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Genome-wide association study of primary dysmenorrhea in the Taiwan Biobank validates associations near the NGF and IL1 gene loci

Journal of Human Genetics volume 67, pages 449–458 (2022)Cite this article

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Abstract

Using the Taiwan Biobank, we aimed to identify traits and genetic variations that could predispose Han Chinese women to primary dysmenorrhea. Cases of primary dysmenorrhea included those who self-reported “frequent dysmenorrhea” in a dysmenorrhea-related Taiwan Biobank questionnaire, and those who have been diagnosed with severe dysmenorrhea by a physician. Controls were those without self-reported dysmenorrhea. Customized Axiom-Taiwan Biobank Array Plates were used to perform whole-genome genotyping, PLINK was used to perform association tests, and HaploReg was used to conduct functional annotations of SNPs and bioinformatic analyses. The GWAS analysis included 1186 cases and 24,020 controls. We identified 53 SNPs that achieved genome-wide significance (P < 5 × 10−8, which clustered in 2 regions. The first SNP cluster was on chromosome 1, and included 24 high LD (R2 > 0.88) variants around the NGF gene (lowest P value of 3.83 × 10−13 for rs2982742). Most SNPs occurred within NGF introns, and were predicted to alter regulatory binding motifs. The second SNP cluster was on chromosome 2, including 7 high LD (R2 > 0.94) variants around the IL1A and IL1B loci (lowest P value of 7.43 × 10−10 for rs11676014) and 22 SNPs that did not reach significance after conditional analysis. Most of these SNPs resided within IL1A and IL1B introns, while 2 SNPs may be in the promoter histone marks or promoter flanking regions of IL1B. To conclude, data from this study suggest that NGF, IL1A, and IL1B may be involved in the pathogenesis of primary dysmenorrhea in the Han Chinese in Taiwan.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Correspondence and requests for materials should be addressed to Chien-Chang Lee (cclee100@gmail.com).

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Acknowledgements

We thank the staff of the Core Labs, the Department of Medical Research, and National Taiwan University Hospital for technical support.

Funding

This study was funded by the Taiwan National Science Foundation Grant NSC 102-2314-B-002 −131 -MY3; National Taiwan University Hospital Grant NTUH.106-P04; Taiwan National Ministry of Science and Technology Grants MOST 104-2314-B-002 −039 -MY3, and MOST 106-2811-B-002-048. No funding bodies had any role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. Yung-Han Chang

    Present address: National Taiwan University Hospital, Taipei, Taiwan

  2. These authors contributed equally: Chieng-Chang Lee, Meng-tse Gabriel Lee.

Authors and Affiliations

  1. Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Chien-Chang Lee, Meng-tse Gabriel Lee, Jasmine Tan, Ke-Ying Su, Tzu-Chun Hsu, Shyr-Chyr Chen, Meng-tse Gabriel Lee, Jasmine Tan, Yung-Han Chang, Sih-Shiang Huang & Chin-Hua Su

  2. School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    Chien-Chang Lee, Ruby Y. J. Huang, Shyr-Chyr Chen & Jasmine Tan

  3. Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan

    I-Hsuan Huang & I-Hsuan Huang

  4. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Zachary R. McCaw

  5. Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Ruby Y. J. Huang

  6. Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Ruby Y. J. Huang

  7. Department of Public Health and Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan

    Po-Hsiu Kuo

  8. Research Center for Genes, Environment and Human Health, National Taiwan University, Taipei, Taiwan

    Po-Hsiu Kuo

  9. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Wan-Ting Hsu

  10. Department of Family Medicine, Taipei City Hospital, Yangming Branch, Taipei, Taiwan

    I-Hsuan Shen

  11. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

    Chung-Yen Huang

  12. National Taiwan University Hospital, Taipei, Taiwan

    Yu-Ting Lee, Jo-Ching Hsiung, Kuei-Yu Liu & Amy HuaiShiuan Huang

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  1. Chien-Chang Lee
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  4. Jasmine Tan
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Consortia

National Taiwan University Hospital, Health Data Science Research Group

  • Meng-tse Gabriel Lee
  • , Jasmine Tan
  • , I-Hsuan Huang
  • , Wan-Ting Hsu
  • , Yung-Han Chang
  • , Yu-Ting Lee
  • , Jo-Ching Hsiung
  • , Kuei-Yu Liu
  • , I-Hsuan Shen
  • , Sih-Shiang Huang
  • , Amy HuaiShiuan Huang
  • , Chin-Hua Su
  •  & Chung-Yen Huang

Contributions

All investigators contributed to the design or execution of the study, and approved the final version. C-CL obtained funding, designed the study, drafted the analytical plan, guided the statistical analysis, interpreted the data, and critically revised the manuscript. M-TL was involved in the study design, guided the analytical plan, guided the statistical analysis, interpreted the data, wrote the final manuscript and point-to-point response. I-HH interpreted the results, and wrote the draft manuscript and point-to-point response. J-T, ZM, K-YS, and T-CH performed the statistical analyses. R-H, and P-HK were involved in grant proposal writing, and critically revised the manuscript. S-CC was involved in grant proposal writing, designed the study, interpreted the data, and critically revised the manuscript.

Corresponding author

Correspondence to Shyr-Chyr Chen.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This research project was approved by the ethics committee of the National Taiwan University Hospital Institutional Review Board and Institutional Review Board of Taiwan Biobank (TWBR10602-05). This database study was performed on de-identified subjects and informed consent was not required.

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Lee, CC., Lee, Mt.G., Huang, IH. et al. Genome-wide association study of primary dysmenorrhea in the Taiwan Biobank validates associations near the NGF and IL1 gene loci. J Hum Genet 67, 449–458 (2022). https://doi.org/10.1038/s10038-022-01023-2

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