title: Han Chinese polycystic ovary syndrome risk variants in women of European ancestry: relationship to FSH levels and glucose tolerance.
abstract: OBJECTIVE
  Are PCOS risk variants identified in women of Han Chinese ethnicity also associated with risk of PCOS or the phenotypic features of PCOS in European women?
  
  
  CONCLUSIONS
  One variant, rs2268361-T, in the intron of FSHR was associated with PCOS and lower FSH levels, while another variant rs705702-G near the RAB5B and SUOX genes was associated with insulin and glucose levels after oral glucose testing in women with PCOS of European ethnicity.
  
  
  BACKGROUND
  Three of the eleven variants associated with PCOS in the Han Chinese genome-wide association studies were also associated with PCOS in at least one European population when corrected for multiple testing (DENND1A, THADA and YAP1). However, additional replication is needed to establish the importance of these variants in European women and to determine the relationship to PCOS phenotypic traits.
  
  
  METHODS
  The study was a case-control examination in a discovery cohort of women with PCOS (n = 485) and controls (n = 407) from Boston (Boston 1). Replication was performed in women from Greece (cases n = 884 and controls n = 311) and an additional cohort from Boston (Boston electronic medical record (EMR); n = 350 cases and n = 1258 controls).
  
  
  METHODS
  Women had PCOS defined by the National Institutes of Health criteria in Boston 1 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. The second cohort from Boston was defined using the EMR and natural language processing. Allele frequencies for variants associated with PCOS in Han Chinese women were examined in PCOS cases and controls, along with the relationship to quantitative traits.
  
  
  RESULTS
  A variant rs2268361-T in an intron of FSHR was associated with PCOS (0.84 [0.76-0.93], OR [95% CI]; P = 0.002). The rs2268361-T was associated with lower FSH levels (-0.15 ± 0.05; P = 0.0029). A variant rs705702-G near RAB5B and SUOX was associated with insulin (-0.16 ± 0.05, P = 0.0029) and glucose levels (-0.20 ± 0.05, P = 0.0002) 120 min after an oral glucose test.
  
  
  CONCLUSIONS
  The study was large and contained replication cohorts, but was limited by a small number of controls in the Greek cohort and a small number of cases in the second Boston cohort. The second Boston group was identified using electronic medical record review, but was validated for the cardinal features of PCOS.
  
  
  CONCLUSIONS
  This study demonstrates a cross-ethnic PCOS risk locus in FSHR in women of European ancestry with PCOS. The variant may influence FSH receptor responsiveness as suggested by the associated change in FSH levels. The relationship between a variant near RAB5B and SUOX and glucose stimulated insulin and glucose levels suggests an influence of one of these genes on glucose tolerance, but the absence of a relationship with PCOS points to potential differences in the international PCOS patient populations.
  
  
  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, award 1-10-CT-57 from the American Diabetes Association and the Partners Healthcare Center for Personalized Genetics Project Grant. 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, USA.
authors.forename: R
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Patras Medical School, Patras, Greece.
authors.forename: N A
authors.initials: NA
authors.lastname: Georgopoulos
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Braaten
authors.affiliation: Department of Anaesthesia and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 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, 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, Greece Division of Endocrinology and Human Reproduction, Second Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Panidis
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, UT, USA cwelt@genetics.utah.edu.
authors.forename: C K
authors.initials: CK
authors.lastname: Welt
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics*
keywords: follicle-stimulating hormone receptor; genome-wide association; polycystic ovary syndrome; single-nucleotide polymorphism