title: Parent-of-origin effects on glucose homeostasis in polycystic ovary syndrome.
abstract: BACKGROUND
  Polycystic ovary syndrome (PCOS) is a highly heritable complex trait. Parents of affected women have reproductive and metabolic phenotypes.
  
  
  OBJECTIVE
  We tested the hypothesis that there are parental effects on the heritability of fasting dysglycemia in women with PCOS.
  
  
  METHODS
  This was a cross-sectional study at an academic medical center.
  
  
  METHODS
  PARTICIPANTS included 367 women with PCOS and their parents (1101 total subjects).
  
  
  METHODS
  We compared maternal and paternal contributions to heritability of fasting dysglycemia and to transmission of the PCOS susceptibility allele of D19S884 within the fibrillin-3 gene (D19S884-A8) on fasting dysglycemia.
  
  
  RESULTS
  Fathers had higher fasting glucose levels, prevalence of fasting dysglycemia and proinsulin to insulin molar ratios (P < .0001), a marker of defective insulin processing, compared with mothers. Heritability of fasting dysglycemia was significant in PCOS families (h(2) = 37%, SE = 10%, P = .001). Maternal heritability (h(2) = 51%, SE = 15%, P = .0009) was higher than paternal heritability (h(2) = 23 %, SE = 23%, P = .186) of fasting dysglycemia after adjustment for age and body mass index. Within dysglycemic probands, there was increased maternal compared with paternal transmission of D19S884-A8 (maternal 84% vs paternal 45%, χ(2) = 6.51, P = .011).
  
  
  CONCLUSIONS
  There was a sex difference in the parental metabolic phenotype with fathers having an increased risk of fasting dysglycemia and evidence for pancreatic β-cell dysfunction compared with mothers. However, only maternal heritability had significant effects on the prevalence of fasting dysglycemia in women with PCOS. Furthermore, there were maternal parent-of-origin effects on transmission of D19S884-A8 probands with fasting dysglycemia. These findings suggest that maternal factors, genetic and perhaps epigenetic, contribute to the metabolic phenotype in affected women.
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine (K.K., P.V., R.K.S., L.A., J.Y.L., M.G.H., M.U., A.D.), Department of Medicine, and Department of Preventive Medicine (J.L.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and Department of Obstetrics and Gynecology (R.S.L.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Kristen
authors.initials: K
authors.lastname: Kobaly
authors.forename: Priyathama
authors.initials: P
authors.lastname: Vellanki
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Sisk
authors.forename: Loren
authors.initials: L
authors.lastname: Armstrong
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Jungwha
authors.initials: J
authors.lastname: Lee
authors.forename: M Geoffrey
authors.initials: MG
authors.lastname: Hayes
authors.forename: Margrit
authors.initials: M
authors.lastname: Urbanek
authors.forename: Richard S
authors.initials: RS
authors.lastname: Legro
authors.forename: Andrea
authors.initials: A
authors.lastname: Dunaif
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000235:genetics*; D003430:Cross-Sectional Studies; D005215:Fasting / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011085:Polycystic Ovary Syndrome / Q000097:blood*; D019655:Quantitative Trait, Heritable; D055815:Young Adult
chemical_list: D001786:Blood Glucose