) | chr7:50411807-50412756 | ||
GeneHancer regions | GH07J050261 | chr7:50300992-50310765 | |
GH07J050293 | chr7:50333047-50334464 | ||
GH07J050301 | chr7:50340632-50340761 | ||
GH07J050303 | chr7:50343395-50362927 | ||
GH07J050326 | chr7:50366368-50368325 | ||
GH07J050329 | chr7:50368690-50370631 | ||
GH07J050341 | chr7:50410631-50437890 | ||
GH07J050392 | chr7:50459865-50466852 | ||
IKZF3 | PC Hi-C interaction regions | IKZF3-ZPBP2 bi-directional promoter | chr17:38018444-38027003 |
5′ I3 | chr17:37965773-37976506 | ||
mid I3 | chr17:37958027-37963133 | ||
3′ E4-7 | chr17:37932293-37957717 | ||
GeneHancer regions | GH17J039753 | chr17:37909296-37916397 | |
GH17J039766 | chr17:37922530-37939749 | ||
GH17J039790 | chr17:37946728-37952847 | ||
GH17J039799 | chr17:37954622-37954701 | ||
GH17J039798 | chr17:37954998-37957986 | ||
GH17J039812 | chr17:37968642-37971311 | ||
GH17J039817 | chr17:37974070-37978821 | ||
GH17J039839 | chr17:37995815-37995875 | ||
GH17J039842 | chr17:37999223-38000547 | ||
GH17J039847 | chr17:38003768-38005630 |
Order | Risk SNP | Pos (hg19) | TF Showing Allele-Specific Binding (ASTF) | Strand | Ref | Alt | Alt-Ref Enrichment |
---|---|---|---|---|---|---|---|
1 | rs34767118 | 50271064 | Sox_5 | + | 12.5 | 11.4 | −1.1 |
VDR_1 | + | −8.1 | 3.9 | 12 | |||
Zbtb12 | + | 11.8 | 14.4 | 2.6 | |||
2 | rs11773763 | 50271499 | CDP_4 | - | 12.6 | 13.2 | 0.6 |
Fox | - | 13.3 | 2.5 | −10.8 | |||
Foxd1_1 | - | 4.5 | 2.5 | −2 | |||
Foxi1 | - | 13.1 | 11.9 | −1.2 | |||
Foxj1_2 | - | 14.2 | 13.9 | −0.3 | |||
Foxj2_1 | - | 12.1 | 12 | −0.1 | |||
Gm397 | - | 6.6 | 10.7 | 4.1 | |||
Pou3f2_2 | + | −9.4 | 2.6 | 12 | |||
Zfp105 | + | 10.8 | 11 | 0.2 | |||
p53_1 | + | −25.8 | −27.5 | −1.7 | |||
3 | rs62445350 | 50278187 | none | 0 | |||
4 | rs62445352 | 50289504 | Arid3a_2 | - | 8.4 | 10.9 | 2.5 |
Barx2 | - | 10.5 | 11.9 | 1.4 | |||
Cdx2_2 | - | 10.6 | 11.2 | 0.6 | |||
Dbx1 | - | 8.7 | 10.6 | 1.9 | |||
Dbx2 | + | 8.8 | 11.5 | 2.7 | |||
Dlx3 | - | 12.1 | 10 | −2.1 | |||
Evi-1_4 | + | 4 | 15.5 | 11.5 | |||
HNF1_1 | - | 12.7 | 10.7 | −2 | |||
HNF1_6 | - | 13.8 | 11.2 | −2.6 | |||
HNF1_7 | + | 11.7 | 10.2 | −1.5 | |||
Hoxa10 | - | 11 | 12.8 | 1.8 | |||
Hoxa3_2 | - | 13.9 | 13.1 | −0.8 | |||
Hoxa5_3 | - | 11.6 | 10.2 | −1.4 | |||
Hoxa7_2 | - | 11 | 12.5 | 1.5 | |||
Hoxb4 | - | 11.2 | 12.4 | 1.2 | |||
Hoxc6 | - | 12.1 | 13 | 0.9 | |||
Hoxc9 | - | 12.2 | 12.7 | 0.5 | |||
Hoxd8 | + | 12.9 | 16.1 | 3.2 | |||
Msx-1_2 | - | 10.7 | 13.2 | 2.5 | |||
Ncx_2 | - | 11.4 | 15.1 | 3.7 | |||
Nkx6-1_2 | - | 9.9 | 14.8 | 4.9 | |||
Nkx6-1_3 | - | 9.7 | 14.9 | 5.2 | |||
Nkx6-2 | - | 11.6 | 12.6 | 1 | |||
Pax-4_2 | - | 11.2 | 8.1 | −3.1 | |||
Pou2f2_known4 | + | 12.8 | 13.3 | 0.5 | |||
Pou3f4 | - | 6 | 11.7 | 5.7 | |||
Pou4f3 | - | 9.1 | 15.1 | 6 | |||
Pou5f1_known1 | + | 11.6 | 4.7 | −6.9 | |||
Prrx1 | + | 11 | 10.4 | −0.6 | |||
5 | rs55935382 | 50289669 | SRF_known5 | + | −0.8 | 11 | 11.8 |
6 | rs11185602 | 50299077 | Cart1 | + | 15.2 | 11.7 | −3.5 |
Cdx | + | 9.6 | 12.1 | 2.5 | |||
HNF1_2 | - | 6.2 | 11.3 | 5.1 | |||
Lhx3_2 | + | 10.7 | 3 | −7.7 | |||
PLZF | + | 13.2 | 13 | −0.2 | |||
Pou2f2_known2 | + | 12.8 | 8.4 | −4.4 | |||
Pou2f2_known9 | + | 7.4 | −4.5 | −11.9 | |||
Pou6f1_1 | - | 10.2 | 13.9 | 3.7 | |||
7 | rs4917014 * | 50305863 | Nkx2_2 | + | 10.9 | 12 | 1.1 |
8 | rs11185603 * | 50306810 | CCNT2_disc2 | + | 12.5 | 7.1 | −5.4 |
ELF1_known1 | - | 13 | 2 | −11 | |||
Nkx2_2 | - | 11.9 | 10.3 | −1.6 | |||
PU.1_disc3 | - | 12.3 | 0.4 | −11.9 | |||
RXRA_disc4 | + | 12.8 | 1.7 | −11.1 | |||
TATA_disc7 | - | 13.6 | 7.3 | −6.3 | |||
9 | rs4385425 * | 50307334 | none | 0 | |||
10 | rs876036 * | 50307710 | ERalpha-a_disc4 | + | 0.2 | 10.7 | 10.5 |
LXR_3 | - | 11.3 | 7.4 | −3.9 | |||
RXRA_known4 | + | 10.4 | −0.2 | −10.6 | |||
VDR_2 | + | 12.4 | 4.6 | −7.8 | |||
VDR_3 | + | 12.2 | 8.3 | −3.9 | |||
11 | rs876038 * | 50308527 | BDP1_disc1 | - | 2.7 | 2.1 | −0.6 |
Brachyury_1 | - | −2.4 | −5.6 | −3.2 | |||
XBP-1_1 | + | 12.2 | 0.2 | −12 | |||
12 | rs876037 * | 50308527 | none | 0 | |||
13 | rs876039 * | 50308811 | Foxa_known2 | - | 11.5 | 12.6 | 1.1 |
Foxa_known3 | - | 12.7 | 13.3 | 0.6 |
# | Group | rs | Chr | Pos (hg19) | A1/A2 | ImmunoChip Association Data | Meta-Analysis | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
MAFEA | PEA | OREA | MAFEA | PAA | ORAA | s | P(R) | OR | OR(R) | Q | I | ||||||
1 | 1 | rs111678394 | 17 | 38021116 | C/G | 0.035 | 2.50 × 10−6 | 1.29 (1.16–1.44) | 0.005 | 0.042 | 1.656 (1.01–2.71) | 5.29 × 10−7 | 5.29 × 10−7 | 1.31 | 1.31 | 0.335 | 0 |
