Researchers identified rare genetic variants in the DENND1A gene that may contribute to the distinctive hormonal traits of polycystic ovary syndrome (PCOS), according to study results published in The Journal of Clinical Endocrinology & Metabolism.

PCOS is a complex, heritable genetic disorder, and next-generation sequencing approaches have identified rare variants that may play an important role in the disease pathogenesis. In this study, the researchers conducted family-based association analyses using whole-genome sequencing data to assess the potential contribution of rare genetic variants to PCOS pathogenesis.

The study enrolled 261 participants aged 14 to 63 years from 62 families with PCOS. All participants were in good health and had both ovaries and a uterus. The investigators tested for associations between genetic variants and PCOS diagnosis, as well as for associations with its quantitative reproductive and metabolic phenotypes, including levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

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The researchers found 32 rare variants (2 coding, 30 noncoding) in the DENND1A gene that collectively were associated with quantitative trait levels. Most of these variants were predicted to alter RNA binding protein, whereas 9 variants had a potential effect on transcription factor binding motifs. Half the families with PCOS in this study carried ≥1 of these rare DENND1A variants.

Women with ≥1 of these DENND1A variants had significantly higher LH:FSH ratios compared with women without these variants. A higher LH:FSH ratio was also evident in women without PCOS with one of these variants in DENND1A compared with unaffected women without these variants.

“[B]y applying family-based sequence kernel association tests on filtered whole-genome variant call data from a cohort of [families with PCOS], we were able to identify rare variants in the DENND1A gene that were associated with quantitative hormonal traits of PCOS,” concluded the researchers.

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Dapas M, Sisk R, Legro RS, Urbanek M, Dunaif A, Hayes MG. Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A in polycystic ovary syndrome [published online April 30, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2018-02496