Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor

Abstract

The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first analysis of the X chromosome. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance (P < 5 × 10^-8). Most loci harbor biologically plausible candidate genes. We refined previously reported associations at 9p24.3 and 19p12 by identifying one and three additional independent SNPs, respectively. In aggregate, the 39 independent markers identified to date explain 37% of father-to-son familial risk, 8% of which can be attributed to the 12 new signals reported here. Our findings substantially increase the number of known TGCT susceptibility alleles, move the field closer to a comprehensive understanding of the underlying genetic architecture of TGCT, and provide further clues to the etiology of TGCT.

Figure 1. All identified SNP markers associated with TGCT susceptibility to date

In the ideogram, red dots and red rs number annotation indicate SNPs identified and described in the current study (P ≤ 1 × 10⁻⁸); blue dots and blue rs number annotation represent previously identified SNP markers achieving genome wide significance (P ≤ 1 × 10⁻⁸) in the current study; and gray dots and gray rs number annotation are previously identified SNPs that fail to achieve genome wide significance in this study (P > 1 × 10⁻⁸).

Figure 2. Genetic association between SNP markers and TGCT risk for regions with multiple independent signals

The strength of the association signals (−log₁₀ P-values) for individual SNPs at (a) 9p24.3 and (b) 19p12-11 are plotted on the Y-axis relative to their genomic locations (GRCh37) along the X-axis. Red diamonds are the newly identified independent SNPs, blue diamonds are previously reported SNP markers, and all other SNPs are colored gray. The line graph shows likelihood ratio statistics (right Y-axis) for recombination hotspots calculated with SequenceLDhot software using 1000 Genomes Project CEU population data. Gene annotation along the X-axis is based on NCBI RefSeq genes from the UCSC Genome Browser.