2 | 1 | rs117278702 | 17 | 38020420 | A/G | 0.032 | 1.13 × 10−5 | 1.28 (1.15–1.44) | 0.004 | 0.136 | 1.50 (0.877–2.55) | 4.38 × 10−6 | 4.38 × 10−6 | 1.30 | 1.30 | 0.588 | 0 |
3 | 2 | rs9905881 | 17 | 38018954 | A/G | 0.036 | 4.44 × 10−6 | 1.28 (1.15–1.43) | 0.256 | 0.004 | 1.13 (1.04–1.24) | 3.16 × 10−7 | 0.003 | 1.19 | 1.20 | 0.079 | 67.8 |
4 | 2 | rs9899336 | 17 | 38017779 | T/C | 0.036 | 3.60 × 10−6 | 1.28 (1.16–1.43) | 0.256 | 0.005 | 1.13 (1.04–1.23) | 3.50 × 10−7 | 0.004 | 1.19 | 1.20 | 0.066 | 70.5 |
5 | 2 | rs9899006 | 17 | 38017064 | A/T | 0.042 | 1.28 × 10−5 | 1.25 (1.13–1.38) | 0.257 | 0.005 | 1.13 (1.04–1.23) | 7.23 × 10−7 | 0.001 | 1.18 | 1.18 | 0.137 | 54.8 |
6 | 1 | rs77924338 | 17 | 38016356 | T/C | 0.035 | 2.50 × 10−6 | 1.29 (1.16–1.44) | 0.005 | 0.042 | 1.66 (1.01–2.71) | 5.29 × 10−7 | 5.29 × 10−7 | 1.31 | 1.31 | 0.335 | 0 |
7 | 2 | rs9915797 | 17 | 38014867 | A/G | 0.036 | 2.75 × 10−6 | 1.29 (1.16–1.44) | 0.256 | 0.005 | 1.13 (1.04–1.23) | 3.40 × 10−7 | 0.005 | 1.19 | 1.20 | 0.056 | 72.6 |
8 | 2 | rs16965367 | 17 | 38014315 | C/T | 0.036 | 3.99 × 10−6 | 1.28 (1.15–1.43) | 0.256 | 0.005 | 1.13 (1.04–1.23) | 3.68 × 10−7 | 0.004 | 1.19 | 1.20 | 0.069 | 69.9 |
9 | 2 | rs113466546 | 17 | 38012586 | A/G | 0.036 | 2.10 × 10−6 | 1.29 (1.16–1.44) | 0.130 | 0.026 | 1.13 (1.02–1.27) | 7.90 × 10−7 | 0.004 | 1.21 | 1.21 | 0.090 | 65.2 |
10 | 2 | rs9907291 | 17 | 38010036 | G/A | 0.036 | 2.75 × 10−6 | 1.29 (1.16–1.44) | 0.257 | 0.003 | 1.14 (1.05–1.24) | 1.57 × 10−7 | 0.003 | 1.20 | 1.21 | 0.072 | 69.1 |
11 | 2 | rs8069531 | 17 | 38009343 | T/A | 0.036 | 3.24 × 10−6 | 1.29 (1.16–1.43) | 0.256 | 0.005 | 1.13 (1.04–1.23) | 3.36 × 10−7 | 0.004 | 1.19 | 1.21 | 0.064 | 70.9 |
12 | 2 | rs8068894 | 17 | 38008999 | G/A | 0.036 | 2.75 × 10−6 | 1.29 (1.16–1.44) | 0.256 | 0.005 | 1.13 (1.04–1.23) | 2.87 × 10−7 | 0.005 | 1.19 | 1.20 | 0.060 | 71.9 |
13 | 1 | rs113233720 | 17 | 38008190 | T/C | 0.035 | 2.50 × 10−6 | 1.29 (1.16–1.44) | 0.005 | 0.042 | 1.66 (1.01–2.71) | 5.29 × 10−7 | 5.29 × 10−7 | 1.31 | 1.31 | 0.335 | 0 |
14 | 1 | rs112677036 | 17 | 38002152 | A/G | 0.035 | 2.50 × 10−6 | 1.29 (1.16–1.44) | 0.005 | 0.042 | 1.66 (1.01–2.71) | 5.29 × 10−7 | 5.29 × 10−7 | 1.31 | 1.31 | 0.335 | 0 |
15 | 2 | rs67600807 | 17 | 38001558 | G/A | 0.036 | 2.75 × 10−6 | 1.29 (1.16–1.44) | 0.262 | 0.007 | 1.13 (1.03–1.22) | 4.54 × 10−7 | 0.008 | 1.19 | 1.20 | 0.049 | 74.2 |
16 | 2 | rs9908694 | 17 | 37997771 | T/C | 0.036 | 2.90 × 10−6 | 1.29 (1.16–1.43) | 0.256 | 0.005 | 1.13 (1.04–1.23) | 2.95 × 10−7 | 0.004 | 1.19 | 1.20 | 0.061 | 71.6 |
17 | 2 | rs9900541 | 17 | 37996070 | C/T | 0.036 | 2.75 × 10−6 | 1.29 (1.16–1.44) | 0.256 | 0.005 | 1.13 (1.04–1.23) | 3.12 × 10−7 | 0.005 | 1.19 | 1.20 | 0.058 | 72.3 |
18 | 1 | rs111691913 | 17 | 37993238 | T/C | 0.035 | 2.24 × 10−6 | 1.30 (1.16–1.44) | 0.005 | 0.042 | 1.66 (1.01–2.71) | 4.60 × 10−7 | 4.60 × 10−7 | 1.31 | 1.31 | 0.338 | 0 |
19 | 2 | rs28449671 | 17 | 37991630 | C/T | 0.036 | 2.47 × 10−6 | 1.29 (1.16–1.44) | 0.256 | 0.005 | 1.13 (1.036–1.23) | 3.27 × 10−7 | 0.006 | 1.19 | 1.20 | 0.055 | 73.0 |
20 | 1 | rs111944912 | 17 | 37988476 | C/T | 0.035 | 3.64 × 10−6 | 1.29 (1.16–1.43) | 0.005 | 0.042 | 1.66 (1.01–2.71) | 7.80 × 10−7 | 7.80 × 10−7 | 1.30 | 1.30 | 0.326 | 0 |
21 | 2 | rs73304123 | 17 | 37987588 | T/C | 0.036 | 3.07 × 10−6 | 1.29 (1.16–1.43) | 0.128 | 0.025 | 1.14 (1.02–1.27) | 9.54 × 10−7 | 0.003 | 1.21 | 1.21 | 0.108 | 61.4 |
22 | 2 | rs112141468 | 17 | 37987464 | T/C | 0.036 | 3.99 × 10−6 | 1.28 (1.15–1.43) | 0.259 | 0.006 | 1.13 (1.04–1.23) | 4.64 × 10−7 | 0.005 | 1.19 | 1.20 | 0.063 | 71.2 |
23 | 1 | rs111734595 | 17 | 37987399 | T/C | 0.035 | 3.64 × 10−6 | 1.29 (1.16–1.43) | 0.005 | 0.042 | 1.66 (1.01–2.71) | 7.80 × 10−7 | 7.80 × 10−7 | 1.30 | 1.30 | 0.326 | 0 |
24 | 1 | rs113479772 | 17 | 37987042 | A/G | 0.035 | 3.64 × 10−6 | 1.29 (1.16–1.43) | 0.005 | 0.042 | 1.66 (1.01–2.71) | 7.80 × 10−7 | 7.80 × 10−7 | 1.30 | 1.30 | 0.326 | 0 |
25 | 1 | rs112797570 | 17 | 37983751 | A/G | 0.035 | 3.64 × 10−6 | 1.29 (1.16–1.43) | 0.005 | 0.042 | 1.66 (1.01–2.71) | 7.80 × 10−7 | 7.80 × 10−7 | 1.30 | 1.30 | 0.326 | 0 |
26 | 1 | rs112437508 | 17 | 37983512 | A/G | 0.035 | 3.09 × 10−6 | 1.29 (1.16–1.44) | 0.023 | 0.564 | 1.07 (0.840–1.38) | 6.90 × 10−6 | 0.016 | 1.25 | 1.22 | 0.190 | 41.7 |
27 | 2 | rs35130019 | 17 | 37983141 | G/A | 0.037 | 6.29 × 10−6 | 1.28 (1.15–1.42) | 0.255 | 0.007 | 1.13 (1.03–1.23) | 7.56 × 10−7 | 0.004 | 1.18 | 1.19 | 0.073 | 68.8 |
28 | 1 | rs111469562 | 17 | 37982696 | C/T | 0.036 | 4.51 − 06 | 1.28 (1.15–1.43) | 0.005 | 0.042 | 1.66 (1.01–2.71) | 9.58 × 10−7 | 9.58 × 10−7 | 1.30 | 1.30 | 0.321 | 0 |
