Matthew Dapas1, Ryan Sisk1, Richard S Legro2, Margrit Urbanek1,3,4, Andrea Dunaif5, M Geoffrey Hayes1,3,6. 1. Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. 2. Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA. 3. Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. 4. Center for Reproductive Science, Northwestern University Feinberg School of Medicine, Chicago, IL. 5. Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, NY. 6. Department of Anthropology, Northwestern University, Evanston, IL.
Abstract
CONTEXT: Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% 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, Padj=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.
CONTEXT: Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% 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, Padj=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.
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