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. 2015 Feb 15;24(4):1169-76.
doi: 10.1093/hmg/ddu511. Epub 2014 Oct 3.

Multi-stage Genome-Wide Association Study Identifies New Susceptibility Locus for Testicular Germ Cell Tumour on Chromosome 3q25

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Free PMC article

Multi-stage Genome-Wide Association Study Identifies New Susceptibility Locus for Testicular Germ Cell Tumour on Chromosome 3q25

Kevin Litchfield et al. Hum Mol Genet. .
Free PMC article

Abstract

Recent genome-wide association studies (GWAS) and subsequent meta-analyses have identified over 25 SNPs at 18 loci, together accounting for >15% of the genetic susceptibility to testicular germ cell tumour (TGCT). To identify further common SNPs associated with TGCT, here we report a three-stage experiment, involving 4098 cases and 18 972 controls. Stage 1 comprised previously published GWAS analysis of 307 291 SNPs in 986 cases and 4946 controls. In Stage 2, we used previously published customised Illumina iSelect genotyping array (iCOGs) data across 694 SNPs in 1064 cases and 10 082 controls. Here, we report new genotyping of eight SNPs showing some evidence of association in combined analysis of Stage 1 and Stage 2 in an additional 2048 cases of TGCT and 3944 controls (Stage 3). Through fixed-effects meta-analysis across three stages, we identified a novel locus at 3q25.31 (rs1510272) demonstrating association with TGCT [per-allele odds ratio (OR) = 1.16, 95% confidence interval (CI) = 1.06-1.27; P = 1.2 × 10(-9)].

Figures

Figure 1.
Figure 1.
Three-stage study design: Genotyping conducted over three stages comprising non-overlapping samples from the UK.
Figure 2.
Figure 2.
Regional plot of the new TGCT loci at 3q25: Plot shows the genomic region of association with TGCT on chromosome 3q25.31. Shown by diamonds are the −log10 association P-values of genotyped SNPs, based on meta-analysis across genotyping Stages 1–3 (for rs1510272) and Stages 1–2 for all other genotyped SNPs. Shown by squares are imputed SNPs at this locus, which were imputed from the Stage 1 dataset (see Materials and methods). The intensity of red shading indicates the strength of LD with the index SNP (labelled). Also shown are the SNP-build 36 coordinates in kilobases (kb), recombination rates in centimorgans (cm) per megabase (Mb) (in blue) and the genes in the region (in green).
Figure 3.
Figure 3.
Linkage disequilibrium structure for the new TGCT loci: Plot shows the LD structure for the new TGCT loci at 3q25 (data from Stage 1). rs1510272 is shown as a green triangle, with other genotyped SNPs shown as green bars. The LD block of 51 kb in which rs1510272 resides is outlined in with a thick black line. Other LD blocks, as defined by Oxford recombination hotspots (26), are outlined with thick black lines.

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