title: Genome-wide two-locus interaction analysis identifies multiple epistatic SNP pairs that confer risk of prostate cancer: A cross-population study.
abstract: Prostate cancer is one of the most common carcinomas among adult males. Recently, genome-wide association studies (GWAS) have identified several susceptibility genes of prostate cancer. However, these single locus results can only explain a small proportion of the genetic etiology. In order to understand how multiple genetic variants may contribute to the penetrance of prostate cancer, we conducted a genome-wide SNP-SNP interaction study in four populations, involving 5,269 cases and 5,289 controls. We exhaustively evaluated all pairs of SNP-SNP interactions for 661,658 SNPs that were consensus in all four groups, and then performed a meta-analysis to combine the results. We found multiple variants within region 7p21.3 and 18p11.22 significantly interacted with each other and reached genome-wide significance levels. The most significant epistasis was between rs1105255 (intergenic, near RBSG3) and rs651431 (intergenic, near VAPA) (p = 1.4 × 10-14). Notably, VAPA was identified to be the protein-coding transcripts as PTEN competing endogenous RNA in prostate cancer. And PTEN is a critical tumor suppressor gene frequently altered in cancers. In addition, 7p21.3 involves several pseudogenes, whose parental genes are cancer-related. Recently, growing evidence strongly suggests they are of multifaceted involvements in the pathogenesis of cancer. Multiple regulatory elements were found within 7p21.3 and 18p11.22, indicating the variants might regulate the nearby genes and confer risk of disease. Additionally, we also found several other significant epistasis, most of which were near or in cancer-related genes. Drug target enrichment analysis suggested genes in top epistasis significantly overlapped with target genes of FDA-approved drugs for treatment of prostate cancer.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China.|Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Shen
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China.|The Biomedical Sciences Institute of Qingdao University, Qingdao Branch of SJTU Bio-X Institutes, Qingdao, 266071, People's Republic of China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Song
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chen
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China.|The Biomedical Sciences Institute of Qingdao University, Qingdao Branch of SJTU Bio-X Institutes, Qingdao, 266071, People's Republic of China.|Department of Psychiatry, The First Teaching Hospital of Xinjiang Medical University, Urumqi, People's Republic of China.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics
chemical_list: C486483:CTDSPL protein, human; D025521:Tumor Suppressor Proteins; C114051:VAPA protein, human; D033921:Vesicular Transport Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: epistasis; genetics; genome-wide; prostate cancer