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Genome-wide association studies and epistasis analyses of candidate genes related to age at menarche and age at natural menopause in a Korean population

Pyun, Jung-A. MS1; Kim, Sunshin PhD1; Cho, Nam H. PhD2; Koh, InSong MD, PhD3; Lee, Jong-Young PhD4; Shin, Chol MD, PhD5; Kwack, KyuBum PhD1

doi: 10.1097/GME.0b013e3182a433f7
Original Articles

Objective: The aim of this study was to identify polymorphisms and gene-gene interactions that are significantly associated with age at menarche and age at menopause in a Korean population.

Methods: A total of 3,452 and 1,827 women participated in studies of age at menarche and age at natural menopause, respectively. Linear regression analyses adjusted for residence area were used to perform genome-wide association studies (GWAS), candidate gene association studies, and interactions between the candidate genes for age at menarche and age at natural menopause.

Results: In GWAS, four single nucleotide polymorphisms (SNPs; rs7528241, rs1324329, rs11597068, and rs6495785) were strongly associated with age at natural menopause (lowest P = 9.66 × 10−8). However, GWAS of age at menarche did not reveal any strong associations. In candidate gene association studies, SNPs with P < 0.01 were selected to test their synergistic interactions. For age at natural menopause, there was a significant interaction between intronic SNPs on ADAM metallopeptidase with thrombospondin type I motif 9 (ADAMTS9) and SMAD family member 3 (SMAD3) genes (P = 9.52 × 10−5). For age at menarche, there were three significant interactions between three intronic SNPs on follicle-stimulating hormone receptor (FSHR) gene and one SNP located at the 3′ flanking region of insulin-like growth factor 2 receptor (IGF2R) gene (lowest P = 1.95 × 10−5).

Conclusions: Novel SNPs and synergistic interactions between candidate genes are significantly associated with age at menarche and age at natural menopause in a Korean population.

From the 1Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Republic of Korea; 2Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Republic of Korea; 3Department of Physiology, Hanyang University College of Medicine, Seoul, Republic of Korea; 4Center for Genome Science, National Institute of Health, Osong, Republic of Korea; and 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Republic of Korea.

Received April 8, 2013; revised and accepted July 1, 2013.

Funding/support: This study was supported by the Korea Centers for Disease Control and Prevention (grants 4845-301, 4851-302, and 4851-307) and the Basic Science Research Program of the National Research Foundation of Korea (grants 2009-0093821 and 2011-0010637), which is funded by the Ministry of Education.

Financial disclosure/conflicts of interest: None reported.

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Address correspondence to: KyuBum Kwack, PhD, Department of Biomedical Science, College of Life Science, CHA University, 222 Yatap-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-836, Republic of Korea. E-mail:;

© 2014 by The North American Menopause Society.