Fig. 1A Manhattan plot of the combined thyroid cancer genome-wide association study (GWAS) results in the populations of European ancestry according to [24]. The vertical axis is the negative log10-transformed P values for association signals of single-nucleotide polymorphisms across 22 autosomal chromosomes (horizontal axis). Annotated in black color are the loci discovered in earlier studies and replicated by different groups. Red color correspond to six novel loci associated with thyroid cancer detected by meta-analysis of GWAS data from 3,001 patients and 287,550 controls of the European descent. Note that statistical significance of association of the newly detected loci is generally lower than of those discovered earlier. The figure is derived from the open access article [24] according to a Creative Commons Attribution 4.0 International License and is presented here with minor modifications. FOXE1, forkhead box E1; PTCSC2, papillary thyroid carcinoma susceptibility candidate 2; PCNXL2, pecanex homolog 2; DIRC3, disrupted in renal carcinoma 3; LRRC34, leucine rich repeat containing 34; TERT, telomerase reverse transcriptase; EPB41L4A, erythrocyte membrane protein band 4.1 like 4A; NRG1, neuregulin 1; OBFC1, STN1, CST complex subunit; PCNXL3, pecanex homolog 3; MBIP1, MAP3K12 binding inhibitory protein 1; SMAD3, SMAD family member 3.
Fig. 2A Manhattan plot of the genome-wide association study of differentiated thyroid cancer (DTC) in the Korean population according to [40]. The vertical axis is the negative log10-transformed P values for association signals of single-nucleotide polymorphisms across 22 autosomal chromosomes (horizontal axis). Annotated in black color are the loci described earlier in the populations of European ancestry. Red color correspond to seven novel loci associated with DTC and specific to the Korean population based on gene scans of 470 patients and 8,279 controls. The red horizontal line represents the genome-wide significance threshold P=5E-08, and the blue horizontal line represents the genome-wide suggestiveness threshold P=1E-05. The figure is derived from the open access article [40] according to a Creative Commons Attribution 4.0 International License and is presented here with minor modifications. VAV3, vav guanine nucleotide exchange factor 3; PCNXL2, pecanex homolog 2; DIRC3, disrupted in renal carcinoma 3; FHIT, fragile histidine triad; SEPT11, septin 11; NRG1, neuregulin 1; FOXE1, forkhead box E1; SLC24A6, solute carrier family 8 member B1; MSRB3, methionine sulfoxide reductase B3; NKX2-1, NK2 homeobox 1; INSR, insulin receptor.
Table 1Major Results of Genome-Wide Association Study of Differentiated Thyroid Cancer in the Population of European Ancestrya
Chromosome |
SNP (RA/OA) |
Annotation |
SNP function |
Nearest gene |
Risk allele frequency |
Allelic ORb
|
Replicatedc
|
2q35 |
rs966423 (C/T) |
Intron |
NE |
DIRC3 |
0.41 |
1.28 |
No |
rs11693806 (C/G) |
Exon, non-coding |
NE |
0.32 |
1.43 |
No |
8p12 |
rs2439302 (G/C) |
Intron 1 |
Risk allele decreases NRG1 expression |
NRG1 |
0.48 |
1.32 |
Yes |
9q22.33 |
rs965513 (A/G) |
Intergenic |
Enhancer element involved in the regulation of PTCSC2 and FOXE1 expression |
FOXE1, PTCSC2 |
0.40 |
1.70 |
Yes |
rs1867277 (A/G)d
|
5′UTR |
Risk allele regulates FOXE1 transcription through the differential recruitment of USF1/USF2 transcription factors |
FOXE1
|
0.52 |
1.49 |
Yes |
14q13.3 |
rs944289 (T/C) |
Non-coding, promoter |
Risk allele decreases promoter activation PTCSC3, by weakening the binding affinity of the NKX2-1 p42 C/EBPα and β |
PTCSC3, NKX2-1 |
0.60 |
1.35 |
Yes |
rs116909374 (T/C) |
Intergenic |
NE |
MBIP1 |
0.04 |
1.71 |
Absente
|
Recently discovered SNPs |
|
|
|
|
|
|
1q42.2 |
rs12129938 (A/G) |
Intron 1 |
NE |
PCNXL2 |
0.80 |
1.32 |
No |
3q26.2 |
rs6793295 (T/C) |
Missense variant (p.Ser249Gly) |
NE |
LRRC34 |
0.76 |
1.23 |
No |
5p15.33 |
rs10069690 (T/C) |
Intron 4 |
NE |
TERT |
0.28 |
1.20 |
No |
5q22.1 |
rs73227498 (A/T) |
Intergenic |
NE |
EPB41L4A |
0.87 |
1.37 |
No |
10q24.33 |
rs7902587 (T/C) |
Intergenic |
NE |
OBFC1 |
0.11 |
1.41 |
Absent |
15q22.33 |
rs2289261 (C/G) |
Intron |
NE |
SMAD3 |
0.68 |
1.23 |
No |
Table 2Results of Genome-Wide Association Study of Differentiated Thyroid Cancer in the Korean Populationa
Chromosome |
SNP (RA/OA) |
Annotation |
Nearest gene |
Risk allele frequency |
Allelic ORb
|
Markers in the loci common with the populations of European ancestry |
2q35 |
rs12990503 (G/C) |
Intron |
DIRC3
|
0.69 |
1.34 |
8p12 |
rs6996585 (G/A) |
Intron |
NRG1
|
0.29 |
1.39 |
rs12542743 (C/T) |
Intron |
0.32 |
1.36 |
rs2439302 (G/C)c
|
Intron 1 |
0.27 |
1.37 |
9q22.33 |
rs72753537 (C/T) |
Intron |
FOXE1
|
0.10 |
1.41 |
14q13.3 |
rs34081947 (T/C) |
Intron |
NKX2-1
|
0.47 |
1.27 |
rs944289 (T/C)c
|
Non-coding, promoter |
0.51 |
1.25 |
1q42.2 |
rs4649295 (T/C) |
Intron |
PCNXL2
|
0.68 |
1.23 |
Markers specific for the Korean population |
12q14.3 |
rs11175834 (T/C) |
Intron |
MSRB3
|
0.20 |
1.37 |
1p13.3 |
rs4915076 (T/C) |
Intron |
VAV3
|
0.76 |
1.33 |
4q21.1 |
rs1874564 (G/A) |
Intron |
SEPT11
|
0.75 |
1.31 |
3p14.2 |
rs9858271 (G/A) |
Intron |
FHIT
|
0.48 |
1.26 |
19p13.2 |
rs7248104 (A/G) |
3′UTR |
INSR
|
0.41 |
1.22 |
12q24.13 |
rs16934253 (A/C/G)d
|
3′UTR |
SLC24A6 (SLC8B1) |
0.03 |
1.51 |