A genetic analysis of nearly 900 women with polycystic ovary syndrome (PCOS) identified 2 distinct subtypes of the disease with unique genetic variants and underlying biological mechanisms, according to study results published in PLOS Medicine.
There are several common diagnostic criteria for PCOS, but they do not differentiate between biologically and genetically distinct disease subtypes. The goal of the current study was to explore phenotypic subtypes of PCOS and identify genetic variants associated with each of these subtypes.
Clinical, biochemical, and genotyped data from a previous PCOS genome-wide association study (GWAS) were used. Cluster analysis, a technique used to aggregate similar data, was performed in a genotyped sample of 893 women with PCOS (median age, 28 years) and the clusters were replicated in an independent, ungenotyped sample of 263 women with PCOS.
The clustering suggested there are 2 distinct PCOS subtypes: a reproductive subtype (23%; 207 patients) and a metabolic subtype (37%; 329 patients). The former was characterized by higher luteinizing hormone and sex-hormone binding globulin levels, along with low body mass index (BMI) and insulin levels. The main features of the latter subtype included higher BMI and glucose and insulin levels, with lower luteinizing hormone and sex-hormone binding globulin levels. The remainder of the cohort (40%; 357 patients) had an indeterminate phenotypic pattern.
When replicated in an independent cohort, the results were unchanged, with a similar distribution of the reproductive (26%), metabolic (39%), and indeterminate (35%) subtypes.
In a GWAS, alleles were identified in 4 loci that were associated with the reproductive phenotype and at a single locus that was associated with the metabolic phenotype.
The researchers developed a predictive model and classified the 2 subtypes in a family-based sample of 73 patients with PCOS, including their sisters. The analysis revealed that the PCOS subtypes tended to cluster in families. In addition, the likelihood of having the reproductive subtype was increased for carriers of at least 1 previously reported rare variant in DENND1A.
The researchers acknowledged several study limitations, including the relatively small sample size, inability to replicate the GWAS findings, and enrollment limited to women of European ancestry diagnosed with PCOS according to the National Institutes of Health (NIH) criteria.
“Our findings indicate that further study into the genetic heterogeneity of PCOS is warranted and could lead to a transformation in the way PCOS is classified, studied, and treated,” wrote the researchers.
Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Dapas M, Lin FTJ, Nadkarni GN, et al. Distinct subtypes of polycystic ovary syndrome with novel genetic associations: an unsupervised, phenotypic clustering analysis. PLoS Med. 2020;17(6):e1003132.