title: Genome-wide association studies and epistasis analyses of candidate genes related to age at menarche and age at natural menopause in a Korean population.
abstract: 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). 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). 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).
  
  
  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.
authors.affiliation: 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.
authors.forename: Jung-A
authors.initials: JA
authors.lastname: Pyun
authors.forename: Sunshin
authors.initials: S
authors.lastname: Kim
authors.forename: Nam H
authors.initials: NH
authors.lastname: Cho
authors.forename: InSong
authors.initials: I
authors.lastname: Koh
authors.forename: Jong-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Chol
authors.initials: C
authors.lastname: Shin
authors.forename: KyuBum
authors.initials: K
authors.lastname: Kwack
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071119:ADAMTS9 Protein; D000328:Adult; D044466:Asian People; D004843:Epistasis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008572:Menarche / Q000235:genetics*; D008593:Menopause / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017527:Receptor, IGF Type 2 / Q000235:genetics; D011962:Receptors, FSH / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics; D055815:Young Adult
chemical_list: D017527:Receptor, IGF Type 2; D011962:Receptors, FSH; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human