Integrating expression‐related SNPs into genome‐wide gene‐ and pathway‐based analyses identified novel lung cancer susceptibility genes

Abstract

Traditional pathway analysis map single nucleotide polymorphisms (SNPs) to genes according to physical position, which lacks sufficient biological bases. Here, we incorporated genetics of gene expression into gene- and pathway-based analysis to identify genes and pathways associated with lung cancer risk. We identified expression-related SNPs (eSNPs) in lung tissues and integrated these eSNPs into three lung cancer genome-wide association studies (GWASs), including 12,843 lung cancer cases and 12,639 controls. We used SKAT-C for gene-based analysis, and conditional analysis to identify independent eSNPs of each gene. ARTP algorithm was used for pathway analysis. A total of 374,382 eSNPs in the GWAS datasets survived quality control, which were mapped to 5,084 genes and 2,752 pathways. In the gene-based analysis, nine genes showed significant associations with lung cancer risk. Among them, TP63 (3q28), RP11-650L12.2 (15q25.1) and CHRNA5 (15q25.1) were located in known lung cancer susceptibility loci. We also validated two newly identified susceptibility loci (RNASET2 and AL133458.1 in 6q27, and MPZL3 in 11q23.3). Besides, DVL3 (3q27.1), RP11-522I20.3 (9q21.32) and CCDC116 (22q11.21) were identified as novel lung cancer susceptibility genes. Pathway analysis showed that pathways involved in protein structure, the Notch signaling pathway and the nicotinic acetylcholine receptor-related pathways were associated with lung cancer risk. Combing eSNPs, gene- and pathway-based analysis identifies novel lung cancer susceptibility genes, which serves as a powerful approach to decipher biological mechanisms underlying GWAS findings.

Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci

“…SKAT is a powerful approach to identify phenotype-related regions (for example, genes and other moving windows across the genome) by combining the effects of both common and rare variants in the same region. This method has been widely applied in previous studies and multiple novel traitrelated genes were successfully identified, including novel oncogenes in lung cancer (21)(22)(23).…”

Identification of an early diagnostic biomarker of lung adenocarcinoma based on co-expression similarity and construction of a diagnostic model

“…In conclusion, the traditional method of finding disease markers is mostly dependent on the expression level of single genes. The assumption is that each gene is relatively independent, so the doctor will use the selected gene’s characteristics to design diagnostic kits, make the combination of chips or sequencing, and predict the risk of illness based on gene expression [ 9 ]. However, in organisms, the gene is not relatively independent, and there is a functional interaction.…”

Biomarkers Associated with CD8+ T Cell Infiltration in Childhood AML

“…Studies have shown that expression of MPZL3 is associated with different cancer types. A previous study reports that MPZL3 is a associated with lung cancer susceptibility 22 . A study on microarray analysis showed that MPZL3 is highly expressed in rectal cancer cells 23 .…”