title: Pathway analysis of expression-related SNPs on genome-wide association study of basal cell carcinoma.
abstract: Genome-wide association studies (GWASs) have primarily focused on the association between individual genetic markers and risk of disease. We applied a novel approach that integrates skin expression-related single-nucleotide polymorphisms (eSNPs) and pathway analysis for GWAS of basal cell carcinoma (BCC) to identify potential novel biological pathways. We evaluated the associations between 70,932 skin eSNPs and risk of BCC among 2,323 cases and 7,275 controls of European ancestry, and then assigned them to the pathways defined by KEGG, GO, and BioCarta databases. Three KEGG pathways (colorectal cancer, actin cytoskeleton, and BCC), two GO pathways (cellular component disassembly in apoptosis, and nucleus organization), and four BioCarta pathways (Ras signaling, T cell receptor signaling, natural killer cell-mediated cytotoxicity, and links between Pyk2 and Map Kinases) showed significant association with BCC risk with p-value<0.05 and FDR<0.2. These pathways also ranked at top in sensitivity analyses. Two positive controls in KEGG, the hedgehog pathway and the BCC pathway, showed significant association with BCC risk in both main and sensitivity analyses. Our results indicate that SNPs that are undetectable by conventional GWASs are significantly associated with BCC when tested as pathways. Biological studies of these gene groups suggest their potential roles in the etiology of BCC.
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Immaculata
authors.initials: I
authors.lastname: De Vivo
authors.affiliation: Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Tang
authors.affiliation: Department of Epidemiology, Fairbanks School of Public Health, Indiana University, and Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Jiali
authors.initials: J
authors.lastname: Han
mesh_terms: D002280:Basal Cell Carcinoma / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012878:Skin Neoplasms / Q000235:genetics*; D059467:Transcriptome
keywords: basal cell carcinoma (BCC); expression-related SNPs (eSNPs); genome-wide association study (GWAS); pathway analysis; pathway databases