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Genome-wide association study of age at menarche in the Taiwan Biobank suggests NOL4 as a novel associated gene

Journal of Human Genetics volume 68, pages 339–345 (2023)Cite this article

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Abstract

Sexual maturation is a complex physiological process that involves multiple variables, such as genetic and environmental factors. Among females, age at menarche (AM) is a critical milestone for sexual maturation. This study aimed to identify genetic markers of AM using nationwide population cohort data in Taiwan. Females with self-reported AM between 10 and 16 years (N = 39,827) were eligible for the final analysis. To identify genetic signals related to AM, we conducted a genome-wide association study using a linear regression model and split-half meta-analysis method to verify our findings. The Functional Mapping and Annotation web-based platform was used for positional mapping and gene-based and gene-set analyses. The meta-analysis identified four significant loci, i.e., LIN28B (pooled P = 1.39 × 10−21), NOL4 (pooled P = 8.94 × 10−9), GPR45 (pooled P = 4.19 × 10−11), and LOC105373831 (pooled P = 4.37 × 10−8), that were associated with AM. MAGMA gene-based analysis revealed that LIN28B (P = 1.13 × 10−8), NOL4 (P = 2.27 × 10−7), RXRG (P = 4.34 × 10−7), ETV5 (P = 1.75 × 10−6), and HACE1 (P = 1.82 × 10−6) were significantly associated with AM, while the gene-set analysis identified a significantly enriched pathway involving mTOR signaling complex (FDR corrected P = 1.28 × 10−2). The results replicated evidence for several genetic markers associated with AM in the Taiwanese female population. Our analysis identified a novel locus (rs7239368) in NOL4 associated with AM (β = 0.051 ± 0.009 years, pooled P = 8.94 × 10−9), whereas additional research is needed to validate its molecular role in sexual maturation.

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The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was supported by the grant awarded to MCT from the National Cheng Kung University Hospital (NCKUH-10902012).

Author information

Authors and Affiliations

  1. Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Meng-Che Tsai

  2. Department of Genomic Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Meng-Che Tsai

  3. Department of Medical Humanities and Social Medicine, Collage of Medicine, National Cheng Kung University, Tainan, Taiwan

    Meng-Che Tsai

  4. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Meng-Che Tsai & Sheng-Hsiang Lin

  5. Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Chih-Hui Hsu & Sheng-Hsiang Lin

  6. Institute of Statistical Science, Academia Sinica, Taipei, Taiwan

    Shih-Kai Chu

  7. Clinical Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Shih-Kai Chu

  8. School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada

    Marie-Hélène Roy-Gagnon

  9. Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Sheng-Hsiang Lin

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Contributions

MCT obtained the funding, conceived and designed the study, drafted the analytical plan, interpreted the data, and drafted and revised the manuscript. CHH managed the data and conducted the statistical analysis. SKC conducted the statistical analysis, interpreted the results, and critically reviewed the manuscript. MHRG provided advice on the statistical analysis and revised the manuscript. SHL supervised the study, guided the statistical analysis, critically reviewed, and revised the manuscript. All authors have read and agreed to the final version of the manuscript.

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Correspondence to Sheng-Hsiang Lin.

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This research project was approved by the Institutional Review Boards of the National Cheng Kung University and the Taiwan Biobank. Subjects were informed and they consented to participate in the Taiwan Biobank. This secondary analysis was conducted on the de-identified database.

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Tsai, MC., Hsu, CH., Chu, SK. et al. Genome-wide association study of age at menarche in the Taiwan Biobank suggests NOL4 as a novel associated gene. J Hum Genet 68, 339–345 (2023). https://doi.org/10.1038/s10038-023-01124-6

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