Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome

Matthew Dapas, Ryan Sisk, Richard S. Legro, Margrit Urbanek, Andrea Dunaif, M. Geoffrey Hayes

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


Context: Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5% to15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date. Objective: The objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis. Design, Patients, and Methods: We performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis. Results: We found rare variants in DENND1A (P = 5.31 × 10-5, adjusted P = 0.039) that were significantly associated with reproductive and metabolic traits in PCOS families. Conclusions: Common variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

Original languageEnglish (US)
Article numberjcem_201802496
Pages (from-to)3835-3850
Number of pages16
JournalJournal of Clinical Endocrinology and Metabolism
Issue number9
StatePublished - Apr 11 2019

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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