Researchers identify shared genetic variants between testosterone traits and PCOS

By Dr. Sushama R. Chaphalkar, PhD.Reviewed by Lily Ramsey, LLMOct 16 2024

New study uncovers genetic links between testosterone regulation and polycystic ovary syndrome, shedding light on the role of androgens in PCOS development.

​​​​​​​Study: Unveiling the shared genetic architecture between testosterone and polycystic ovary syndrome. Image Credit: Kittyfly/Shutterstock.com

In a genome-wide, cross-trait study published in Scientific Reports, researchers from China investigated the potential genetic association and polygenic overlap between polycystic ovary syndrome (PCOS) and testosterone (T)-related traits.

They found a significant genetic overlap between PCOS and T-related traits, identified shared causal variants, and suggested that androgen abnormalities influence PCOS through genes, including FSHB (beta subunit of the follicle-stimulating hormone).

Background

PCOS is a common endocrine disorder affecting 6–20% of women of reproductive age. It is characterized by three main features: hyperandrogenism (HA), ovulatory dysfunction (OD), and polycystic ovarian morphology (PCOM).

The 1990 criteria from the National Institutes of Health defined PCOS based on HA and OD, while PCOM was additionally included in the 2003 Rotterdam criteria. Hyperandrogenism is now seen as a key factor driving PCOS, linked to ovulatory issues, metabolic dysfunction, insulin resistance, and excess fat accumulation.

T, a key androgen in women, plays a pivotal role in the disorder, with free T and bioavailable T being critical markers of HA in clinical diagnoses. Genome-wide association studies (GWAS) have made progress in understanding the genetic foundations of PCOS and T-related traits, identifying numerous susceptibility loci.

However, previous studies have not fully explored the shared genetic architecture between PCOS and T-related traits. Therefore, researchers in the present study investigated the genetic correlation and shared risk loci between PCOS and three T-related traits.

About the study

The study used GWAS data from 10,074 PCOS cases and 103,164 controls of European descent, as well as United Kingdom (UK) Biobank data of 425,097 participants for examining T-related traits. The genetic correlation between PCOS and T-related characteristics was assessed using linkage disequilibrium score regression (LDSR) and a bivariate causal mixture model (MiXeR).

Shared genetic variants were identified using the cond/conjunctive false discovery rate (conjFDR) method, with a threshold of <0.05 to pinpoint single-nucleotide polymorphisms (SNPs) jointly associated with PCOS and T-related traits.

Functional annotation of these variants was performed using FUMA, linking them to genes based on positional mapping, gene expression, and chromatin interactions. SNPs were further analyzed for regulatory impact using combined annotation-dependent depletion (CADD) scores, RegulomeDB, and their chromatin states.

Results and discussion

A significant genetic overlap was found between PCOS and T-related traits. Total and bioavailable T showed strong positive genetic correlations with PCOS (r_g = 0.212 and 0.433, respectively), while sex hormone-binding globulin (SHBG) showed a negative correlation (r_g = -0.395).

Bivariate MiXeR analysis confirmed these results, showing high levels of polygenic overlap. Notably, 98% of total T-related variants and 68% of bioavailable T variants also impacted PCOS, while 95% of SHBG variants influenced PCOS.  

Conditional quantile-quantile plots further highlighted the enrichment of T-related variants in PCOS but showed weaker effects of PCOS-related variants on T traits.

Four lead SNPs were found to be jointly associated with total T and PCOS, with three of them showing the same effect direction on both traits. Bioavailable T shared six lead SNPs with PCOS, while SHBG shared four, all showing opposite effect directions.

A significant locus on chromosome 11 (rs11031006 and rs11031005) was associated with all three T-related traits and PCOS, with consistent effect directions across traits.

Functional annotation of the lead SNPs shared between PCOS and T-related traits revealed that most were intergenic or intronic, with only one SNP, rs695872, located in an exon region within ATXN2 (ataxin-2), displaying a high CADD score (> 12.37) indicating high deleteriousness.

Another notable locus, rs11031006, was associated with both total and bioavailable T, while its close variant, rs11031005, was significantly linked to SHBG. This locus is located in a long non-coding ribonucleic acid (RNA) segment, with the nearest gene, FSHB, suggesting its potential role in regulating PCOS and testosterone-related traits through FSH synthesis.

This comprehensive study highlights shared genetic influences between PCOS and T-related traits. The findings align with previous literature and clinical observations.

However, the study is limited by the absence of free T data, a focus on European ancestry, and the inclusion of non-hyperandrogenic PCOS patients. In the future, studies involving further validation of the identified causal variants would be required.

Conclusion

In conclusion, the present study confirms that elevated T levels play a key role in PCOS development, revealing significant genetic overlap between T-related traits and PCOS.

Shared genetic loci suggest common biological mechanisms, with FSHB emerging as a potential target for understanding T-related abnormalities in PCOS.

These insights enhance our understanding of how androgen abnormalities contribute to PCOS and open new avenues for targeted research and therapeutic strategies.