Table 2.
Association results for lead markers of regions entering the validation stage of the primary and sensitivity GWAS analysis
| Lead SNPs |
Locus | Chr | SNP ID | EA, ED |
Discovery (stage 1) | Replication (stage 2) | Eff. Dir. |
I2 | p heterog. | Combined (stage 1 & 2)‡ | |||||
| P value*† | OR (95% CI) | EAF Ca|Co|Eur |
Meta P value+*† |
OR (95% CI) | Meta P value+*† | OR(95% CI) | I2 | ||||||||
| GWAS analysis 1 (pc adjusted)* | |||||||||||||||
| SNP 1 | PNPLA3§ | 22 | rs2294915 | T+ | 6.21×10−15 | 1.71 (1.50 to 1.96) | .49|.36|.24 | 6.19×10-6 | 1.89 (1.44 to 2.50) | +++ | 0 | 0.517 | 2.44×10−19 | 1.75 (1.55 to 1.97) | 0 |
| PNPLA3 | 22 | rs738409 | G+ | 7.23×10−15 | 1.71 (1.49 to 1.96) | .48|.35|.22 | 9.74×10-6 | 1.89 (1.42 to 2.50) | +++ | 0 | 0.578 | 4.31×10−19 | 1.74 (1.54 to 1.97) | 0 | |
| SNP 2 | TM6SF2¶ | 19 | rs58489806 | T+ | 1.42×10−9 | 1.87 (1.53 to 2.29) | .17|.10|.08 | 5.22×10-4 | 1.91 (1.33 to 2.76) | ++− | 54 | 0.110 | 3.04×10−12 | 1.88 (1.57 to 2.25) | 32 |
| TM6SF2 | 19 | rs58542926 | T+ | 2.81×10−9 | 1.94 (1.56 to 2.42) | .15|.08|.07 | 7.58×10-5 | 2.11 (1.46 to 3.04) | ++− | 61 | 0.076 | 1.00×10−12 | 1.98 (1.64 to 2.40) | 43 | |
| SNP 3 | TERT | 5 | rs2242652 | A- | 7.87×10−7 | 0.64 (0.53 to 0.76) | .13|.19|.19 | 1.07×10-3 | 0.48 (0.31 to 0.74) | −−− | 0 | 0.814 | 6.40×10−9 | 0.61 (0.52 to 0.72) | 0 |
| SNP 4 | LINC00939 | 12 | rs12371263 | A- | 9.59×10−7 | 0.63 (0.52 to 0.76) | .16|.21|.20 | 0.332 | 0.83 (0.57 to 1.21) | −+− | 0 | 0.535 | – | – | – |
| SNP 5 | DMAC2 | 19 | rs17318596 | A- | 2.49×10−6 | 0.71 (0.61 to 0.82) | .33|.40|.37 | 0.849 | 1.03 (0.77 to 1.38) | −+− | 15 | 0.308 | – | – | – |
| SNP 6 | SP100 | 2 | rs6743289 | C- | 2.77×10−6 | 0.72 (0.62 to 0.82) | .45|.52|.47 | 0.046 | 0.75 (0.57 to 1.00) | −−− | 0 | 0.936 | – | – | – |
| SNP 7 | GPIHBP1 | 8 | rs118088203 | T- | 3.60×10−6 | 0.24 (0.13 to 0.44) | .01|.03|.02 | 0.229 | 1.64 (0.73 to 3.07) | +++ | 0 | 0.697 | – | – | – |
| SNP 8 | CNPY1 | 7 | rs12698003 | T+ | 3.65×10−6 | 1.39 (1.21 to 1.60) | .46|.39|.41 | 0.053 | 0.74 (0.55 to 1.00) | −−− | 41 | 0.179 | – | – | – |
| SNP 9 | GLYR1 | 16 | rs741692 | T+ | 4.16×10−6 | 1.58 (1.30 to 1.92) | .18|.12|.15 | 0.783 | 1.05 (0.73 to 1.51) | ++− | 0 | 0.541 | – | – | – |
| GWAS analysis 2 (pc, sex, age adjusted)† | |||||||||||||||
| SNP 1 | PNPLA3§ | 22 | rs2294915 | T+ | 6.31×10−14 | 1.76 (1.52 to 2.05) | .49|.36|.24 | 3.24×10-5 | 1.89 (1.40 to 2.54) | +++ | 0 | 0.428 | 1.06×10-17 | 1.79 (1.57 to 2.04) | 0 |
| PNPLA3 | 22 | rs738409 | G+ | 1.67×10−13 | 1.75 (1.51 to 2.03) | .48|.35|.22 | 4.17×10-5 | 1.85 (1.37 to 2.50) | +++ | 0 | 0.448 | 5.35×10-17 | 1.77 (1.55 to 2.02) | 0 | |
| SNP 2 | TM6SF2¶ | 19 | rs143988316 | T+ | 4.40×10−8 | 1.91 (1.51 to 2.41) | .16|.09|.07 | 5.17×10-2 | 1.54 (1.00 to 2.38) | ++− | 0 | 0.621 | 9.14×10-9 | 1.81 (1.51 to 2.16) | 0 |
| TM6SF2 | 19 | rs58542926 | T+ | 1.21×10−7 | 1.93 (1.51 to 2.45) | .15|.08|.07 | 1.56×10-4 | 2.16 (1.45 to 3.22) | ++− | 48 | 0.149 | 8.80×10-11 | 1.99 (1.61 to 2.44) | 26 | |
