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Genetic effects on gestational diabetes mellitus and their interactions with environmental factors among Japanese women

Journal of Human Genetics volume 70, pages 265–273 (2025)Cite this article

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Abstract

Gestational diabetes mellitus (GDM) is common in Japanese women, posing serious risks to mothers and offspring. This study investigated the influence of maternal genotypes on the risk of GDM and examined how these genotypes modify the effects of psychological and dietary factors during pregnancy. We analyzed data from 20,399 women in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort. Utilizing two customized SNP arrays for the Japanese population (Affymetrix Axiom Japonica Array v2 and NEO), we performed a meta-analysis to combine the datasets. Gene-environment interactions were assessed by modeling interaction terms between genome-wide significant single nucleotide polymorphisms (SNPs) and psychological and dietary factors. Our analysis identified two SNP variants, rs7643571 (p = 9.14 × 10−9) and rs140353742 (p = 1.24 × 10−8), located in an intron of the MDFIC2 gene, as being associated with an increased risk of GDM. Additionally, although there were suggestive patterns for interactions between these SNPs and both dietary factors (e.g., carbohydrate and fruit intake) and psychological distress, none of the interaction terms remained significant after Bonferroni correction (p < 0.05/8). While nominal significance was observed in some models (e.g., psychological distress, p = 0.04), the data did not provide robust evidence of effect modification on GDM risk once adjusted for multiple comparisons. These findings reveal novel genetic associations with GDM in Japanese women and highlight the importance of gene-environment interactions in its etiology. Given that previous genome-wide association studies (GWAS) on GDM have primarily focused on Western populations, our study provides new insights by examining an Asian population using a population-specific array.

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Data availability

We will upload our GWAS summary statistics to J-Morp (https://jmorp.megabank.tohoku.ac.jp/), the Japanese Multi Omics Reference Panel, a widely used public database for genomic data in the Japanese population. Individual genotyping results and other cohort data used for the association study are stored in Tohoku Medical Megabank Organization. In response to reasonable requests for these data, we will assemble and share the stored data after approval of the Ethics Committee and the Materials and Information Distribution Review Committee of Tohoku Medical Megabank Organization.

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Funding

This work was supported by the National Institutes of Health (NIH) (grant R21 HD101778)

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Authors and Affiliations

  1. Department of Public Health, Institute of Science Tokyo, Tokyo, Japan

    Tomoki Kawahara, Nobutoshi Nawa & Takeo Fujiwara

  2. Department of Clinical Information Applied Sciences, Institute of Science Tokyo, Tokyo, Japan

    Tomoki Kawahara

  3. Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan

    Keiko Murakami, Akira Narita, Taku Obara, Mami Ishikuro, Masatsugu Orui, Aoi Noda, Genki Shinoda, Yuki Nagata, Satoshi Nagaie, Soichi Ogishima, Junichi Sugawara, Shigeo Kure, Kengo Kinoshita, Atsushi Hozawa, Nobuo Fuse, Gen Tamiya & Shinichi Kuriyama

  4. Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan

    Toshihiro Tanaka

  5. Bioresource Research Center, Institute of Science Tokyo, Tokyo, Japan

    Toshihiro Tanaka

  6. Graduate School of Medicine, Tohoku University, Sendai, Japan

    Hisashi Ohseto, Ippei Takahashi, Taku Obara, Mami Ishikuro, Masatsugu Orui, Aoi Noda & Shinichi Kuriyama

  7. Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA

    Wendy L. Bennett

  8. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Margaret A. Taub

  9. Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Pamela J. Surkan & Takeo Fujiwara

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Contributions

Nobutoshi Nawa, Toshihiro Tanaka, Wendy L. Bennett, Margaret A. Taub, Pamela J. Surkan, Shinichi Kuriyama, and Takeo Fujiwara contributed to the conception and design of the study. Tomoki Kawahara, Nobutoshi Nawa, Pamela J. Surkan, Margaret A. Taub, Wendy L. Bennett, and Takeo Fujiwara contributed to the oversight of this analysis and interpretation of the results. Tomoki Kawahara, Nobutoshi Nawa, and Takeo Fujiwara were responsible for data analysis. Tomoki Kawahara and Nobutoshi Nawa drafted the initial manuscript. Keiko Murakami, Hisashi Ohseto, Ippei Takahashi, Akira Narita, Taku Obara, Mami Ishikuro, Masatsugu Orui, Aoi Noda, Genki Shinoda, Yuki Nagata, Satoshi Nagaie, Soichi Ogishima, Junichi Sugawara, Shigeo Kure, Kengo Kinoshita, Atsushi Hozawa, Nobuo Fuse, and Gen Tamiya contributed to data collection and management. Takeo Fujiwara and Nobutoshi Nawa served as guarantors, with full access to all study data and responsibility for the integrity and accuracy of the data analysis. All authors reviewed, provided critical revisions, and approved the final manuscript.

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Correspondence to Nobutoshi Nawa.

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Competing interests

Funding for the study described in this publication included a subaward agreement to Institute of Science Tokyo, formerly Tokyo Medical and Dental University. PJS also maintains a paid academic appointment at Institute of Science Tokyo. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies.

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Kawahara, T., Nawa, N., Murakami, K. et al. Genetic effects on gestational diabetes mellitus and their interactions with environmental factors among Japanese women. J Hum Genet 70, 265–273 (2025). https://doi.org/10.1038/s10038-025-01330-4

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