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New genetic risk factors in polycystic ovary syndrome found

Researchers at the Institute of Genomics of the University of Tartu have described new links between polycystic ovary syndrome and genetics.

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. It is characterised by irregular periods, high levels of androgen hormones and/or enlarged ovaries with many follicles containing eggs (polycystic ovaries). This can affect fertility and put individuals at risk factor for other metabolic disorders. The prevalence of PCOS among fertile-aged women is as high as 18%. It can produce several phenotypes.

Despite its high prevalence, the origins of PCOS remain unclear. Due to its complex nature, it is likely that both genetics and the environment increase the risk of development. Estimates indicate that the heritability of PCOS is around 70%. Several genome-wide association studies and meta-analysis studies have been conducted and have reported over 20 susceptibility loci. However, these common variants only explain around 10% of heritability. This suggests that rare variants with large effect sizes may contribute to the heritability of PCOS. Nevertheless, identifying such variants is difficult in datasets with large genetic variation.

Leveraging Northern European population history

In a recent study, published in Human Reproduction, researchers utilised the unique population history of Northern European populations to identify novel variants associated with PCOS. More specifically, they used genome-wide association analyses and data from the FinnGen project and the Estonian Biobank. In addition, as previous studies have found a causal role for obesity in PCOS, the team also examined the influence of BMI on the detected associations.

The team identified three novel genome-wide significant associations. Two of the variants were found to be enriched in the Finnish and Estonian populations and were linked with the checkpoint kinase 2 (CHEK2) gene. The third association was a common variant near myosin X (MYO10). The researchers also replicated four previous associations near the genes ERBB4, DENND1A, FSHB and ZBTB16. When adding BMI as a covariate only one of the novel variants remained genome-wide significant (in CHEK2).

This study highlights the value of using isolated populations to perform genetic association studies for identifying rare variants. It also serves as a base for further research into the role of CHEK2 variation in PCOS.

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