Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis

Autoři: Matthew Dapas aff001;  Frederick T. J. Lin aff001;  Girish N. Nadkarni aff002;  Ryan Sisk aff001;  Richard S. Legro aff003;  Margrit Urbanek aff001;  M. Geoffrey Hayes aff001;  Andrea Dunaif aff007
Působiště autorů: Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America aff001;  Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff002;  Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, Pennsylvania, United States of America aff003;  Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America aff004;  Center for Reproductive Science, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America aff005;  Department of Anthropology, Northwestern University, Evanston, Illinois, United States of America aff006;  Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff007
Vyšlo v časopise: Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis. PLoS Med 17(6): e32767. doi:10.1371/journal.pmed.1003132
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003132



Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive-age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive of an underlying genetic heterogeneity, but a recent meta-analysis of European ancestry PCOS cases found that the genetic architecture of PCOS defined by different diagnostic criteria was generally similar, suggesting that the criteria do not identify biologically distinct disease subtypes. We performed this study to test the hypothesis that there are biologically relevant subtypes of PCOS.

Methods and findings

Using biochemical and genotype data from a previously published PCOS genome-wide association study (GWAS), we investigated whether there were reproducible phenotypic subtypes of PCOS with subtype-specific genetic associations. Unsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped cohort of 893 PCOS cases (median and interquartile range [IQR]: age = 28 [25–32], body mass index [BMI] = 35.4 [28.2–41.5]). The clusters were replicated in an independent, ungenotyped cohort of 263 PCOS cases (median and IQR: age = 28 [24–33], BMI = 35.7 [28.4–42.3]). The clustering revealed 2 distinct PCOS subtypes: a “reproductive” group (21%–23%), characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low BMI and insulin levels, and a “metabolic” group (37%–39%), characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels. We performed a GWAS on the genotyped cohort, limiting the cases to either the reproductive or metabolic subtypes. We identified alleles in 4 loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN, P = 2.2 × 10−10; IQCA1, P = 2.8 × 10−9; BMPR1B/UNC5C, P = 9.7 × 10−9; CDH10, P = 1.2 × 10−8) and one locus that was significantly associated with the metabolic subtype (KCNH7/FIGN, P = 1.0 × 10−8). We developed a predictive model to classify a separate, family-based cohort of 73 women with PCOS (median and IQR: age = 28 [25–33], BMI = 34.3 [27.8–42.3]) and found that the subtypes tended to cluster in families and that carriers of previously reported rare variants in DENND1A, a gene that regulates androgen biosynthesis, were significantly more likely to have the reproductive subtype of PCOS. Limitations of our study were that only PCOS cases of European ancestry diagnosed by National Institutes of Health (NIH) criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated.


In conclusion, we have found reproducible reproductive and metabolic subtypes of PCOS. Furthermore, these subtypes were associated with novel, to our knowledge, susceptibility loci. Our results suggest that these subtypes are biologically relevant because they appear to have distinct genetic architecture. This study demonstrates how phenotypic subtyping can be used to gain additional insights from GWAS data.

Klíčová slova:

Genetic loci – Genome-wide association studies – Human genetics – Insulin – Molecular genetics – Phenotypes – Polycystic ovary syndrome – Quantitative traits


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Interní lékařství

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PLOS Medicine

2020 Číslo 6

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