Novel pleiotropic variants associated with type 2 diabetes and polycystic ovary syndrome detected using a pleiotropic cFDR method

Genome-wide association studies (GWASs) on polycystic ovary syndrome (PCOS) and type 2 diabetes (T2D) are usually conducted as single trait, rather than a simultaneous analysis of the related traits. Therefore, the overlapping genetic mechanisms underlying those traits were largely unknown.

This study aims to investigate the overlapping genetic mechanisms between type 2 diabetes and polycystic ovary syndrome and discover the novel pleiotropic variants between those two traits.

We used an established genetic pleiotropic conditional false discovery rate (cFDR) approach to discover novel loci associated with PCOS and T2D by incorporating the summary statistics from existing GWASs of these two traits. Lab experiment was also conducted to verify the identified pleiotropic loci. Mendelian randomization approach was also performed to clarify the causal relationship between those two.

Both conditional Q-Q and fold enrichment plots were present to demonstrate the pleiotropic enrichment between PCOS and T2D. Using the cFDR level of 0.05, we identified 5 loci for PCOS, 1441 loci for T2D, and five of them were associated with both and were validated in the lab experiment. Significant pleiotropic enrichment was observed between PCOS and T2D. However, we did not observe any causal association between PCOS and T2D.

These findings may provide novel insights into the etiology of PCOS and T2D and may further influence the disease development both individually and jointly.