Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations

Abstract

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 × 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 × 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 × 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.

Figure 1. Association results, recombination, and linkage disequilibrium plots for the 5q31.2 and 17p13.1 regions identified in stage 1 (joint analysis of three independent GWAS), for the two replications sets (Beijing and Henan), and the joint estimate from all data

(a) 5q31.2:138,701,120–138,885,920 and (b) 17p13.1:7,435,040–7,644,641. Association results from a trend test in –log10 Pvalues (y axis, left; gray diamonds, stage I association result; sky blue diamonds, Beijing replication result; purple diamonds, Henan replication results; red diamonds, joint result) of the SNPs are shown according to their chromosomal positions (x axis). Linkage disequilibrium structure based on the 1000 Genomes CHB data (n=91) was visualized by snp.plotter software. The line graph shows likelihood ratio statistics (y axis, right) for recombination hotspot by SequenceLDhot software based on the background recombination rates inferred by PHASE v2.1 using the 1000 Genomes CHB data. Physical locations are based on NCBI human genome build 37. Gene annotation was based on the NCBI RefSeq genes from the UCSC Genome Browser.

Figure 1. Association results, recombination, and linkage disequilibrium plots for the 5q31.2 and 17p13.1 regions identified in stage 1 (joint analysis of three independent GWAS), for the two replications sets (Beijing and Henan), and the joint estimate from all data

(a) 5q31.2:138,701,120–138,885,920 and (b) 17p13.1:7,435,040–7,644,641. Association results from a trend test in –log10 Pvalues (y axis, left; gray diamonds, stage I association result; sky blue diamonds, Beijing replication result; purple diamonds, Henan replication results; red diamonds, joint result) of the SNPs are shown according to their chromosomal positions (x axis). Linkage disequilibrium structure based on the 1000 Genomes CHB data (n=91) was visualized by snp.plotter software. The line graph shows likelihood ratio statistics (y axis, right) for recombination hotspot by SequenceLDhot software based on the background recombination rates inferred by PHASE v2.1 using the 1000 Genomes CHB data. Physical locations are based on NCBI human genome build 37. Gene annotation was based on the NCBI RefSeq genes from the UCSC Genome Browser.