29 | 2 | rs12942660 | 17 | 37982037 | T/C | 0.036 | 4.44 × 10−6 | 1.28 (1.15–1.43) | 0.252 | 0.003 | 1.14 (1.04–1.24) | 2.54 × 10−7 | 0.002 | 1.19 | 1.20 | 0.085 | 66.2 |
30 | 2 | rs8076347 | 17 | 37977540 | T/G | 0.036 | 3.78 × 10−6 | 1.28 (1.16–1.42) | 0.252 | 0.003 | 1.14 (1.04–1.24) | 2.29 × 10−7 | 0.002 | 1.19 | 1.20 | 0.081 | 67.1 |
31 | 2 | rs9908983 | 17 | 37976926 | A/G | 0.036 | 3.42 × 10−6 | 1.29 (1.16–1.43) | 0.124 | 0.023 | 1.14 (1.02–1.27) | 8.39 × 10−7 | 0.002 | 1.21 | 1.21 | 0.122 | 58.2 |
32 | 2 | rs9911069 | 17 | 37976601 | C/T | 0.036 | 3.07 × 10−6 | 1.29 (1.16–1.43) | 0.124 | 0.023 | 1.14 (1.02–1.27) | 7.99 × 10−7 | 0.002 | 1.22 | 1.21 | 0.120 | 58.7 |
33 | 2 | rs9901917 | 17 | 37976205 | C/G | 0.036 | 3.42 × 10−6 | 1.29 (1.16–1.43) | 0.124 | 0.023 | 1.14 (1.02–1.27) | 8.39 × 10−7 | 0.002 | 1.21 | 1.21 | 0.122 | 58.2 |
34 | 1 | rs112743130 | 17 | 37975855 | C/G | 0.035 | 3.46 × 10−6 | 1.29 (1.16–1.43) | 0.005 | 0.059 | 1.59 (0.979–2.58) | 8.55 × 10−7 | 8.55 × 10−7 | 1.30 | 1.30 | 0.406 | 0 |
35 | 2 | rs34053394 | 17 | 37975660 | G/A | 0.036 | 3.42 × 10−6 | 1.29 (1.16–1.43) | 0.124 | 0.023 | 1.13 (1.02–1.27) | 8.39 × 10−7 | 0.002 | 1.21 | 1.21 | 0.122 | 58.2 |
36 | 2 | rs58075375 | 17 | 37975592 | T/C | 0.036 | 3.42 × 10−6 | 1.287 (1.157–1.432) | 0.124 | 0.023 | 1.14 (1.02–1.27) | 8.39 × 10−7 | 0.002 | 1.21 | 1.21 | 0.122 | 58.2 |
37 | 2 | rs9902621 | 17 | 37973010 | A/G | 0.036 | 3.42 × 10−6 | 1.29 (1.16–1.43) | 0.124 | 0.023 | 1.14 (1.02–1.27) | 8.39 × 10−7 | 0.002 | 1.21 | 1.21 | 0.122 | 58.2 |
38 | 2 | rs9898031 | 17 | 37972647 | G/C | 0.036 | 6.45 × 10−6 | 1.28 (1.16–1.42) | 0.124 | 0.023 | 1.14 (1.02–1.27) | 1.38 × 10−6 | 0.001 | 1.21 | 1.20 | 0.147 | 52.4 |
39 | 1 | rs112412105 | 17 | 37971635 | G/A | 0.036 | 4.06 × 10−6 | 1.29 (1.16–1.43) | 0.005 | 0.059 | 1.59 (0.979–2.58) | 9.57 × 10−7 | 9.57 × 10−7 | 1.30 | 1.30 | 0.402 | 0 |
40 | 1 | rs113115305 | 17 | 37970686 | C/A | 0.036 | 9.37 × 10−6 | 1.27 (1.14–1.42) | 0.005 | 0.059 | 1.59 (0.979–2.58) | 2.28 × 10−6 | 2.28 × 10−6 | 1.29 | 1.29 | 0.380 | 0 |
41 | 1 | rs112238900 | 17 | 37968494 | T/C | 0.036 | 4.06 × 10−6 | 1.29 (1.16–1.43) | 0.005 | 0.059 | 1.59 (0.979–2.58) | 9.57 × 10−7 | 9.57 × 10−7 | 1.30 | 1.30 | 0.402 | 0 |
42 | 2 | rs67135646 | 17 | 37967871 | G/C | 0.036 | 5.47 × 10−6 | 1.28 (1.15–1.42) | 0.252 | 0.004 | 1.13 (1.04–1.24) | 4.03 × 10−7 | 0.003 | 1.19 | 1.20 | 0.082 | 66.9 |
43 | 2 | rs114777282 | 17 | 37967649 | A/C | 0.036 | 5.47 × 10−6 | 1.28 (1.15–1.42) | 0.250 | 0.005 | 1.13 (1.04–1.23) | 4.48 × 10−7 | 0.003 | 1.19 | 1.20 | 0.080 | 67.3 |
44 | 2 | rs4337325 | 17 | 37964435 | T/C | 0.036 | 9.22 × 10−6 | 1.27 (1.14–1.41) | 0.250 | 0.005 | 1.13 (1.04–1.23) | 7.12 × 10−7 | 0.002 | 1.18 | 1.19 | 0.095 | 64.2 |
45 | 2 | rs9901617 | 17 | 37964175 | C/G | 0.036 | 4.24 × 10−6 | 1.284 (1.15–1.43) | 0.125 | 0.027 | 1.13 (1.01–1.27) | 1.27 × 10−6 | 0.002 | 1.21 | 1.21 | 0.116 | 59.6 |
46 | 1 | rs113064843 | 17 | 37960421 | C/T | 0.036 | 5.02 × 10−6 | 1.28 (1.15–1.43) | 0.005 | 0.059 | 1.59 (0.979–2.58) | 1.25 × 10−6 | 1.25 × 10−6 | 1.29 | 1.29 | 0.395 | 0 |
47 | 2 | rs7211998 | 17 | 37959788 | G/A | 0.036 | 6.42 × 10−6 | 1.28 (1.15–1.42) | 0.235 | 0.005 | 1.13 (1.04–1.23) | 5.27 × 10−7 | 0.002 | 1.19 | 1.20 | 0.089 | 65.4 |
48 | 2 | rs36097841 | 17 | 37958112 | A/G | 0.036 | 6.08 × 10−6 | 1.28 (1.15–1.42) | 0.252 | 0.002 | 1.14 (1.05–1.24) | 2.69 × 10−7 | 0.001 | 1.19 | 1.20 | 0.101 | 62.8 |
49 | 2 | rs34988504 | 17 | 37957631 | T/C | 0.036 | 5.47 × 10−6 | 1.28 (1.15–1.42) | 0.252 | 0.004 | 1.14 (1.04–1.24) | 3.14 × 10−7 | 0.002 | 1.19 | 1.20 | 0.089 | 65.4 |
50 | 1 | rs16965347 | 17 | 37957566 | C/G | 0.030 | 1.24 × 10−5 | 1.29 (1.15–1.45) | 0.004 | 0.154 | 1.52 (0.852–2.70) | 5.12 × 10−6 | 5.12 × 10−6 | 1.30 | 1.30 | 0.595 | 0 |
51 | 2 | rs12937330 | 17 | 37957316 | A/C | 0.036 | 6.02 × 10−6 | 1.28 (1.15–1.42) | 0.268 | 0.009 | 1.12 (1.03–1.22) | 1.33 × 10−6 | 0.008 | 1.18 | 1.19 | 0.056 | 72.7 |
52 | 2 | rs34344462 | 17 | 37955193 | G/A | 0.036 | 5.47 × 10−6 | 1.28 (1.15–1.42) | 0.252 | 0.005 | 1.13 (1.04–1.23) | 4.78 × 10−7 | 0.003 | 1.19 | 1.20 | 0.078 | 67.82 |
53 | 2 | rs9899345 | 17 | 37954757 | A/G | 0.035 | 2.37 × 10−5 | 1.26 (1.13–1.41) | 0.251 | 0.004 | 1.13 (1.04–1.24) | 1.17 × 10−6 | 0.001 | 1.18 | 1.20 | 0.125 | 57.4 |
54 | 1 | rs113369293 | 17 | 37952654 | T/C | 0.036 | 4.51 × 10−6 | 1.28 (1.15–1.43) | 0.007 | 0.287 | 1.27 (0.820–1.95) | 2.63 × 10−6 | 2.63 × 10−6 | 1.28 | 1.28 | 0.948 | 0 |
