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


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 (


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


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.

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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.

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Correspondence to Shyr-Chyr Chen.

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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).

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