title: Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts.
abstract: BACKGROUND
  Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined.
  
  
  RESULTS
  The study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (p(combined cohorts)=10(-8)); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80% power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40%) for LHCGR at p=0.0001. The study had sufficient power (57-88%) for LHCGR at p=0.01.
  
  
  CONCLUSIONS
  At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Jones
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.forename: Angela K
authors.initials: AK
authors.lastname: Chua
authors.forename: Obed A
authors.initials: OA
authors.lastname: Garcia
authors.forename: Yii-Der I
authors.initials: YD
authors.lastname: Chen
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Wendy
authors.initials: W
authors.lastname: Ankener
authors.forename: Richard S
authors.initials: RS
authors.lastname: Legro
authors.forename: Ricardo
authors.initials: R
authors.lastname: Azziz
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
authors.forename: Andrea
authors.initials: A
authors.lastname: Dunaif
authors.forename: Margrit
authors.initials: M
authors.lastname: Urbanek
mesh_terms: D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C571984:DENND1A protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; C477698:THADA protein, human