Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry

J Clin Endocrinol Metab. 2012 Jul;97(7):E1342-7. doi: 10.1210/jc.2011-3478. Epub 2012 Apr 30.

Abstract

Context: A genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry.

Objective: The objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry.

Design: This was a case-control study.

Setting: The study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States.

Patients: Cases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively.

Intervention: There were no interventions.

Main outcomes: Main outcomes were allele frequencies for seven variants in PCOS cases and controls.

Results: Two strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria.

Conclusions: We replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Asian Continental Ancestry Group / genetics
  • Case-Control Studies
  • Death Domain Receptor Signaling Adaptor Proteins / genetics*
  • European Continental Ancestry Group / genetics*
  • European Continental Ancestry Group / statistics & numerical data
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Middle Aged
  • Mutation* / physiology
  • Polycystic Ovary Syndrome / diagnosis
  • Polycystic Ovary Syndrome / epidemiology
  • Polycystic Ovary Syndrome / ethnology
  • Polycystic Ovary Syndrome / genetics*
  • Polymorphism, Single Nucleotide / physiology
  • Young Adult

Substances

  • DENND1A protein, human
  • Death Domain Receptor Signaling Adaptor Proteins
  • Guanine Nucleotide Exchange Factors