55 | 1 | rs75148376 | 17 | 37952508 | T/C | 0.036 | 4.51 × 10−6 | 1.28 (1.15–1.43) | 0.007 | 0.287 | 1.27 (0.820–1.95) | 2.63 × 10−6 | 2.63 × 10−6 | 1.28 | 1.28 | 0.948 | 0 |
56 | 2 | rs73302152 | 17 | 37952350 | C/G | 0.036 | 6.84 × 10−6 | 1.28 (1.15–1.42) | 0.127 | 0.059 | 1.11 (0.996–1.25) | 5.54 × 10−6 | 0.010 | 1.20 | 1.19 | 0.081 | 67.1 |
57 | 2 | rs113159227 | 17 | 37952091 | A/G | 0.036 | 3.81 × 10−6 | 1.29 (1.16–1.43) | 0.127 | 0.063 | 1.11 (0.994–1.24) | 4.04 × 10−6 | 0.014 | 1.20 | 1.20 | 0.065 | 70.7 |
58 | 2 | rs56928975 | 17 | 37952031 | G/A | 0.048 | 2.38 × 10−7 | 1.28 (1.16–1.40) | 0.250 | 0.014 | 1.11 (1.02–1.22) | 1.18 × 10−7 | 0.011 | 1.19 | 1.19 | 0.034 | 77.7 |
59 | 2 | rs12938749 | 17 | 37951847 | T/C | 0.036 | 3.81 × 10−6 | 1.29 (1.16–1.43) | 0.127 | 0.063 | 1.11 (0.994–1.24) | 4.04 × 10−6 | 0.014 | 1.20 | 1.20 | 0.064 | 70.7 |
60 | 2 | rs35938199 | 17 | 37950812 | T/C | 0.036 | 4.24 × 10−6 | 1.28 (1.15–1.43) | 0.127 | 0.063 | 1.11 (0.994–1.24) | 4.23 × 10−6 | 0.014 | 1.20 | 1.20 | 0.066 | 70.4 |
61 | 2 | rs35105110 | 17 | 37950421 | A/G | 0.036 | 3.24 × 10−6 | 1.29 (1.16–1.43) | 0.127 | 0.063 | 1.11 (0.994–1.24) | 3.63 × 10−6 | 0.014 | 1.20 | 1.20 | 0.062 | 71.3 |
62 | 2 | rs35352075 | 17 | 37949790 | C/T | 0.036 | 3.81 × 10−6 | 1.29 (1.16–1.43) | 0.127 | 0.063 | 1.11 (0.994–1.24) | 4.04 × 10−6 | 0.014 | 1.20 | 1.20 | 0.064 | 70.7 |
63 | 1 | rs112771646 | 17 | 37945708 | C/A | 0.036 | 4.51 × 10−6 | 1.28 (1.15–1.43) | 0.007 | 0.287 | 1.27 (0.820–1.95) | 2.63 × 10−6 | 2.63 × 10−6 | 1.28 | 1.28 | 0.950 | 0 |
64 | 1 | rs112301322 | 17 | 37944518 | G/C | 0.036 | 4.51 × 10−6 | 1.28 (1.15–1.43) | 0.007 | 0.287 | 1.27 (0.820–1.95) | 2.63 × 10−6 | 2.63 × 10−6 | 1.28 | 1.28 | 0.950 | 0 |
65 | 2 | rs35088469 | 17 | 37944481 | T/C | 0.036 | 2.21 × 10−6 | 1.29 (1.16–1.44) | 0.119 | 0.096 | 1.10 (0.983–1.24) | 4.27 × 10−6 | 0.024 | 1.20 | 1.20 | 0.048 | 74.4 |
66 | 2 | rs34291217 | 17 | 37944410 | A/C | 0.036 | 3.81 × 10−6 | 1.29 (1.16–1.43) | 0.127 | 0.063 | 1.11 (0.994–1.24) | 4.04 × 10−6 | 0.014 | 1.20 | 1.20 | 0.065 | 70.7 |
67 | 2 | rs9911688 | 17 | 37943800 | T/C | 0.036 | 4.71 × 10−6 | 1.28 (1.15–1.43) | 0.127 | 0.060 | 1.11 (0.996–1.24) | 4.20 × 10−6 | 0.011 | 1.20 | 1.20 | 0.073 | 69.0 |
68 | 2 | rs9911669 | 17 | 37943766 | G/C | 0.036 | 3.81 × 10−6 | 1.29 (1.16–1.43) | 0.127 | 0.063 | 1.11 (0.994–1.24) | 4.04 × 10−6 | 0.014 | 1.20 | 1.20 | 0.065 | 70.7 |
69 | 1 | rs111862642 | 17 | 37942983 | G/C | 0.036 | 4.51 × 10−6 | 1.28 (1.15–1.43) | 0.007 | 0.287 | 1.27 (0.820–1.95) | 2.63 × 10−6 | 2.63 × 10−6 | 1.28 | 1.28 | 0.945 | 0 |
70 | 2 | rs34599546 | 17 | 37942971 | T/C | 0.036 | 4.93 × 10−6 | 1.28 (1.15–1.42) | 0.255 | 0.010 | 1.12 (1.03–1.22) | 1.10 × 10−6 | 0.008 | 1.18 | 1.19 | 0.055 | 72.8 |
71 | 1 | rs112345383 | 17 | 37942017 | T/C | 0.036 | 4.51 × 10−6 | 1.28 (1.15–1.43) | 0.007 | 0.287 | 1.27 (0.82–1.95) | 2.63 × 10−6 | 2.63 × 10−6 | 1.28 | 1.28 | 0.950 | 0 |
72 | 2 | rs1510475 | 17 | 37941379 | C/A | 0.036 | 3.81 × 10−6 | 1.29 (1.16–1.43) | 0.127 | 0.063 | 1.11 (0.994–1.24) | 4.04 × 10−6 | 0.014 | 1.20 | 1.20 | 0.065 | 70.7 |
73 | 2 | rs113812449 | 17 | 37940167 | C/T | 0.036 | 4.93 × 10−6 | 1.28 (1.15–1.42) | 0.255 | 0.010 | 1.12 (1.03–1.22) | 1.10 × 10−6 | 0.008 | 1.18 | 1.20 | 0.055 | 72.8 |
74 | 2 | rs9909365 | 17 | 37939958 | G/A | 0.036 | 4.93 × 10−6 | 1.28 (1.15–1.42) | 0.255 | 0.010 | 1.12 (1.03–1.22) | 1.10 × 10−6 | 0.008 | 1.18 | 1.19 | 0.055 | 72.76 |
75 | 2 | rs34016964 | 17 | 37938976 | T/G | 0.036 | 4.93 × 10−6 | 1.28 (1.15–1.42) | 0.255 | 0.010 | 1.12 (1.03–1.22) | 1.10 × 10−6 | 0.008 | 1.18 | 1.19 | 0.055 | 72.8 |
76 | 2 | rs67605703 | 17 | 37938496 | C/T | 0.036 | 4.24 × 10−6 | 1.28 (1.15–1.43) | 0.128 | 0.078 | 1.11 (0.989–1.24) | 5.78 × 10−6 | 0.019 | 1.20 | 1.19 | 0.057 | 72.5 |
77 | 2 | rs35506518 | 17 | 37938093 | C/T | 0.036 | 2.61 × 10−6 | 1.29 (1.16–1.44) | 0.127 | 0.060 | 1.11 (0.996–1.24) | 2.70 × 10−6 | 0.01404 | 1.20 | 1.20 | 0.060 | 71.8 |
78 | 2 | rs13380871 | 17 | 37936248 | C/T | 0.036 | 3.78 × 10−6 | 1.28 (1.16–1.43) | 0.255 | 0.020 | 1.11 (1.02–1.21) | 2.39 × 10−6 | 0.019 | 1.17 | 1.19 | 0.034 | 77.6 |
79 | 2 | rs7224641 | 17 | 37934910 | C/T | 0.036 | 2.60 × 10−6 | 1.29 (1.16–1.44) | 0.255 | 0.011 | 1.12 (1.03–1.22) | 9.12 × 10−7 | 0.013 | 1.18 | 1.20 | 0.039 | 76.5 |
80 | 2 | rs12709364 | 17 | 37933822 | G/A | 0.036 | 2.22 × 10−6 | 1.29 (1.16–1.44) | 0.128 | 0.079 | 1.11 (0.988–1.24) | 3.83 × 10−6 | 0.023 | 1.20 | 1.20 | 0.046 | 74.9 |
81 | 1 | rs113370572 | 17 | 37933467 | C/T | 0.035 | 2.94 × 10−6 | 1.29 (1.16–1.44) | 0.007 | 0.287 | 1.27 (0.820–1.95) | 1.78 × 10−6 | 1.78 × 10-6 | 1.29 | 1.29 | 0.932 | 0 |
