Abstract
Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer with genetic susceptibility loci identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) using imputed gene expression levels can identify additional gene-level associations. Here we impute gene expression levels in 6891 cSCC cases and 54,566 controls in the Kaiser Permanente Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort and 25,558 self-reported cSCC cases and 673,788 controls from 23andMe. In a discovery-validation study, we identify 19 loci containing 33 genes whose imputed expression levels are associated with cSCC at false discovery rate < 10% in the GERA cohort and validate 15 of these candidate genes at Bonferroni significance in the 23andMe dataset, including eight genes in five novel susceptibility loci and seven genes in four previously associated loci. These results suggest genetic mechanisms contributing to cSCC risk and illustrate advantages and disadvantages of TWAS as a supplement to traditional GWAS analyses.
Highlights
Cutaneous squamous cell carcinoma is a common skin cancer with genetic susceptibility loci identified in recent genome-wide association studies (GWAS)
We identified ten loci containing single nucleotide polymorphisms (SNPs) whose dosages were associated with Cutaneous squamous cell carcinoma (cSCC) at genome-wide significance, including six loci (5p13, 6p25, 11q14, 15q13, 16q24 and 20q11) containing genes involved in the pigmentation pathway that regulates the synthesis of melanin[9] and four additional susceptibility loci (3p13, 3q28, 6p21 and 9p22), including the HLA class II gene locus at 6p21 that encodes the major histocompatibility complex (MHC) class II proteins
We conducted a two-phase discovery and validation study to test for gene expression level associations with cSCC case/control status, using the Kaiser GERA cohort for discovery and the 23andMe research participant dataset for validation, and using prediXcan tissue-specific gene expression imputation models trained on Genotype-Tissue Expression (GTEx) expression data
Summary
Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer with genetic susceptibility loci identified in recent genome-wide association studies (GWAS). In a discovery-validation study, we identify 19 loci containing 33 genes whose imputed expression levels are associated with cSCC at false discovery rate < 10% in the GERA cohort and validate 15 of these candidate genes at Bonferroni significance in the 23andMe dataset, including eight genes in five novel susceptibility loci and seven genes in four previously associated loci These results suggest genetic mechanisms contributing to cSCC risk and illustrate advantages and disadvantages of TWAS as a supplement to traditional GWAS analyses. An independent cSCC GWAS was performed in 6579 self-reported cSCC cases and 280,558 selfreported non-cSCC controls consented for research with 23andMe, Inc., a personal genetics company, and validated in 825 cSCC cases and 11,518 non-cSCC controls from the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS)[5] This GWAS identified 11 loci containing SNPs associated with cSCC at genome-wide significance, including the six pigmentation loci and 9p22 from the Kaiser GWAS, as well as four additional susceptibility loci (2p22, 7p21, 9q34 and 11q23). TWAS approaches still suffer from challenges in interpreting causality, such as correlated imputed gene expression levels for nearby genes in the same locus[16]
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