Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome

Nat Commun. 2015 Sep 29;6:8464. doi: 10.1038/ncomms9464.

Abstract

Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ∼2,000 clinically validated cases and ∼100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 × 10(-8)), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 × 10(-9)), higher insulin resistance (P=6 × 10(-4)) and lower serum sex hormone binding globulin concentrations (P=5 × 10(-4)). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 × 10(-8)) and PCOS-susceptibility alleles are associated with higher serum anti-Müllerian hormone concentrations in girls (P=8.9 × 10(-5)). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Aging / physiology
  • Case-Control Studies
  • DNA Repair Enzymes / genetics
  • DNA-Binding Proteins / genetics
  • ErbB Receptors / genetics
  • European Continental Ancestry Group / genetics*
  • Female
  • Follicle Stimulating Hormone, beta Subunit / genetics
  • Genome-Wide Association Study
  • Humans
  • Neoplasm Proteins / genetics
  • Ovary / physiology
  • Phosphoproteins / genetics
  • Polycystic Ovary Syndrome / genetics*
  • Selection, Genetic*
  • Transcription Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Follicle Stimulating Hormone, beta Subunit
  • Neoplasm Proteins
  • Phosphoproteins
  • THADA protein, human
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • ErbB Receptors
  • Rad50 protein, human
  • DNA Repair Enzymes