82 | 2 | rs9901483 | 17 | 37932773 | A/T | 0.036 | 2.60 × 10−6 | 1.29 (1.16–1.44) | 0.255 | 0.011 | 1.12 (1.03–1.22) | 9.12 × 10−7 | 0.013 | 1.18 | 1.20 | 0.039 | 76.5 |
83 | 2 | rs9894898 | 17 | 37932220 | C/T | 0.036 | 1.99 × 10−6 | 1.30 (1.16–1.44) | 0.127 | 0.073 | 1.11 (0.991–1.24) | 3.13 × 10−6 | 0.021 | 1.20 | 1.20 | 0.047 | 74.8 |
84 | 2 | rs9913596 | 17 | 37932062 | A/G | 0.036 | 1.99 × 10−6 | 1.30 (1.16–1.44) | 0.127 | 0.122 | 1.09 (0.977–1.22) | 6.92 × 10−6 | 0.041 | 1.19 | 1.20 | 0.031 | 78.6 |
85 | 2 | rs9652840 | 17 | 37929427 | T/A | 0.037 | 3.32 × 10−5 | 1.25 (1.13–1.39) | 0.201 | 0.045 | 1.1 (1.00–1.21) | 2.24 × 10−5 | 0.015 | 1.16 | 1.17 | 0.074 | 68.7 |
86 | 2 | rs71369788 | 17 | 37927144 | A/G | 0.036 | 3.42 × 10−6 | 1.29 (1.16–1.43) | 0.200 | 0.052 | 1.10 (0.999–1.20) | 6.32 × 10−6 | 0.033 | 1.18 | 1.19 | 0.027 | 79.5 |
87 | 2 | rs8072612 | 17 | 37927119 | G/A | 0.036 | 3.06 × 10−6 | 1.29 (1.16–1.43) | 0.255 | 0.011 | 1.12 (1.03–1.22) | 9.31 × 10−7 | 0.011 | 1.18 | 1.20 | 0.043 | 75.7 |
88 | 2 | rs9894370 | 17 | 37926003 | C/G | 0.037 | 4.77 × 10−7 | 1.31 (1.18–1.45) | 0.318 | 0.018 | 1.10 (1.02–1.20) | 8.05 × 10−7 | 0.037 | 1.17 | 1.20 | 0.011 | 84.6 |
89 | 2 | rs34758895 | 17 | 37925467 | T/C | 0.037 | 5.33 × 10-7 | 1.31 (1.18–1.45) | 0.318 | 0.018 | 1.10 (1.02–1.20) | 7.76 × 10-7 | 0.034 | 1.17 | 1.20 | 0.012 | 84.2 |
90 | 1 | rs112771360 | 17 | 37923770 | G/A | 0.035 | 2.79 × 10−6 | 1.29 (1.16–1.44) | 0.007 | 0.287 | 1.27 (0.820–1.95) | 1.59 × 10−6 | 1.59 × 10−6 | 1.29 | 1.29 | 0.926 | 0 |
91 | 1 | rs112876941 | 17 | 37922803 | T/A | 0.035 | 2.36 × 10−6 | 1.29 (1.16–1.44) | 0.007 | 0.287 | 1.27 (0.820–1.95) | 1.37 × 10−6 | 1.37 × 10−6 | 1.29 | 1.29 | 0.921 | 0 |
92 | 2 | rs2941509 | 17 | 37921193 | T/C | 0.037 | 1.30 × 10−5 | 1.27 (1.14–1.41) | 0.244 | 0.052 | 1.09 (0.999–1.19) | 2.07 × 10−5 | 0.034 | 1.16 | 1.17 | 0.034 | 77.9 |
93 | 2 | rs67571561 | 17 | 37920846 | C/T | 0.036 | 2.44 × 10−6 | 1.29 (1.16–1.43) | 0.230 | 0.049 | 1.09 (1–1.20) | 6.03 × 10−6 | 0.041 | 1.17 | 1.18 | 0.019 | 81.8 |
# | Group | rs | Chr | Pos | PC Hi-C Interaction Region | Pos (hg19) | GeneHancer | Pos (hg19) |
---|---|---|---|---|---|---|---|---|
1 | 1 | rs111678394 | 17 | 38021116 | IKZF3-ZPBP2 | 38018444-38027003 | GH17J039859 | 38015831-38025531 |
2 | 1 | rs117278702 | 17 | 38020420 | ||||
3 | 2 | rs9905881 | 17 | 38018954 | ||||
4 | 2 | rs9899336 | 17 | 38017779 | ||||
5 | 2 | rs9899006 | 17 | 38017064 | ||||
6 | 1 | rs77924338 | 17 | 38016356 | ||||
7 | 2 | rs9915797 | 17 | 38014867 | ||||
8 | 2 | rs16965367 | 17 | 38014315 | ||||
9 | 2 | rs113466546 | 17 | 38012586 | ||||
10 | 2 | rs9907291 | 17 | 38010036 | ||||
11 | 2 | rs8069531 | 17 | 38009343 | GH17J039852 | 38008382-38009513 | ||
12 | 2 | rs8068894 | 17 | 38008999 | ||||
13 | 1 | rs113233720 | 17 | 38008190 | ||||
14 | 1 | rs112677036 | 17 | 38002152 | ||||
15 | 2 | rs67600807 | 17 | 38001558 | ||||
16 | 2 | rs9908694 | 17 | 37997771 | ||||
17 | 2 | rs9900541 | 17 | 37996070 | ||||
18 | 1 | rs111691913 | 17 | 37993238 | ||||
19 | 2 | rs28449671 | 17 | 37991630 | ||||
20 | 1 | rs111944912 | 17 | 37988476 | GH17J039817 | 37974070-37978821 | ||
21 | 2 | rs73304123 | 17 | 37987588 | ||||
22 | 2 | rs112141468 | 17 | 37987464 | ||||
23 | 1 | rs111734595 | 17 | 37987399 | ||||
24 | 1 | rs113479772 | 17 | 37987042 | ||||
25 | 1 | rs112797570 | 17 | 37983751 | ||||
26 | 1 | rs112437508 | 17 | 37983512 | ||||
27 | 2 | rs35130019 | 17 | 37983141 | ||||
28 | 1 | rs111469562 | 17 | 37982696 | ||||
29 | 2 | rs12942660 | 17 | 37982037 | ||||
30 | 2 | rs8076347 | 17 | 37977540 | ||||
31 | 2 | rs9908983 | 17 | 37976926 | ||||
32 | 2 | rs9911069 | 17 | 37976601 | ||||
33 | 2 | rs9901917 | 17 | 37976205 | 5′ (I3) | 37965773-37976506 | ||
34 | 1 | rs112743130 | 17 | 37975855 | ||||
35 | 2 | rs34053394 | 17 | 37975660 | ||||
36 | 2 | rs58075375 | 17 | 37975592 | ||||
37 | 2 | rs9902621 | 17 | 37973010 | ||||
38 | 2 | rs9898031 | 17 | 37972647 | ||||
39 | 1 | rs112412105 | 17 | 37971635 | ||||
40 | 1 | rs113115305 | 17 | 37970686 | GH17J039812 | 37968642-37971311 | ||
41 | 1 | rs112238900 | 17 | 37968494 | ||||
42 | 2 | rs67135646 | 17 | 37967871 | ||||
43 | 2 | rs114777282 | 17 | 37967649 | ||||
44 | 2 | rs4337325 | 17 | 37964435 | ||||
45 | 2 | rs9901617 | 17 | 37964175 | ||||
46 | 1 | rs113064843 | 17 | 37960421 | ||||
47 | 2 | rs7211998 | 17 | 37959788 | ||||
48 | 2 | rs36097841 | 17 | 37958112 | ||||
49 | 2 | rs34988504 | 17 | 37957631 | 3′ (E4-7) | 37932293-37957717 | GH17J039798 | 37954998-37957986 |
