title: Investigation of six testicular germ cell tumor susceptibility genes suggests a parent-of-origin effect in SPRY4.
abstract: Recent genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with testicular germ cell tumor (TGCT) risk in the genes ATF7IP, BAK1, DMRT1, KITLG, SPRY4 and TERT. In the present study, we validate these associations in a Scandinavian population, and explore effect modification by parental sex and differences in associations between the major histological subtypes seminoma and non-seminoma. A total of 118 SNPs in the six genes were genotyped in a population-based Swedish-Norwegian sample comprising 831 TGCT case-parent triads, 474 dyads, 712 singletons and 3919 population controls. Seven hundred and thirty-four additional SNPs were imputed using reference haplotypes from the 1000 genomes project. SNP-TGCT association was investigated using a likelihood-based association test for nuclear families and unrelated subjects implemented in the software package UNPHASED. Forward stepwise regression within each gene was applied to determine independent association signals. Effect modifications by parent-of-origin and effect differences between histological subtypes were explored. We observed strong association between SNPs in all six genes and TGCT (lowest P-value per gene: ATF7IP 6.2 × 10(-6); BAK1 2.1 × 10(-10); DMRT1 6.7 × 10(-25); KITLG 2.1 × 10(-48); SPRY4 1.4 × 10(-29); TERT 1.8 × 10(-18)). Stepwise regression indicated three independent signals for BAK1 and TERT, two for SPRY4 and one each for DMRT1, ATF7IP and KITLG. A significant parent-of-origin effect was observed for rs10463352 in SPRY4 (maternal odds ratio = 1.72, paternal odds ratio = 0.99, interaction P = 0.0013). No significant effect differences between seminomas and non-seminomas were found. In summary, we validated previously reported genetic associations with TGCT in a Scandinavian population, and observed suggestive evidence of a parent-of-origin effect in SPRY4.
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. robert.karlsson@ki.se
authors: Robert
authors: R
authors: Karlsson
authors: Kristine E
authors: KE
authors: Andreassen
authors: Wenche
authors: W
authors: Kristiansen
authors: Elin L
authors: EL
authors: Aschim
authors: Roy M
authors: RM
authors: Bremnes
authors: Olav
authors: O
authors: Dahl
authors: Sophie D
authors: SD
authors: Fosså
authors: Olbjørn
authors: O
authors: Klepp
authors: Carl W
authors: CW
authors: Langberg
authors: Arne
authors: A
authors: Solberg
authors: Steinar
authors: S
authors: Tretli
authors: Patrik K E
authors: PK
authors: Magnusson
authors: Hans-Olov
authors: HO
authors: Adami
authors: Trine B
authors: TB
authors: Haugen
authors: Tom
authors: T
authors: Grotmol
authors: Fredrik
authors: F
authors: Wiklund
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010290:Parents; D020641:Polymorphism, Single Nucleotide; D018239:Seminoma / Q000235:genetics*; D019098:Telomerase / Q000235:genetics; D013736:Testicular Neoplasms / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics
chemical_list: C494772:BAK1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C499038:SPRY4 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; C509186:TERT protein, human; D019098:Telomerase