Article Text

other Versions

PDF
Original article
Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts
  1. Mark O Goodarzi1,2,3,4,
  2. Michelle R Jones1,
  3. Xiaohui Li3,
  4. Angela K Chua1,
  5. Obed A Garcia5,
  6. Yii-Der I Chen2,3,
  7. Ronald M Krauss6,
  8. Jerome I Rotter3,4,
  9. Wendy Ankener7,
  10. Richard S Legro8,
  11. Ricardo Azziz2,4,9,
  12. Jerome F Strauss III10,
  13. Andrea Dunaif5,
  14. Margrit Urbanek5
  1. 1Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
  2. 2Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  3. 3Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  4. 4Department of Medicine, the David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  5. 5Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  6. 6Children's Hospital Oakland Research Institute, Oakland, California, USA
  7. 7Department of Human Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  8. 8Department of Obstetrics and Gynecology, Pennsylvania State College of Medicine, Hershey, Pennsylvania, USA
  9. 9Department of Obstetrics and Gynecology, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia
  10. 10Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia, USA
  1. Correspondence to Dr Margrit Urbanek, Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University School of Medicine, 303 E Chicago Avenue, Tarry 15-717, Chicago, IL 60611, USA; m-urbanek{at}northwestern.edu

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.

Methods and 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 (pcombined 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.

  • PCOS
  • DENND1A
  • THADA
  • genome-wide association study
  • genetic epidemiology
  • endocrinology
  • genetics
  • reproductive medicine
  • obstetrics and gynaecology
  • endocrinology
  • epigenetics
  • obesity
  • diabetes

Statistics from Altmetric.com

Footnotes

  • Funding This study was supported by National Institutes of Health (U54-HD034449 to RSL, JFS, AD, and MU, P50-HD044405 to AD and MU, RR10732 and C06-RR016499 to Pennsylvania State University General Clinical Research Center (GCRC), M01-RR00048 to Northwestern University GCRC, M01-RR10732 and M01-RR02635 to Brigham and Women's Hospital GCRC, R01-HD029364 and K24-HD001346 to RA, R01-HL069757 to RMK, R01-DK079888 to MOG, R01-HD057450 to MU and OAG, and M01-RR00425 to the Harbor-UCLA/CSMC GCRC) and the Winnick Clinical Scholars Award to MOG.

  • Competing interests None.

  • Ethics approval Ethics approval was provided by Massachusetts, California, Pennsylvania, Illinois, Alabama.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Specific genotype and phenotype information will be made available as requested.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.