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PCOS Traits Tied to Rare Variants in Testosterone-Related Gene

NEW YORK (GenomeWeb) – A team led by investigators at Northwestern University and the Icahn School of Medicine at Mount Sinai has identified rare genetic variants that appear to influence susceptibility to certain polycystic ovarian syndrome (PCOS) traits.

The researchers did whole-genome sequencing on hundreds of individuals from dozens of families affected by PCOS, uncovering rare, previously unappreciated contributors to PCOS in DENND1A, a gene from a pathway that produces the male hormone testosterone in the ovaries. The findings, which implicated the rare DENND1A variants specifically in reproductive or metabolic features of PCOS, appeared online today in The Journal of Clinical Endocrinology & Metabolism.

"Our findings provide important new insights into the mechanisms by which genetic variation causes PCOS," co-senior and co-corresponding author Andrea Dunaif said in a statement, noting that "rare genetic variants we found may be much better for predicting the condition than the common variants."

Dunaif was based at Northwestern's Feinberg School of Medicine when the study began. She is currently chief of Icahn School of Medicine's endocrinology, diabetes, and bone disease division.

Depending on the specific criteria used, the team noted that some 5 to 15 percent of pre-menopausal women are diagnosed with PCOS, an endocrine condition marked by higher-than-usual levels of male sex hormones, ovulation or fertility problems, and increased risk of other conditions such as type 2 diabetes.

"We hope our results will help uncover some of the involved hereditary mechanisms and ultimately teach us more about the molecular drivers of the disorder," co-senior and co-corresponding author Geoffrey Hayes, an endocrinology, metabolism, and molecular medicine researcher at Northwestern, said in a statement.

The researchers did genome sequencing on 261 individuals from 62 PCOS-prone families, including women with or without PCOS and their parents, generating 56-fold average coverage over more than 96 percent of the genome. From the more than 4 million variants identified in the genomes they saw 339 genes marked by rare, potentially deleterious variants.

None of those variants showed genome-wide significant ties to PCOS status, the team reported, But two coding and 30 non-coding variants in the DENND1A gene did show ties to specific PCOS-related traits such as metabolism or hormone ratios. Among them were nine variants suspected of altering the transcription factor binding motifs, and many more variants fell at sites corresponding with RNA-binding protein motifs.

The researchers noted that those results seemed to line up with prior genome-wide association studies that implicated common variants in DENND1A in PCOS, though the rare variants identified in the current analysis did not appear to be in linkage disequilibrium with common DENND1A alleles identified in past PCOS GWAS.

"Since DENND1A is an important regulator of androgen biosynthesis, these findings provide additional genetic evidence to support our hypothesis that hyperandrogenemia is a core biologic pathway in PCOS," the author wrote. "Our results also suggest that rare non-coding variants contribute to the distinctive hormonal profile of PCOS."

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