GWAS of five gynecologic diseases and cross-trait analysis in Japanese

Tatsuo Masuda, Siew‐Kee Low, Masato Akiyama, Makoto Hirata, Yutaka Ueda, Koichi Matsuda, Tadashi Kimura, Yoshinori Murakami, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada
European journal of human genetics : EJHG · 2019 · vol. 28(1) , pp. 95–107 · doi:10.1038/s41431-019-0495-1 · PMID:31488892 · PMC6906293 · W2971673405
article OA: gold CC0 ⤵ 14 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-10 ⓘ

Genome-wide association studies in Japanese women identified nine significant associations with gynecologic diseases, including four novel loci, and revealed strong genetic correlations between ovarian cancer and endometrial cancer/endometriosis.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

This study conducted genome-wide association studies in 46,837 Japanese participants (5,236 uterine fibroid, 645 endometriosis, 647 ovarian cancer, 909 uterine endometrial cancer, and 538 uterine cervical cancer cases, plus 39,556 shared female controls) from Biobank Japan, using logistic regression, a linear mixed model (BOLT-LMM), and summary-statistics correlation methods (MTAG) with population-specific genotype imputation. Across analyses and meta-analytic approaches that accounted for overlapping subjects, the authors report multiple significant loci and estimate heritability ranging from 0.026 for ovarian cancer to 0.220 for endometriosis, along with stronger genetic correlations among ovarian cancer, uterine endometrial cancer, and endometriosis than between uterine cervical cancer and the other diseases. A key limitation is that known risk gene carrier status (e.g., BRCA1/BRCA2), histopathologic subtypes, and clinical severity were not considered, which could obscure signals. Relevance to endometriosis: endometriosis was one of the five gynecologic diseases studied, contributing to novel loci discovery, heritability estimation, and genetic correlations with ovarian and uterine endometrial cancers.

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Abstract

We performed genome-wide association studies of five gynecologic diseases using data of 46,837 subjects (5236 uterine fibroid, 645 endometriosis, 647 ovarian cancer (OC), 909 uterine endometrial cancer (UEC), and 538 uterine cervical cancer (UCC) cases allowing overlaps, and 39,556 shared female controls) from Biobank Japan Project. We used the population-specific imputation reference panel (n = 3541), yielding 7,645,193 imputed variants. Analyses performed under logistic model, linear mixed model, and model incorporating correlations identified nine significant associations with three gynecologic diseases including four novel findings (rs79219469:C > T, LINC02183, P = 3.3 × 10−8 and rs567534295:C > T, BRCA1, P = 3.1 × 10−8 with OC, rs150806792:C > T, INS-IGF2, P = 4.9 × 10−8 and rs140991990:A > G, SOX9, P = 3.3 × 10−8 with UCC). Random-effect meta-analysis of the five GWASs correcting for the overlapping subjects suggested one novel shared risk locus (rs937380553:A > G, LOC730100, P = 2.0 × 10−8). Reverse regression analysis identified three additional novel associations (rs73494486:C > T, GABBR2, P = 4.8 × 10−8, rs145152209:A > G, SH3GL3/BNC1, P = 3.3 × 10−8, and rs147427629:G > A, LOC107985484, P = 3.8 × 10−8). Estimated heritability ranged from 0.026 for OC to 0.220 for endometriosis. Genetic correlations were relatively strong between OC and UEC, endometriosis and OC, and uterine fibroid and OC (rg > 0.79) compared with relatively weak correlations between UCC and the other four (rg = −0.08 ~ 0.25). We successfully identified genetic associations with gynecologic diseases in the Japanese population. Shared genetic effects among multiple related diseases may help understanding the pathophysiology.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Leiomyoma Ovarian Neoplasms Polymorphism, Single Nucleotide Uterine Neoplasms BRCA1 Protein BRCA1 Protein Endometriosis Female Humans Japan Leiomyoma Mutant Chimeric Proteins Mutant Chimeric Proteins Ovarian Neoplasms SOX9 Transcription Factor SOX9 Transcription Factor Uterine Neoplasms

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