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Transcriptome-Wide Association Study Identifies Susceptibility Loci and Genes for Age at Natural Menopause

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Abstract

Objective

To identify novel susceptibility genes for age at natural menopause (ANM).

Methods

Using transcription data generated in tissues from normal hypothalami (n = 73) and ovaries (n = 68) and high-density genotyping data provided by the Genotype-Tissue Expression (GTEx) database, we built 16 164 genetic models to predict gene expression across the transcriptome in these tissues. We used these models and summary statistics data from genome-wide association studies (GWAS) of ANM generated in 69 360 women of European ancestry to identify genes with their predicted expression related to ANM.

Results

We found the predicted expression of 34 genes to be significantly associated with ANM at a Bonferroni-corrected threshold of P < 3.09 ×10−6. These include 4 genes located more than 1 Mb away from any previously GWAS-identified ANM-associated variants, 24 genes that reside in known GWAS-identified loci but have not been previously implicated, and 6 genes previously implicated as ANM-associated genes.

Conclusion

Results from this transcriptome-wide association study, which integrated Expression quantitative trait loci (eQTL) data with summary statistics of GWAS of ANM, improves our understanding of the genetics and biology of female reproductive aging.

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Author information

Authors and Affiliations

  1. Department of Medicine, Vanderbilt Epidemiology Center and Division of Epidemiology, Vanderbilt University School of Medicine, 2525 West End Avenue, Suite 600, IMPH, Nashville, TN, 37203, USA

    Jiajun Shi PhD, Lang Wu PhD, Yingchang Lu MD, PhD, Xingyi Guo PhD, Qiuyin Cai MD, PhD, Jirong Long PhD, Wanqing Wen MD, Wei Zheng MD, PhD & Xiao-Ou Shu MD, PhD

  2. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    Bingshan Li PhD

  3. Vanderbilt Genetics Institute, Nashville, TN, USA

    Bingshan Li PhD

Authors
  1. Jiajun Shi PhD
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  2. Lang Wu PhD
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  3. Bingshan Li PhD
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  4. Yingchang Lu MD, PhD
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  5. Xingyi Guo PhD
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  9. Wei Zheng MD, PhD
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  10. Xiao-Ou Shu MD, PhD
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Corresponding author

Correspondence to Xiao-Ou Shu MD, PhD.

Additional information

Authors’ Note

Jiajun Shi, PhD, and Lang Wu, PhD, contributed equally to this study.

X.O.S. and W.Z. conceived the study. L.W. and J.S. contributed to the study design and performed the statistical analyses. J.S. and L.W. drafted the manuscript with significant contributions from X.O.S. and W. Z. Y. L. contributed to the model building. X.G. contributed to the pathway analyses. All authors provided suggestions during the data analyses, participated in data interpretation, and critically reviewed and approved the final manuscript.

The Genotype-Tissue Expression (GTEx) Project data were obtained from the GTEx Portal (https://www.gtexportal.org/home/datasets). Institution of Research: Vanderbilt University School of Medicine.

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Shi, J., Wu, L., Li, B. et al. Transcriptome-Wide Association Study Identifies Susceptibility Loci and Genes for Age at Natural Menopause. Reprod. Sci. 26, 496–502 (2019). https://doi.org/10.1177/1933719118776788

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