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PCOS GWAS Points to Consistent Genetic Contributors Across Diagnostic Criteria

NEW YORK (GenomeWeb) - A team from the UK, US, and elsewhere has identified a handful of new risk loci for polycystic ovary syndrome (PCOS), revealing genetic similarities across PCOS cases regardless of the criteria used to diagnose them.

"Only one locus differed significantly in its association by diagnostic criteria," co-corresponding authors Corrine Welt, a researcher affiliated with the University of Utah, and Cecilia Lindgren, a human genetics researcher at the Wellcome Trust Centre for Human Genetics, and their colleagues wrote.

The researchers did a genome-wide association study meta-analysis involving 10,074 individuals with PCOS and 103,164 without, leading to three previously undetected loci and 11 loci linked to the endocrine disorder in the past. Of those, 13 loci were associated with self-reported PCOS and cases diagnosed using National Institutes of Health or Rotterdam criteria.

According to the NIH criteria, PCOS diagnoses are based on excess androgen hormone levels and ovulatory dysfunction, the team explained, which represents roughly 7 percent of reproductive age women around the world. On the other hand, more general criteria from Rotterdam defines PCOS as polycystic ovarian morphology in combination with either hyperandrogenism or ovulatory dysfunction, representing an estimated 15 to 20 percent of women globally.

The team's results, published online this week in PLOS Genetics, saw further ties between the variants contributing to PCOS and those implicated in other metabolic conditions such as obesity, type 2 diabetes, and coronary artery disease, either through direct associations or linkage disequilibrium. Likewise, a Mendelian randomization analysis revealed overlap between PCOS-associated variants and variants linked to traits such as body mass index, insulin levels, timing of menopause, and male-pattern baldness.

"There was genetic evidence for shared biologic pathways between PCOS and a number of metabolic disorders, menopause, depression, and male-pattern balding, a putative male phenotype," the authors wrote.

In their search for new genetic contributors to PCOS, the researchers started with data from 2,540 NIH criteria-based cases, 2,669 cases diagnosed with Rotterdam criteria, and 5,184 individuals with self-reported PCOS enrolled through seven prior studies, ultimately performing a GWAS meta-analysis based on 10,074 PCOS cases and 103,164 controls of European ancestry.

The team saw new associations at loci in or around the PLGRKT, ZBTB16, and MAPRE1 genes, which are believed to contribute to metabolic and reproductive pathways. The meta-analysis also led to 11 known risk loci, which were overrepresented for variants in and around genes from neuroendocrine and metabolic pathways.

The set of known risk loci included half a dozen sites previously implicated in PCOS in women of Han Chinese ancestry, and a variant near the GATA4/NEIL2 genes that showed strong ties to the PCOS diagnosed using NIH criteria but weaker associations to the self-reported PCOS cases.

For their follow up analyses, the researchers looked at potential PCOS overlap with other conditions, while digging into the subsets of variants suspected of contributing to specific PCOS symptoms.

"[T]he genetic underpinnings of PCOS implicate neuroendocrine, metabolic, and reproductive pathways in the pathogenesis of disease," the authors wrote. "Although specific phenotype stratified analyses are needed, genetic findings were consistent across the diagnostic criteria for all but one susceptibility locus, suggesting a common genetic architecture underlying the different phenotypes."

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