title: Gene variants associated with age at menopause are also associated with polycystic ovary syndrome, gonadotrophins and ovarian volume.
abstract: OBJECTIVE
  Is there a relationship between the genetic risk for polycystic ovary syndrome (PCOS) and genetic variants that influence timing of menopause?
  
  
  CONCLUSIONS
  The genetic risk score, which sums the contribution of variants at all menopause loci, was associated with PCOS.
  
  
  BACKGROUND
  Ovarian parameters and anti-Mullerian hormone levels suggest that women with PCOS should have a later age at menopause.
  
  
  METHODS
  The study was a case-control examination of genetic variants associated with age at menopause in a discovery cohort of women with PCOS (n = 485) and controls (n = 407) from Boston recruited from 2003 to 2012. Replication was performed in women from Greece (cases, n = 884 and controls, n = 311).
  
  
  METHODS
  PCOS was defined by the National Institutes of Health criteria in Boston and Greece (n = 783), with additional subjects fulfilling the Rotterdam criteria (hyperandrogenism, polycystic ovary morphology and regular menses) in Greece (n = 101). Controls in Boston and Greece had regular menstrual cycles and no hyperandrogenism. Allele frequencies for variants previously associated with age at menopause were examined in PCOS cases and controls, along with the relationship to quantitative traits.
  
  
  RESULTS
  The variant rs11668344-G was associated with decreased risk of PCOS (odds ratio: 0.77 [0.59-0.93]; P = 0.004). There was a strong relationship between the late menopause allele rs12294104-T and increased LH levels (β ± SE; 0.26 ± 0.06; P = 5.2 × 10(-5)) and the LH:FSH ratio (0.28 ± 0.06; P = 2.7 × 10(-6)). The minor allele at rs10852344-T was associated with smaller ovarian volume (-0.16 ± 0.05; P = 0.0012). A genetic risk score calculated from 16 independent variants associated with age at menopause was also associated with PCOS (P < 0.02), LH and the LH:FSH ratio (both P < 0.05).
  
  
  CONCLUSIONS
  The variant rs11668344 was not associated with PCOS in the Greek cohort, but results exhibited the same direction of effect as the Boston cohort. However, it is possible that the individual association was a false positive in the Boston cohort.
  
  
  CONCLUSIONS
  The study demonstrates that gene variants known to influence age at menopause are also associated with risk for PCOS. Further, our data suggest that the relationship between age at menopause and PCOS may be explained, at least in part, by effects on LH levels and follicle number. The data point to opposing influences of the genetic variants on both menopausal age and PCOS.
  
  
  BACKGROUND
  The project was supported by award number R01HD065029 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, award number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources and award 1-10-CT-57 from the American Diabetes Association. C.K.W. is a consultant for Takeda Pharmaceuticals.
  
  
  BACKGROUND
  NCT00166569.
authors.affiliation: Department of Anaesthesia and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: R
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Department of Anaesthesia and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Bjonnes
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Patras Medical School, Patras 26500, Greece.
authors.forename: N A
authors.initials: NA
authors.lastname: Georgopoulos
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Patras Medical School, Patras 26500, Greece.
authors.forename: V
authors.initials: V
authors.lastname: Koika
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Patras Medical School, Patras 26500, Greece Division of Endocrinology and Human Reproduction, Second Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki 54621, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Panidis
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, University of Utah, EIHG, 15 N 2030 E, Salt Lake City, UT 84112, USA cwelt@genetics.utah.edu.
authors.forename: C K
authors.initials: CK
authors.lastname: Welt
mesh_terms: D000367:Age Factors; D001900:Boston; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood*; D005787:Gene Frequency / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D006115:Greece; D006801:Humans; D017588:Hyperandrogenism / Q000097:blood / Q000235:genetics; D007986:Luteinizing Hormone / Q000097:blood*; D008593:Menopause / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D010053:Ovary / Q000000981:diagnostic imaging*; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000235:genetics; D014463:Ultrasonography
chemical_list: D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone
keywords: LH; genetic variant; ovarian volume; ultrasound