title: FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome.
abstract: Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (χ(2) = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism.
authors.affiliation: Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Ewens
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Jones
authors.forename: Wendy
authors.initials: W
authors.lastname: Ankener
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Stewart
authors.forename: Margrit
authors.initials: M
authors.lastname: Urbanek
authors.forename: Andrea
authors.initials: A
authors.lastname: Dunaif
authors.forename: Richard S
authors.initials: RS
authors.lastname: Legro
authors.forename: Angela
authors.initials: A
authors.lastname: Chua
authors.forename: Ricardo
authors.initials: R
authors.lastname: Azziz
authors.forename: Richard S
authors.initials: RS
authors.lastname: Spielman
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
mesh_terms: D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D016022:Case-Control Studies; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009765:Obesity / Q000235:genetics*; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D055815:Young Adult
chemical_list: C470072:MC4R protein, human; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human