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Unraveling time-dependent genetic components underlying alcohol response

Neuropsychopharmacology volume 50, pages 1665–1673 (2025)Cite this article

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Abstract

While numerous studies have examined the subjective response to alcohol as an intermediate phenotype to understand its variability, heritability, and predictive capacity for alcohol-related disorders, in-depth analyses linking alcohol reactivity indicators to genetic factors within a large cohort have been absent. Our study aimed to quantify the exact contribution of each genetic variant relevant to the alcohol metabolism to the variability in alcohol response. Specifically, we focused on two primary genes involved in alcohol metabolism (ALDH2 and ADH1B) and three additional loci (ALDH1B1, ALDH1A1, and GCKR) that have been shown to have significant associations with drinking behaviors in Japanese individuals. We conducted the first study to assess the relationship between subjective response to alcohol (SR), evaluated by various assessment subscales, and genetic factors using an intravenous clamp technique in 429 healthy Japanese young adults. By reducing the dimensionality of the data to assess similarity structures, we identified three distinct clusters of SRs and participants. Each participant cluster exhibited a distinct alcohol response profile shaped by specific genetic contributions. Participant cluster 1 demonstrated the strongest response, followed by participant cluster 2, and then participant cluster 3. Participant cluster 1 may also be the most strongly influenced by the allelic status of ALDH2 and ADH1B. SR patterns varied accordingly, and the enrichment of the ALDH2*2 and ADH1B*2, differed across both participant and subscale clusters. Notably, the three participant clusters closely aligned with the three subscale clusters, highlighting a consistent genotype–phenotype relationship. Furthermore, the proportion of variance explained by these genes also varied across subscale clusters. Contrary to known functions, ADH1B showed associations at later timings when ALDH2 associations attenuate. Our three-cluster classification may improve prevention by enabling early identification of individuals at health risk.

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Fig. 1: Cluster subgrouping of participants into three clusters.
Fig. 2: Comparisons of the scores of BSS, BAES and SHAS measured every 30 min after administering alcohol in the participants with ALDH2 1*1 vs ALDH2 1*2.
Fig. 3: Comparisons of the scores of BSS, BAES and SHAS measured every 30 min after administering alcohol in the participants with ADH1B 1*1 vs ADH1B 1*2 or 2*2.
Fig. 4: Time courses of attribution of tag SNPs in ALDH2 and ADH1B to each subscale.

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Summary Statistics will be available in JENGER (http://jenger.riken.jp/en/).

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Acknowledgements

We thank Ms. Sachiko Hara, Ms. Mayumi Ogawa, Ms. Minori Tsukahara, and Ms. Mitsuko Kotake at the National Hospital Organization Kurihama Medical and Addiction Center for their assistance for conducting alcohol clamp method. We appreciate all the patients who participated in this study. This research was supported by Asahi Quality & Innovations, Ltd., the Japan Agency for Medical Research and Development (AMED) (Grant Numbers: 21ek0109555, 21tm0424220, 21ck0106642, 23ek0410114, and 23tm0424225), and the Japan Society for the Promotion of Science (JSPS) KAKENHI grant JP20H00462. We express our gratitude to all the staff of Asahi Quality & Innovations, Ltd. and BBJ for their assistance.

Funding

This work was supported by Asahi Quality & Innovations, Ltd., Japan Agency for Medical Research and Development (AMED) grants 21ek0109555, 21tm0424220, 21ck0106642, 23ek0410114, and 23tm0424225, Japan Society for the Promotion of Science (JSPS) KAKENHI grant JP20H00462.

Author information

Authors and Affiliations

  1. Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan

    Keiko Hikino & Taisei Mushiroda

  2. Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan

    Ikuo Otsuka & Akitoyo Hishimoto

  3. Sustainable Technology Laboratories, Asahi Quality & Innovations, Ltd., 1-21, Midori 1-Chome, Moriya-shi 302-0106, Ibaraki, Japan

    Shunji Oshima

  4. Department of Psychiatry, Yokohama City University Graduate School of Medicine, 22-2 Seto Kanazawa-ku, Yokohama, Kanagawa, Japan

    Akitoyo Hishimoto

  5. Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology 7-430 Moriokacho, Obu, Aichi, Japan

    Kouichi Ozaki

  6. Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho Tsurumi-ku, Yokohama, Kanagawa, Japan

    Xiaoxi Liu, Yuki Ishikawa & Chikashi Terao

  7. National Hospital Organization Kurihama Medical and Addiction Center, 5 Chome-3-1 Nobi, Yokosuka, Kanagawa, Japan

    Sachio Matsushita

  8. Clinical Research Center, Shizuoka General Hospital, 4 Chome-27-1 Kitaando Aoi Ward, Shizuoka, Japan

    Chikashi Terao

  9. The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada Suruga Ward, Shizuoka, Japan

    Chikashi Terao

Authors
  1. Keiko Hikino
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Contributions

KH, SM, and CT made substantial contributions to the conception and design of the study. SM contributed to the acquisition of data. KH, SO, SM, and CT contributed to the analysis of data. KH, IO, SO, AH, KO, XL, YI, TM, SM, and CT contributed to the interpretation of data. KH drafted the manuscript, and IO, SO, AH, KO, XL, YI, TM, SM, and CT critically revised it for important intellectual content and approved the final version for publication. All authors agree to be accountable for all aspects of the work, ensuring that any questions related to accuracy or integrity are appropriately investigated and resolved.

Corresponding author

Correspondence to Chikashi Terao.

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Hikino, K., Otsuka, I., Oshima, S. et al. Unraveling time-dependent genetic components underlying alcohol response. Neuropsychopharmacol. 50, 1665–1673 (2025). https://doi.org/10.1038/s41386-025-02147-7

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