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Pathway analysis of bladder cancer genome-wide association study identifies novel pathways involved in bladder cancer development.

ABSTRACT: Genome-wide association studies (GWAS) are designed to identify individual regions associated with cancer risk, but only explain a small fraction of the inherited variability. Alternative approach analyzing genetic variants within biological pathways has been proposed to discover networks of susceptibility genes with additional effects. The gene set enrichment analysis (GSEA) may complement and expand traditional GWAS analysis to identify novel genes and pathways associated with bladder cancer risk. We selected three GSEA methods: Gen-Gen, Aligator, and the SNP Ratio Test to evaluate cellular signaling pathways involved in bladder cancer susceptibility in a Texas GWAS population. The candidate genetic polymorphisms from the significant pathway selected by GSEA were validated in an independent NCI GWAS. We identified 18 novel pathways (P < 0.05) significantly associated with bladder cancer risk. Five of the most promising pathways (P ? 0.001 in any of the three GSEA methods) among the 18 pathways included two cell cycle pathways and neural cell adhesion molecule (NCAM), platelet-derived growth factor (PDGF), and unfolded protein response pathways. We validated the candidate polymorphisms in the NCI GWAS and found variants of RAPGEF1, SKP1, HERPUD1, CACNB2, CACNA1C, CACNA1S, COL4A2, SRC, and CACNA1C were associated with bladder cancer risk. Two CCNE1 variants, rs8102137 and rs997669, from cell cycle pathways showed the strongest associations; the CCNE1 signal at 19q12 has already been reported in previous GWAS. These findings offer additional etiologic insights highlighting the specific genes and pathways associated with bladder cancer development. GSEA may be a complementary tool to GWAS to identify additional loci of cancer susceptibility.

SUBMITTER: Chen M

PROVIDER: S-EPMC5059113 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Pathway analysis of bladder cancer genome-wide association study identifies novel pathways involved in bladder cancer development.

Chen Meng M Rothman Nathaniel N Ye Yuanqing Y Gu Jian J Scheet Paul A PA Huang Maosheng M Chang David W DW Dinney Colin P CP Silverman Debra T DT Figueroa Jonine D JD Chanock Stephen J SJ Wu Xifeng X

Genes & cancer 20160701 7-8

Genome-wide association studies (GWAS) are designed to identify individual regions associated with cancer risk, but only explain a small fraction of the inherited variability. Alternative approach analyzing genetic variants within biological pathways has been proposed to discover networks of susceptibility genes with additional effects. The gene set enrichment analysis (GSEA) may complement and expand traditional GWAS analysis to identify novel genes and pathways associated with bladder cancer r ...[more]

PMID: 27738493

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Project description:Understanding how genomes encode complex cellular and organismal behaviors has become the outstanding challenge of modern genetics. Unlike classical screening methods, analysis of genetic variation that occurs naturally in wild populations can enable rapid, genome-scale mapping of genotype to phenotype with a medium-throughput experimental design. Here we describe the results of the first genome-wide association study (GWAS) used to identify novel loci underlying trait variation in a microbial eukaryote, harnessing wild isolates of the filamentous fungus Neurospora crassa. We genotyped each of a population of wild Louisiana strains at 1 million genetic loci genome-wide, and we used these genotypes to map genetic determinants of microbial communication. In N. crassa, germinated asexual spores (germlings) sense the presence of other germlings, grow toward them in a coordinated fashion, and fuse. We evaluated germlings of each strain for their ability to chemically sense, chemotropically seek, and undergo cell fusion, and we subjected these trait measurements to GWAS. This analysis identified one gene, NCU04379 (cse-1, encoding a homolog of a neuronal calcium sensor), at which inheritance was strongly associated with the efficiency of germling communication. Deletion of cse-1 significantly impaired germling communication and fusion, and two genes encoding predicted interaction partners of CSE1 were also required for the communication trait. Additionally, mining our association results for signaling and secretion genes with a potential role in germling communication, we validated six more previously unknown molecular players, including a secreted protease and two other genes whose deletion conferred a novel phenotype of increased communication and multi-germling fusion. Our results establish protein secretion as a linchpin of germling communication in N. crassa and shed light on the regulation of communication molecules in this fungus. Our study demonstrates the power of population-genetic analyses for the rapid identification of genes contributing to complex traits in microbial species.

Project description:Understanding how genomes encode complex cellular and organismal behaviors is an outstanding challenge of modern genetics. Unlike classical screening methods, analysis of the genetic variation that occurs naturally in wild populations can enable rapid, genome-scale trait mapping with a medium-throughput experimental design. Here we describe the results of the first genome-wide association analysis (GWAS) of a microbial eukaryote, using wild isolates of the filamentous fungus Neurospora crassa. We transcriptionally profiled each of 112 individuals collected in Louisiana and used RNA-seq data to genotype each strain at thousands of genetic loci genome-wide. We used these genotypes in a mapping analysis of microbial communication. In N. crassa, germinated asexual spores (germlings) sense the presence of other germlings, grow toward them in a coordinated fashion, and fuse. We evaluated germlings of each strain for their ability to chemically sense, chemotropically seek, and undergo cell fusion. GWAS identified one gene, NCU04379 (cse-1, encoding a homolog of neuronal calcium sensor), at which inheritance was strongly associated with the efficiency of germling communication. Deletion of cse-1 significantly lowered germling communication and fusion, and two genes encoding predicted binding partners of CSE-1 were also required for the communication trait. Additionally, mining our association results for signaling and secretion genes with a potential role in germling communication, we validated six more novel determinants of germling communication, including a secreted protease and two other genes whose deletion conferred a novel phenotype of increased communication and multi-germling fusion. These results establish protein secretion as a linchpin of germling communication in N. crassa and shed light on the regulation of communication molecules in this fungus. Our study demonstrates the power of population-genetic analyses for the rapid identification of genes contributing to complex traits in microbial species. 112 mycelial mRNA profiles of 16 hour wild type (WT) Neurospora crassa strains were generated by deep sequencing, using Illumina GAIIx.

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Pathway analysis of bladder cancer genome-wide association study identifies novel pathways involved in bladder cancer development.

Publications

Pathway analysis of bladder cancer genome-wide association study identifies novel pathways involved in bladder cancer development.

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