| SNP 3 | SCN5A | 3 | rs6599222 | C+ | 2.86×10−6 | 1.53 (1.28 to 1.84) | .25|.20|.21 | 0.977 | 1.01 (0.68 to 1.48) | −++ | 0 | 0.984 | – | – | – |
| SNP 4 | intergenic | 13 | rs148892410 | A- | 3.77×10−6 | 0.16 (0.07 to 0.35) | .01|.02|.01 | 0.798 | 1.45 (0.09 to 24.2) | ++− | 17 | 0.299 | – | – | – |
| SNP 5 | intergenic | 2 | rs6739777 | G- | 5.03×10−6 | 0.69 (0.59 to 0.81) | .29|.34|.30 | 0.388 | 0.86 (0.61 to 1.21) | −+− | 40 | 0.193 | – | – | – |
| SNP 6 | ENSG00000269151 | 19 | rs143660337 | A- | 5.14×10−6 | 0.41 (0.28 to 0.60) | .03|.05|.04 | 0.151 | 1.68 (0.83 to 3.41) | ++− | 0 | 0.589 | – | – | – |
| SNP 7 | LOC105374308 | 3 | rs58339845 | T- | 5.84×10−6 | 0.46 (0.33 to 0.65) | .05|.07|.07 | 0.361 | 1.34 (0.72 to 2.50) | +++ | 0 | 0.919 | – | – | – |
| SNP 8 | intergenic | 7 | rs16869539 | G+ | 5.96×10−6 | 1.48 (1.25 to 1.75) | .36|.30|.37 | 0.537 | 0.90 (0.65 to 1.25) | −−− | 0 | 0.983 | – | – | – |
| SNP 9 | CELF2 | 10 | rs2277212 | T+ | 6.84×10−6 | 1.57 (1.29 to 1.91) | .75|.70|.74 | 0.282 | 1.22 (0.85 to 1.74) | +−+ | 16 | 0.303 | – | – | – |
| SNP 10 | intergenic | 7 | rs6462611 | C+ | 7.82×10−6 | 1.41 (1.21 to 1.64) | .49|.44|.50 | 0.017 | 0.68 (0.49 to 0.93) | ++− | 0 | 0.465 | – | – | – |
| SNP 11 | ENSG00000227757 | 21 | rs2017196 | T+ | 8.73×10−6 | 1.70 (1.34 to 2.14) | .89|.85|.88 | 0.092 | 0.68 (0.44 to 1.06) | −−− | 0 | 0.513 | – | – | – |
| SNP 12 | TERT | 5 | rs2242652 | A- | 9.28×10−6 | 0.64 (0.52 to 0.78) | .13|.19|.19 | 2.60×10-4 | 0.41 (0.25 to 0.66) | ++− | 0 | 0.699 | 4.08×10-8 | 0.60 (0.50 to 0.72) | 17 |
| SNP 13 | RARB | 3 | rs7617311 | A+ | 9.32×10−6 | 1.50 (1.25 to 1.80) | .28|.21|.26 | 0.454 | 0.87 (0.61 to 1.25) | −+− | 0 | 0.751 | – | – | – |
| SNP 14 | CIAO2A | 15 | rs2922508 | T+ | 9.53×10−6 | 1.61 (1.30 to 1.99) | .17|.13|.15 | 0.153 | 1.33 (0.90 to 1.97) | +++ | 0 | 0.797 | – | – | – |
| SNP 15 | intergenic | 2 | rs56209271 | T- | 9.67×10−6 | 0.69 (0.59 to 0.82) | .28|.34|.30 | 0.168 | 0.78 (0.55 to 1.11) | −−− | 61 | 0.075 | – | – | – |
*OR and p value adjusted for top 15 PCs of genetic ancestry.
†OR and p value adjusted for sex, age and top 15 PCs of genetic ancestry.
‡The results of the combined analyses are only provided for variants meeting a Bonferroni corrected p<0.05 at the replication stage (printed in bold face).
§The tag SNP rs2294915 in PNPLA3 is in LD (r2= 0.92) with the functional variant rs738409 previously reported at the PNPLA3 locus58 59.
¶The intergenic tag SNP rs143988316 is in strong LD (r2= 0.88) with the functional variant rs58542926 previously reported at the TM6SF2 locus.60
+, Significance derived from a fixed effect meta-analysis; Ca, Cases (Cirrhosis with HCC); Chr, chromosome; Co, Controls (Cirrhosis without HCC); EA, effect allele; EAF, allele frequency of the effect allele; ED, effect direction; HCC, hepatocellular carcinoma; I2, percentage of between cohort heterogeneity; LD, linkage disequilibrium; pheterog, heterogeneity p value of the meta-analysis; SNP, single-nucleotide polymorphism.