50 | 1 | rs16965347 | 17 | 37957566 | ||||
51 | 2 | rs12937330 | 17 | 37957316 | ||||
52 | 2 | rs34344462 | 17 | 37955193 | ||||
53 | 2 | rs9899345 | 17 | 37954757 | ||||
54 | 1 | rs113369293 | 17 | 37952654 | GH17J039790 | 37946728-37952847 | ||
55 | 1 | rs75148376 | 17 | 37952508 | ||||
56 | 2 | rs73302152 | 17 | 37952350 | ||||
57 | 2 | rs113159227 | 17 | 37952091 | ||||
58 | 2 | rs56928975 | 17 | 37952031 | ||||
59 | 2 | rs12938749 | 17 | 37951847 | ||||
60 | 2 | rs35938199 | 17 | 37950812 | ||||
61 | 2 | rs35105110 | 17 | 37950421 | ||||
62 | 2 | rs35352075 | 17 | 37949790 | ||||
63 | 1 | rs112771646 | 17 | 37945708 | ||||
64 | 1 | rs112301322 | 17 | 37944518 | ||||
65 | 2 | rs35088469 | 17 | 37944481 | ||||
66 | 2 | rs34291217 | 17 | 37944410 | ||||
67 | 2 | rs9911688 | 17 | 37943800 | ||||
68 | 2 | rs9911669 | 17 | 37943766 | ||||
69 | 1 | rs111862642 | 17 | 37942983 | ||||
70 | 2 | rs34599546 | 17 | 37942971 | ||||
71 | 1 | rs112345383 | 17 | 37942017 | ||||
72 | 2 | rs1510475 | 17 | 37941379 | ||||
73 | 2 | rs113812449 | 17 | 37940167 | ||||
74 | 2 | rs9909365 | 17 | 37939958 | ||||
75 | 2 | rs34016964 | 17 | 37938976 | GH17J039766 | 37922530-37939749 | ||
76 | 2 | rs67605703 | 17 | 37938496 | ||||
77 | 2 | rs35506518 | 17 | 37938093 | ||||
78 | 2 | rs13380871 | 17 | 37936248 | ||||
79 | 2 | rs7224641 | 17 | 37934910 | ||||
80 | 2 | rs12709364 | 17 | 37933822 | ||||
81 | 1 | rs113370572 | 17 | 37933467 | ||||
82 | 2 | rs9901483 | 17 | 37932773 | ||||
83 | 2 | rs9894898 | 17 | 37932220 | ||||
84 | 2 | rs9913596 | 17 | 37932062 | ||||
85 | 2 | rs9652840 | 17 | 37929427 | ||||
86 | 2 | rs71369788 | 17 | 37927144 | ||||
87 | 2 | rs8072612 | 17 | 37927119 | ||||
88 | 2 | rs9894370 | 17 | 37926003 | ||||
89 | 2 | rs34758895 | 17 | 37925467 | ||||
90 | 1 | rs112771360 | 17 | 37923770 | ||||
91 | 1 | rs112876941 | 17 | 37922803 | ||||
92 | 2 | rs2941509 | 17 | 37921193 | ||||
93 | 2 | rs67571561 | 17 | 37920846 |
Group I Risk Variants | SNPs in IKZF3-ZPBP2 bi-Directional Promoter | |||||||
---|---|---|---|---|---|---|---|---|
Risk SNP | Location | Interact. Fragment | ASTF | Alt-Ref Enrich. | Promoter SNP | Shared Promoter TF | Alt-Ref Enrich. | |
A | rs193004755 | I1 | no | - | − | - | - | − |
B | rs115164861 | I1 | no | - | − | - | - | − |
C | rs142142756 | I1 | no | Foxj1_1 | −2.5 | rs145735506 | Foxj1_1 | 11.8 |
Foxo_3 | −2.3 | rs184525456 rs138959946 | Foxo_3 | −12 −3 | ||||
p300_disc3 | 2.0 | rs188089973 rs9907794 rs116467677 rs145275643 rs138461720 rs112745149 rs192412458 | p300_disc5 p300_disc5 p300_disc9 p300_disc10 p300_disc5 p300_disc5 p300_disc1 | 1.9 −5.9 −1.7 11.9 −2.5 3.2 11.9 | ||||
D | rs145168309 | I2 | no | AP-1_disc8 | 11.2 | rs190729974 rs4795397 rs192412458 rs192412458 rs147224870 rs1453558 rs1453560 rs36111081 rs66565390 | AP-1_disc1 AP-1_disc2 AP-1_disc3/7/9 AP-1_known2/3/4 AP-1_disc7 AP-1_disc2 AP-1_known1 AP-1_disc7 AP-1_disc7 | 12 −6.8 11.9/0.4/12 11.8/4.2/12 −10.9 11.9 −2.5 11.1 −11.1 |
Irf_known7 | 9.0 | rs9907564 rs188089973 rs75027016 rs138461720 rs112745149 rs184525456 | Irf_known9 Irf_disc5/known9 Irf_known1/2 Irf_disc3 Irf_disc3/known9 Irf_known1/9 | −1.1 11.9/−0.6 11.9/12 5.5 9.6/12 12/11.9 | ||||
Pax-5_disc4 | 4.7 | - | - | − | ||||
Pou2f2_disc1 Pou2f2_known10 | 4.7 3.1 | rs202227901 rs191534721 rs9905881 rs193079571 rs140511615 rs4622539 rs184966935 rs145101657 rs145975450 | Pou2f2_known4 Pou2f2_known4 Pou2f2_known2 Pou2f2_known2 Pou2f2_known8 Pou2f2_known8 Pou2f2_known2 Pou2f2_known10 Pou2f2_known2 | −0.2 −0.6 2.6 4.3 −5.4 −5.2 1.9 4.9 1 | ||||
p300_disc5 | 2.9 | rs188089973 rs9907794 rs116467677 rs145275643 rs138461720 rs112745149 rs192412458 | p300_disc5 p300_disc5 p300_disc9 p300_disc10 p300_disc5 p300_disc5 p300_disc1 | 1.9 −5.9 −1.7 11.9 −2.5 3.2 11.9 | ||||
E | rs111907649 | I3 | no | AP-1_disc7 | −10.9 | rs190729974 rs4795397 rs192412458 rs192412458 rs147224870 rs1453558 rs1453560 rs36111081 rs66565390 | AP-1_disc1 AP-1_disc2 AP-1_disc3/7/9 AP-1_known2/3/4 AP-1_disc7 AP-1_disc2 AP-1_known1 AP-1_disc7 AP-1_disc7 | 12 −6.8 11.9/0.4/12 11.8/4.2/12 −10.9 11.9 −2.5 11.1 −11.1 |
BHLHE40_disc2 | −11.2 | rs145275643 rs11557466 | BHLHE40_known1 BHLHE40_known1 | −0.2 1.3 | ||||
F | rs140386398 | I3 | no | BDP1_disc3 | −12 | rs79042302 | BDP1_disc1 | −5.3 |
GR_disc5 | −12 | rs199994111 rs183478341 rs192412458 rs190942850 rs192800564 rs11655198 | GR_disc6 GR_disc1 GR_disc2 GR_known3/9 GR_disc6 GR_disc4 | −0.3 6.6 11.8 −0.2/−0.3 −9.2 12 | ||||
G | rs149317842 | I3 | 3′ E4-7 | Dlx2 | −10.1 | rs191534721 | Dlx2 | −1.9 |
Dlx3 | −9.4 | rs191534721 | Dlx2 | −1.3 | ||||
