TY - JOUR
T1 - Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome
AU - Dapas, Matthew
AU - Sisk, Ryan
AU - Legro, Richard S.
AU - Urbanek, Margrit
AU - Dunaif, Andrea
AU - Hayes, M. Geoffrey
N1 - Funding Information:
Financial Support: This study was supported by National Institutes of Health Grants P50 HD044405 (to A.D.) and R01 HD085227 (to A.D.). M.D. was supported by National Institutes of Health National Research Service Award T32 DK007169. This study uses data from the Scripps Wellderly Genome Resource, which is funded under National Institutes of Health Grant UL1 TR001114 and a Scripps Translational Science Institute Clinical and Translational Science Award.
Funding Information:
This study was supported by National Institutes of Health Grants P50 HD044405 (to A.D.) and R01HD085227 (to A.D.). M.D. was supported by National Institutes of Health National Research Service Award T32 DK007169. This study uses data from the Scripps Wellderly Genome Resource, which is funded under National Institutes of Health Grant UL1 TR001114 and a Scripps Translational Science Institute Clinical and Translational Science Award.
Publisher Copyright:
© 2019 Endocrine Society.
PY - 2019/4/11
Y1 - 2019/4/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071976204&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071976204&partnerID=8YFLogxK
U2 - 10.1210/jc.2018-02496
DO - 10.1210/jc.2018-02496
M3 - Article
C2 - 31038695
AN - SCOPUS:85071976204
SN - 0021-972X
VL - 104
SP - 3835
EP - 3850
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 9
M1 - jcem_201802496
ER -