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

PLoS One. 2018 Dec 17;13(12):e0209096. doi: 10.1371/journal.pone.0209096. eCollection 2018.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Case-Control Studies
  • Chromosomes, Human, Pair 22 / genetics*
  • Female
  • Genetic Variation*
  • Genome-Wide Association Study*
  • Genotyping Techniques
  • Humans
  • Japan
  • Middle Aged
  • Ovarian Neoplasms / genetics*
  • Polymorphism, Single Nucleotide

Grant support

This study was partially supported by the BioBank Japan project (to KM) and the Tohoku Medical Megabank project (to NF), which is supported by the Ministry of Education, Culture, Sports, Sciences and Technology Japan and the Japan Agency for Medical Research and Development. The JPHC Study has been supported by the National Cancer Center Research and Development Fund since 2011 and was supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan from 1989 to 2010 to ST. The J-MICC Study was supported by Grants-in-Aid for Scientific Research for Priority Areas of Cancer (17015018) and Innovative Areas (221S0001) and the JSPS KAKENHI Grant (16H06277) from the Japan Ministry of Education, Science, Sports, Culture and Technology to KW.