Irx | −5.6 | - | - | − | ||||
Lhx3_1 | −12 | rs138350717 | Lhx3_1 | −1 | ||||
Pou3f2_2 | −11 | rs202227901 rs182045388 rs200781948 rs11078924 | Pou3f2_2 Pou3f2_2 Pou3f2_2 Pou3f2_2 | −12 −11 −12 −2.9 | ||||
SRF_known3 | 4.3 | rs188089973 rs75027016 | SRF_known3 SRF_known3 | −1 1.3 | ||||
STAT_known3 | 4.9 | rs202227901 rs191534721 rs4622539 rs145275643 rs79042302 rs79042302 rs112745149 rs192412458 rs181849193 rs185870642 rs145975450 rs74805134 | STAT_disc5/known1 STAT_disc5 STAT_disc4 STAT_known13 STAT_disc1 STAT_known10/11/12/15/4/6/7 STAT_disc3 STAT_disc2 STAT_disc6 STAT_known14/15 STAT_known11 STAT_disc7 | 2.2/4.7 −11.8 12 5.2 −4 −11.9/1.2/−1/0.1/−3/−12/−0.9 12 12 11.9 11.9/11.9 −4.3 −11.7 | ||||
YY1_known6 | 3.7 | rs188089973 rs147224870 rs28661251 | YY1_known6 YY1_disc4 YY1_disc1/known2 | −1.6 −3.1 −3.9/−0.6 | ||||
H | rs186234194 | I7 | 3′ E4-7 | - | - | - | − | |
I | rs145335424 | I7 | no | AP-1_disc2 | −12 | rs190729974 rs4795397 rs192412458 rs192412458 rs147224870 rs1453558 rs1453560 rs36111081 rs66565390 | AP-1_disc1 AP-1_disc2 AP-1_disc3/7/9 AP-1_known2/3/4 AP-1_disc7 AP-1_disc2 AP-1_known1 AP-1_disc7 AP-1_disc7 | 12 −6.8 11.9/0.4/12 11.8/4.2/12 −10.9 11.9 −2.5 11.1 −11.1 |
Gfi1_3 | −12 | - | - | − | ||||
NF-Y_disc1 | −12 | - | - | − | ||||
NF-Y_known1 | −5.2 | - | - | − | ||||
RFX5_disc2 | −11.9 | rs4795397 | RFX5_disc2 | −7.5 | ||||
TATA_disc6 | −5.4 | rs188089973 rs140511615 rs4622539 rs184966935 rs112745149 rs184525456 rs185009382 rs192678773 | TATA_known4 TATA_disc9 TATA_disc9 TATA_known1 TATA_disc7 TATA_known1 TATA_disc7 TATA_disc7 | 0.7 −5.1 −3.2 −2.1 1.3 −0.6 −2.8 −7 | ||||
J | rs113730542 | I7 | no | Fox | 8.3 | rs111678394 | Fox | −1 |
SNP | DNAse HotSpot (ENCODE) | Interaction Region Hi-C | Shared TF between IKZF3-ZPBP2 and 3′ (E4-7) Interaction Regions | Shared DNase HotSpot between IKZF3-ZPBP2 and 3′ (E4-7) Interaction Regions | Source |
---|---|---|---|---|---|
rs111678394 | y | IKZF3-ZPBP2 | (Foxi1) Foxo_1, Pax-4_5 | CD20, CD4, CD34+, LCL, Th1, Th2, Treg | Table 2 |
rs75148376 | y | 3′ (E4-7) | Ncx, Nkx6, Pou4f3, Dbx1, Hoxb4 | LCL, Th1, Th2, Treg | Table 2 |
rs113370572 | y | 3′ (E4-7) | HDAC2 | LCL, Th1, Th2, Treg | Table 2 |
rs113730542 * | y | <2kb from 3′ (E4-7) | Fox | CD4, LCL, Th1, Th2, Treg | Table A6 |
rs112876941 | y | <10kb from 3′ (E4-7) | Foxa, Foxj1, Foxo, HNF1, TCF12 | CD14+, LCL | Table 2 |
References
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Enhancer Region (Enh) | Promoter/TSS Region (PC Hi-C) | GeneHancer Promoter Region (GH07J050293) | |||||||
---|---|---|---|---|---|---|---|---|---|
Risk SNP | TF Showing Allele-Specific Binding (ASTF) | Alt-Ref Enrichment | TSS SNP with Same TF Binding Site as Risk Allele | TF Binding to TSS SNP | Alt-Ref Enrichment | TSS SNP with Same TF Binding Site as Risk Allele | TF Binding to TSS SNP | Alt-Ref Enrichment | |
rs11185603 * | A | RXRA_disc4 | −11.1 | rs146295095 | RXRA_known1 | 3 | |||
rs141865623 | RXRA_disc2 | −0.8 | |||||||
rs11765436 # | RXRA_disc2 | 5.7 | rs11765436 # | RXRA_disc2 | 5.7 | ||||
rs187496825 | RXRA_known2 | 12 | |||||||
rs180969166 ^ | RXRA_known6 | 0 | |||||||
rs183264036 ^ | RXRA_disc1 | 0.2 | rs7802443 # | RXRA_disc2 | 11.4 | ||||
B | PU.1_disc3 | −11.9 | rs191336126 rs80161560 | PU.1_disc2 | 0.8 | rs9886239 * | PU.1_disc2 | −12 | |
PU.1_disc3 | 1.6 | ||||||||
C | TATA_disc7 | −6.3 | rs142010565 | TATA_known1 | −1.9 | rs7777365 | TATA_known3 | −2.4 | |
rs142762599 | TATA_known1 | 0.1 | |||||||
rs79391891 | TATA_disc2 | −12 | |||||||
rs186224998 | TATA_disc9 | −4 | |||||||
rs62447182 | TATA_disc9 | −5.1 | |||||||
rs876036 | D | ERalpha-a_disc4 | 10.5 | rs180969166 ^ rs183264036 rs151114892 rs145086785 | ERalpha-a_disc2/4 | −2/−0.3 | |||
ERalpha-a_disc4 | 3.3 | ||||||||
ERalpha-a_disc4 | −3.6 | ||||||||
ERalpha-a_disc4 | 0.5 | ||||||||
D | VDR_2/3 | −7.8, −3.9 | rs180969166 ^ | VDR_4 | 12 | ||||
rs151114892 | VDR_4 | −11.5 | |||||||
E | RXRA_known4 | −10.6 | rs11765436 # | RXRA_disc2 | 5.7 | ||||
rs7802443 # | RXRA_disc2 | 11.4 | |||||||
rs876038 * | A | XBP-1_1 | −12 | rs184933329 | XBP-1_2 | −11.9 | |||
rs74607523 | XBP-1_2 | −2.3 | |||||||
B | BDP1_disc1 | −0.6 | rs11761922 * | BDP1_disc1 | 12 | ||||
rs7781977 # | BDP1_disc1 | 12 | |||||||
C | Brachyury_1 | −3.2 | rs10269380 * | Brachyury_1 | 4.8 | ||||
rs876039 | Foxa_known2,3 | 1.1, 0.6 | rs7777365 # | Foxa_known1 | −2.7 |
Group I Risk Variants | SNPs in IKZF3-ZPBP2 Bi-Directional Promoter | ||||||
---|---|---|---|---|---|---|---|
Risk SNP | Interaction Fragment | ASTF * | Alt-Ref Enrichment | Promoter SNP | Shared Promoter TF | Alt-Ref Enrichment | |
