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The genetic architecture of age at menarche and its causal effects on other traits

Journal of Human Genetics volume 69, pages 645–653 (2024)Cite this article

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Abstract

Age at menarche (AAM) is a sign of puberty of females. It is a heritable trait associated with various adult diseases. However, the genetic mechanism that determines AAM and links it to disease risk is poorly understood. Aiming to uncover the genetic basis for AAM, we conducted a joint association study in up to 438,089 women from 3 genome-wide association studies of European and East Asian ancestries. A series of bioinformatical analyses and causal inference were then followed to explore in-depth annotations at the associated loci and infer the causal relationship between AAM and other complex traits/diseases. This largest meta-analysis identified a total of 21 novel AAM associated loci at the genome wide significance level (P < 5.0  × 10−8), 4 of which were European ancestry-specific loci. Functional annotations prioritized 33 candidate genes at newly identified loci. Significant genetic correlations were observed between AAM and 67 complex traits. Further causal inference demonstrated the effects of AAM on 13 traits, including forced vital capacity (FVC), high blood pressure, age at first live birth, etc, indicating that earlier AAM causes lower FVC, worse lung function, hypertension and earlier age at first (last) live birth. Enrichment analysis identified 5 enriched tissues, including the hypothalamus middle, hypothalamo hypophyseal system, neurosecretory systems, hypothalamus and retina. Our findings may provide useful insights that elucidate the mechanisms determining AAM and the genetic interplay between AAM and some traits of women.

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Data availability

Genome-wide summary statistics from the three samples are available to download from the following websites: (i) the ReproGen Consortium (http://www.reprogen.org/); (ii) the BBJ sample (https://humandbs.biosciencedbc.jp/en/) under data set identifier hum0014.v9.Men.v1and hum0014.v9.MP.v1.

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Acknowledgements

We acknowledge the Reproductive Genetics Consortium, the Biobank Japan project and UK Biobank Cohort for releasing the age at menarche GWAS summary results.

Funding

YFP is benefited from national natural science foundation of China (32170670), a project funded by the Priority Academic Program Development (PAPD) of Jiangsu higher education institutions.

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Authors and Affiliations

  1. The First People’s Hospital of Lianyungang, Jiangsu, PR China

    Gui-Juan Feng

  2. Department of Epidemiology and Biostatistics, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, PR China

    Gui-Juan Feng, Qian Xu, Qi-Gang Zhao, Bai-Xue Han, Shan-Shan Yan & Yu-Fang Pei

  3. Department of Gynaecology and Obstetrics, Suzhou Ninth Hospital Affiliated to Soochow University, 2666 Lu‑dang Rd., Wujiang District, Suzhou, 215200, Jiangsu, China

    Jie Zhu

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Contributions

Gui-Juan Feng: Analysis and interpretation of data, writing-original draft and review. Qian Xu: Conception and design of the work. Bai-Xue Han: Analysis and interpretation of data. Qi-Gang Zhao: Acquisition of data. Shan-Shan Yan: Writing-critical review and supervision. Jie Zhu: Conceptualization, Interpretation of data, writing-review and editing. Yu-Fang Pei: Conceptualization, Interpretation of data, writing-critical review and editing.

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Correspondence to Jie Zhu or Yu-Fang Pei.

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Feng, GJ., Xu, Q., Zhao, QG. et al. The genetic architecture of age at menarche and its causal effects on other traits. J Hum Genet 69, 645–653 (2024). https://doi.org/10.1038/s10038-024-01287-w

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