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

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

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Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Institute of Pharmaceutical and Biological Sciences, University Claude Bernard Lyon 1, Lyon, France.
Department of Hematology, Teikyo University Chiba Medical Center, Chiba, Japan.
Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.
Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Environmental Medicine and Infectious Disease, Kyushu University, Fukuoka, Japan.
Department of Oral Epidemiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.


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.

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