1 | rs111678394 | IKZF3-ZPBP2 | Foxi1 | −3.9 | - | - | - |
Foxo_1 | −2.1 | rs138959946 a | Foxo1 | −2.4 | |||
Pax-4_5 | −2.3 | rs189743120 a | Pax_4_5 | 1 | |||
2 | rs117278702 | IKZF3-ZPBP2 | - | - | - | - | - |
3 | rs77924338 | no | VDR_4 | −9.1 | rs74805134 b | VDR_2 | −11.5 |
4 | rs113233720 | no | DMRT4 | −11.5 | rs147630723 a | DMRT4 | 11.9 |
5 | rs112677036 | no | Mef2_known5 | 11.5 | rs73985223 b | Mef2_known6 | 11.9 |
rs73985223 b | Mef2_disc1 | 6.4 | |||||
rs4622539 b | Mef2_known5 | −3.2 | |||||
rs192412458 a | Mef2_disc3 | 11.9 | |||||
rs188089973 | Mef2_known5 | −3.8 | |||||
rs185330833 a | Mef2_known6 | 11.7 | |||||
rs184966935 a | Mef2_known1 | −10 | |||||
rs184525456 a | Mef2_known5 | −3.1 | |||||
rs140511615 a | Mef2_known5 | −11.8 | |||||
6 | rs111691913 | no | Zntb3 | 8.0 | - | - | - |
7 | rs111944912 | no | Hoxa13 | 2 | rs12150079 | Hoxa13 | 0.7 |
8 | rs111734595 | no | - | - | - | - | - |
9 | rs113479772 | no | - | - | - | - | - |
10 | rs112797570 | no | - | - | - | - | - |
11 | rs111734595 | no | SETDB1 Zfx | 8.2 −5.7 | rs201229892 rs117064469 | SETDB1 Zfx | −0.6 −1.4 |
12 | rs111469562 | no | Obox6 | 4.6 | rs11078925 | Obox3 | −6.7 |
Dmbx1 | 4.1 | rs11078925 | Dmbx1 | −9 | |||
13 | rs112743130 | 5′ (I3) | - | - | - | - | - |
14 | rs112412105 | 5′ (I3) | GR_disc4 | −12 | rs183478341 u/k | GR_disc1 | 6.6 |
15 | rs113115305 | 3′ (E4-7) | - | - | - | - | - |
16 | rs112238900 | 3′ (E4-7) | - | - | - | - | - |
17 | rs113064843 | 3′ (E4-7) | - | - | - | - | - |
18 | rs16965347 | 3′ (E4-7) | Pou6f1_2 | - | - | - | |
19 | rs113369293 | 3′ (E4-7) | Irf_disc3 | 2.3 | rs138461720 u/k | Irf_disc3 | 5.5 |
Irf_disc3 | 2.3 | rs112745149 u/k | Irf_disc3 | 9.6 | |||
20 | rs75148376 | 3′ (E4-7) | Ncx_2 | 4 | rs9905881 b | Ncx_2 | 3.2 |
Nkx6-1_2 | 6.7 | rs149800216 a | Nkx6-1_3 | −9.7 | |||
Nkx6-1_2 | 6.7 | rs149800216 a | Nkx6-1_2 | −10.2 | |||
Nkx6-1_2 | 6.7 | rs149800216 a | Nkx6-1_1 | −12 | |||
Ncx_2 | 4 | rs149800216 a | Ncx_2 | −6.4 | |||
Pou4f3 | 5.6 | rs138350717 a | Pou4f3 | 5.9 | |||
Nkx6-1_2 | 6.7 | rs138350717 a | Nkx6-1_2 | 3.5 | |||
Nkx6-1_2 | 6.7 | rs138350717 a | Nkx6-1_1 | 7.9 | |||
Dbx1 | 2.2 | rs202227901 b | Dbx1 | −0.1 | |||
Dbx1 | 2.2 | rs138350717 a | Dbx1 | 0.6 | |||
Dbx1 | 2.2 | rs145735506 a | Dbx1 | 1.4 | |||
Dbx1 | 2.2 | rs185330833 a | Dbx1 | −1.2 | |||
Hoxb4 | 2.1 | rs202227901 b | Hoxb4 | −0.5 | |||
21 | rs112771646 | 3′ (E4-7) | GR_disc5 | −3.8 | rs192800564 a | GR_disc6 | −9.2 |
GR_disc5 | −3.8 | rs192412458 a | GR_disc2 | 11.8 | |||
GR_disc5 | −3.8 | rs11655198 | GR_disc4 | 12 | |||
22 | rs112301322 | 3′ (E4-7) | NF-E2_disc1 | 11.9 | rs201229892 a | NF-E2_disc1 | 12 |
Rad21_disc10 | −11.5 | rs187549822 a | Rad21_disc2 | −4.2 | |||
23 | rs111862642 | 3′ (E4-7) | Sin3Ak-20_disc1 | −2.9 | rs116467677 a | Sin3Ak-20_disc6 | −0.6 |
24 | rs112345383 | 3′ (E4-7) | HNF1_2 | 6.1 | rs202236981 a | HNF1_2 | −1.8 |
25 | rs113370572 T | 3′ (E4-7) | HDAC2_disc5 | 9.6 | rs202227901 b | HDAC2_disc6 | 10.6 |
HDAC2_disc5 | 9.6 | rs200781948 a | HDAC2_disc6 | −3.9 | |||
26 | rs112771360 | no | - | - | - | - | - |
27 | rs112876941 | no | HNF1_7 | 3.5 | - | - | - |
HNF1_6 | 3.1 | rs9905881 b | HNF1_6 | −2.7 | |||
HNF1_6 | 3.1 | rs9907564 b | HNF1_6 | −1.1 | |||
HNF1_6 | 3.1 | rs138350717 a | HNF1_6 | 0.7 | |||
HNF1_1 | 4.3 | rs9905881 b | HNF1_1 | −4.3 | |||
Foxo_2 | 11.9 | rs184525456 a | Foxo_2 | −12 | |||
Foxa_disc2 | −10.6 | rs145895912 a | Foxa_disc3 | 11.7 | |||
Foxj1_1 | 4.6 | rs145735506 a | Foxj1_1 | 11.8 | |||
Foxo_2 | 11.9 | rs138959946 a | Foxo_2 | −12 |
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Vyse, T.J.; Cunninghame Graham, D.S. Trans-Ancestral Fine-Mapping and Epigenetic Annotation as Tools to Delineate Functionally Relevant Risk Alleles at IKZF1 and IKZF3 in Systemic Lupus Erythematosus. Int. J. Mol. Sci. 2020, 21, 8383. https://doi.org/10.3390/ijms21218383
Vyse TJ, Cunninghame Graham DS. Trans-Ancestral Fine-Mapping and Epigenetic Annotation as Tools to Delineate Functionally Relevant Risk Alleles at IKZF1 and IKZF3 in Systemic Lupus Erythematosus. International Journal of Molecular Sciences. 2020; 21(21):8383. https://doi.org/10.3390/ijms21218383
Chicago/Turabian StyleVyse, Timothy J., and Deborah S. Cunninghame Graham. 2020. "Trans-Ancestral Fine-Mapping and Epigenetic Annotation as Tools to Delineate Functionally Relevant Risk Alleles at IKZF1 and IKZF3 in Systemic Lupus Erythematosus" International Journal of Molecular Sciences 21, no. 21: 8383. https://doi.org/10.3390/ijms21218383