PLGRKT and Polycystic Ovary Syndrome

The association between PLGRKT and polycystic ovary syndrome (PCOS) has been explored in large-scale genetic studies, revealing a potential role for this locus in the genetic architecture of the disorder (PMID:30566500). The meta‐analysis conducted on European cohorts included 10,074 cases and 103,164 controls, and identified PLGRKT as one of three novel loci associated with PCOS. This robust sample size and replication across multiple diagnostic criteria provide strong initial evidence for the involvement of PLGRKT in PCOS. However, due to the complex nature of PCOS, the effect sizes remain modest and the biological mechanism awaits further clarification. The study design and statistical power support the inclusion of PLGRKT in the panel of risk loci, suggesting that common variants at this locus contribute to disease susceptibility. Overall, the meta‐analysis provides a foundational context for understanding the genetic predisposition to PCOS.

A subsequent study in an Indian cohort, which analyzed 497 women with PCOS diagnosed by Rotterdam criteria and 233 controls, specifically evaluated two variants, including rs10739076, in PLGRKT. In this study, the frequency distribution of the PLGRKT variant was similar between cases and controls, and no significant influence on PCOS risk was observed (PMID:38245954). The contrasting result from this case–control study raises questions about potential ethnic or population-specific effects and highlights the challenges of genetic replication in complex disorders. The lack of association in this smaller cohort tempers the initial findings and calls for further replication across diverse populations. This study thereby contributes conflicting evidence regarding the role of PLGRKT in PCOS risk. The methodological differences between the studies may also account for the divergence in findings.

Genetic evidence for PLGRKT in PCOS is derived from these two large-scale studies, with the meta-analysis providing strong statistical support and the replication study suggesting a null effect in a specific population. While the meta-analysis indirectly implicates PLGRKT based on genome-wide signals, the absence of clear segregation data and a definitive HGVS-coded variant (e.g., a c. variant in the appropriate format) limits the resolution of the genetic evidence. There is currently no complete coding variant available in HGVS nomenclature for PLGRKT from the supplied evidence. Consequently, the genetic evidence rests on common variant associations rather than rare, high-penetrance mutations. Inheritance in PCOS is complex and does not conform to classical Mendelian modes, adding to the interpretative challenge. Overall, the genetic evidence supports a moderate contribution of PLGRKT to PCOS susceptibility.

Functional and experimental evidence for PLGRKT in PCOS remains sparse. No direct functional assays, cellular models, or animal studies have been provided to elucidate a pathogenic mechanism for PLGRKT in the context of PCOS. Although pathway analyses from the meta‐analysis imply a role in metabolic and reproductive processes, the experimental confirmation of these findings is not yet available. The absence of rescue experiments or studies demonstrating concordance between in vitro findings and patient phenotypes limits the functional support for a pathogenic role. Therefore, current functional data are limited and do not substantiate the genetic association on their own. More comprehensive functional studies are warranted to clarify the molecular underpinnings of PLGRKT in PCOS.

In integrating the evidence, the meta‐analysis offers statistically significant support for PLGRKT’s involvement in PCOS, while the replication study in Indian women does not corroborate the association. The genetic findings are reinforced by the large sample size in the meta‐analysis, yet the lack of segregation evidence and a validated HGVS variant highlight the need for additional studies. Furthermore, the limited functional evidence precludes a full mechanistic understanding of how PLGRKT may contribute to the pathogenesis of PCOS. The combined evidence points to a moderately supported association with some conflicting data that underscores the complexity inherent in polygenic traits such as PCOS. Despite these challenges, PLGRKT remains a candidate for further investigation in the context of metabolic and reproductive dysfunction.

Key take‐home sentence: While large meta‐analytic data support an association between PLGRKT and PCOS, conflicting replication and limited functional evidence call for further research to delineate its clinical utility.

References

• PLoS Genetics • 2018 • Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnostic criteria PMID:30566500
• European Journal of Obstetrics, Gynecology, and Reproductive Biology • 2024 • Investigating the association of previously identified genome-wide significant loci (rs10739076 and rs1784692) with PCOS susceptibility and its related traits in Indian women PMID:38245954

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