title: Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors.
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.
authors.affiliation: Translational Medicine and Human Genetics, Department of Medicine.
authors.forename: Roelof
authors.initials: R
authors.lastname: Koster
authors.affiliation: Department of Biostatistics and Epidemiology.
authors.forename: Nandita
authors.initials: N
authors.lastname: Mitra
authors.affiliation: Translational Medicine and Human Genetics, Department of Medicine.
authors.forename: Kurt
authors.initials: K
authors.lastname: D'Andrea
authors.affiliation: Department of Biostatistics and Epidemiology.
authors.forename: Saran
authors.initials: S
authors.lastname: Vardhanabhuti
authors.affiliation: Division of Cancer Epidemiology and Genetics, Department of Health and Human Services,National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, USA and.
authors.forename: R
authors.initials: R
authors.lastname: Loren Erickson
authors.affiliation: Division of Hematology-Oncology, Department of Medicine and, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaughn
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Litchfield
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
authors.affiliation: Division of Cancer Epidemiology and Genetics, Department of Health and Human Services,National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Greene
authors.affiliation: Division of Cancer Epidemiology and Genetics, Department of Health and Human Services,National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: McGlynn
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Turnbull
authors.affiliation: Division of Cancer Epidemiology and Genetics, Department of Health and Human Services,National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Translational Medicine and Human Genetics, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Department of Biostatistics and Epidemiology, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA, peter.kanetsky@moffitt.org.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
mesh_terms: D016022:Case-Control Studies; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D019849:Sex Determination Processes; D013736:Testicular Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: C110547:DMRT1 protein; D005819:Genetic Markers; D014157:Transcription Factors