Rare Variation in LMNA Underlies Polycystic Ovary Syndrome Pathogenesis in 2 Independent Cohorts.

Context: Polycystic ovary syndrome (PCOS) is a common, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive age women. Variants in LMNA cause partial lipodystrophy, a syndrome with overlapping features to PCOS.

Objective: We tested the hypothesis that rare variation in LMNA contributes to PCOS pathogenesis and selects a lipodystrophy-like subtype of PCOS.

Methods: We sequenced LMNA by targeted sequencing a Discovery cohort of 811 PCOS patients and 164 healthy controls. We then analyzed LMNA from whole-exome sequencing of a Replication cohort of 718 PCOS patients and 281 healthy controls. We evaluated variation in the LMNA gene and hormone and lipid profiles of participants.

Results: In the Discovery cohort, we identified 8 missense variants in 15/811 cases, and 1 variant in 1/172 reproductively healthy controls. There is strong evidence for association between the variants and PCOS compared to gnomAD non-Finnish European population controls (χ2 = 17, P = 3.7 × 10-5, OR = 2.9). In the Replication cohort, we identified 11 unique variants in 15/718 cases, and 1 variant in 281 reproductively healthy controls. Again, there is strong evidence for association with population controls (χ2 = 30.5, P = 3.4 × 10-8, OR = 4.0). In both the Discovery and Replication cohorts, variants in LMNA identify women with PCOS with high triglycerides and extreme insulin resistance.

Conclusion: Rare missense variation in LMNA is reproducibly associated with PCOS and identifies some individuals with lipodystrophy-like features. The overlap between this PCOS phenotype and genetic partial lipodystrophy syndromes warrants further investigation into additional lipodystrophy genes and their potential in PCOS etiology.