Dataset Information

Genome-wide association study (GWAS) of ovarian cancer in Japanese predicted regulatory variants in 22q13.1.

ABSTRACT: Genome-wide association studies (GWAS) have identified greater than 30 variants associated with ovarian cancer, but most of these variants were investigated in European populations. Here, we integrated GWAS and subsequent functional analyses to identify the genetic variants with potential regulatory effects. We conducted GWAS for ovarian cancer using 681 Japanese cases and 17,492 controls and found that rs137672 on 22q13.1 exhibited a strong association with a P-value of 1.05 × 10(-7) and an odds ratio of 0.573 with a 95% confidence interval of 0.466-0.703. In addition, three previously reported SNPs, i.e., rs10088218, rs9870207 and rs1400482, were validated in the Japanese population (P < 0.05) with the same risk allele as noted in previous studies. Functional studies including regulatory feature analysis and electrophoretic mobility shift assay (EMSA) revealed two regulatory SNPs in 22q13.1, rs2072872 and rs6509, that affect the binding affinity to some nuclear proteins in ovarian cancer cells. The plausible regulatory proteins whose motifs could be affected by the allele changes of these two SNPs were also proposed. Moreover, the protective G allele of rs6509 was associated with a decreased SYNGR1 expression level in normal ovarian tissues. Our findings elucidated the regulatory variants in 22q13.1 that are associated with ovarian cancer risk.

SUBMITTER: Yodsurang V

PROVIDER: S-EPMC6296504 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Genome-wide association study (GWAS) of ovarian cancer in Japanese predicted regulatory variants in 22q13.1.

Yodsurang Varalee V Tang Yaqi Y Takahashi Yukie Y Tanikawa Chizu C Kamatani Yoichiro Y Takahashi Atsushi A Momozawa Yukihide Y Fuse Nobuo N Sugawara Junichi J Shimizu Atsushi A Fukushima Akimune A Hishida Asahi A Furusyo Norihiro N Naito Mariko M Wakai Kenji K Yamaji Taiki T Sawada Norie N Iwasaki Motoki M Tsugane Shoichiro S Hirata Makoto M Murakami Yoshinori Y Kubo Michiaki M Matsuda Koichi K

PloS one 20181217 12

Genome-wide association studies (GWAS) have identified greater than 30 variants associated with ovarian cancer, but most of these variants were investigated in European populations. Here, we integrated GWAS and subsequent functional analyses to identify the genetic variants with potential regulatory effects. We conducted GWAS for ovarian cancer using 681 Japanese cases and 17,492 controls and found that rs137672 on 22q13.1 exhibited a strong association with a P-value of 1.05 × 10(-7) and an odd ...[more]

PMID: 30557369

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Project description:Genome wide association studies (GWAS) are a population-scale approach to the identification of segments of the genome in which genetic variations may contribute to disease risk. Current methods focus on the discovery of single nucleotide polymorphisms (SNPs) associated with disease traits. As there are many SNPs within identified risk loci, and the majority of these are situated within non-coding regions, a key challenge is to identify and prioritize variants affecting regulatory sequences that are likely to contribute to the phenotype assessed.We focused investigation on SNPs within lung and breast cancer GWAS loci that reached genome-wide significance for potential roles in gene regulation with a specific focus on SNPs likely to disrupt transcription factor binding sites. Within risk loci, the regulatory potential of sub-regions was classified using relevant open chromatin and epigenetic high throughput sequencing data sets from the ENCODE project in available cancer and normal cell lines. Furthermore, transcription factor affinity altering variants were predicted by comparison of position weight matrix scores between disease and reference alleles. Lastly, ChIP-seq data of transcription associated factors and topological domains were included as binding evidence and potential gene target inference.The sets of SNPs, including both the disease-associated markers and those in high linkage disequilibrium with them, were significantly over-represented in regulatory sequences of cancer and/or normal cells; however, over-representation was generally not restricted to disease-relevant tissue specific regions. The calculated regulatory potential, allelic binding affinity scores and ChIP-seq binding evidence were the three criteria used to prioritize candidates. Fitting all three criteria, we highlighted breast cancer susceptibility SNPs and a borderline lung cancer relevant SNP located in cancer-specific enhancers overlapping multiple distinct transcription associated factor ChIP-seq binding sites.Incorporating high throughput sequencing epigenetic and transcription factor data sets from both cancer and normal cells into cancer genetic studies reveals potential functional SNPs and informs subsequent characterization efforts.

Dataset Information

Genome-wide association study (GWAS) of ovarian cancer in Japanese predicted regulatory variants in 22q13.1.

Publications

Genome-wide association study (GWAS) of ovarian cancer in Japanese predicted regulatory variants in 22q13.1.

Similar Datasets

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