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: Roelof Koster, Nandita Mitra, Kurt D'Andrea, Saran Vardhanabhuti, Charles C Chung, Zhaoming Wang, R Loren Erickson, David J Vaughn, Kevin Litchfield, Nazneen Rahman, Mark H Greene, Katherine A McGlynn, Clare Turnbull, Stephen J Chanock, Katherine L Nathanson, Peter A Kanetsky
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 22 Pg. 6061-8 (Nov 15 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 24943593 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• DMRT1 protein
• Genetic Markers
• Transcription Factors

Topics

• Case-Control Studies
• Female
• Genetic Markers
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genotype
• Humans
• Male
• Neoplasms, Germ Cell and Embryonal (genetics)
• Polymorphism, Single Nucleotide
• Sex Determination Processes
• Testicular Neoplasms (genetics)
• Transcription Factors (genetics)