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Hum Mol Genet. 2014 Nov 15;23(22):6061-8. doi: 10.1093/hmg/ddu305. Epub 2014 Jun 18.

Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors.

Author information

1
Translational Medicine and Human Genetics, Department of Medicine.
2
Department of Biostatistics and Epidemiology.
3
Division of Cancer Epidemiology and Genetics, Department of Health and Human Services,National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
4
Division of Cancer Epidemiology and Genetics, Department of Health and Human Services,National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, Cancer Genome Research Laboratory, Division of Cancer Epidemiology and Genetics, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, USA.
5
Walter Reed Army Institute of Research, Silver Spring, MD, USA and.
6
Division of Hematology-Oncology, Department of Medicine and, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
7
Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.
8
Translational Medicine and Human Genetics, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
9
Department of Biostatistics and Epidemiology, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, peter.kanetsky@moffitt.org.

Abstract

Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We analyzed a custom-built sex determination gene set consisting of 32 genes using three different methods of pathway-based analysis. The sex determination gene set ranked highly compared with canonical gene sets, and it was associated with TGCT (FDRG = 2.28 × 10(-5), FDRM = 0.014 and FDRI = 0.008 for Gene Set Analysis-SNP (GSA-SNP), Meta-Analysis Gene Set Enrichment of Variant Associations (MAGENTA) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) analysis, respectively). The association remained after removal of DMRT1 from the gene set (FDRG = 0.0002, FDRM = 0.055 and FDRI = 0.009). Using data from the NCI GWA scan (582 TGCT cases and 1056 controls) and UK scan (986 TGCT cases and 4946 controls), we replicated these findings (NCI: FDRG = 0.006, FDRM = 0.014, FDRI = 0.033, and UK: FDRG = 1.04 × 10(-6), FDRM = 0.016, FDRI = 0.025). After removal of DMRT1 from the gene set, the sex determination gene set remains associated with TGCT in the NCI (FDRG = 0.039, FDRM = 0.050 and FDRI = 0.055) and UK scans (FDRG = 3.00 × 10(-5), FDRM = 0.056 and FDRI = 0.044). With the exception of DMRT1, genes in the sex determination gene set have not previously been identified as TGCT susceptibility loci in these GWA scans, demonstrating the complementary nature of a pathway-based approach for genome-wide analysis of TGCT.

PMID:
24943593
PMCID:
PMC4204765
DOI:
10.1093/hmg/ddu305
[Indexed for MEDLINE]
Free PMC Article

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