title: Genome-wide two-locus epistasis scans in prostate cancer using two European populations.
abstract: Approximately 40 single nucleotide polymorphisms (SNPs) that are associated with prostate cancer (PCa) risk have been identified through genome-wide association studies (GWAS). However, these GWAS-identified PCa risk-associated SNPs can explain only a small proportion of heritability (~13%) of PCa risk. Gene-gene interaction is speculated to be one of the major factors contributing to the so-called missing heritability. To evaluate the gene-gene interaction and PCa risk, we performed a two-stage genome-wide gene-gene interaction scan using a novel statistical approach named "Boolean Operation-based Screening and Testing". In the first stage, we exhaustively evaluated all pairs of SNP-SNP interactions for ~500,000 SNPs in 1,176 PCa cases and 1,101 control subjects from the National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) study. No SNP-SNP interaction reached a genome-wide significant level of 4.4E-13. The second stage of the study involved evaluation of the top 1,325 pairs of SNP-SNP interactions (P(interaction) <1.0E-08) implicated in CGEMS in another GWAS population of 1,964 PCa cases from the Johns Hopkins Hospital (JHH) and 3,172 control subjects from the Illumina iControl database. Sixteen pairs of SNP-SNP interactions were significant in the JHH population at a P(interaction) cutoff of 0.01. However, none of the 16 pairs of SNP-SNP interactions were significant after adjusting for multiple tests. The current study represents one of the first attempts to explore the high-dimensional etiology of PCa on a genome-wide scale. Our results suggested a list of SNP-SNP interactions that can be followed in other replication studies.
authors.affiliation: Center for Genetic Epidemiology and Prevention, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Tao
authors.forename: Junjie
authors.initials: J
authors.lastname: Feng
authors.forename: Timothy
authors.initials: T
authors.lastname: Webster
authors.forename: Guangfu
authors.initials: G
authors.lastname: Jin
authors.forename: Fang-Chi
authors.initials: FC
authors.lastname: Hsu
authors.forename: Shyh-Huei
authors.initials: SH
authors.lastname: Chen
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Siqun L
authors.initials: SL
authors.lastname: Zheng
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Jielin
authors.initials: J
authors.lastname: Sun
mesh_terms: D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000208:ethnology* / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics*