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.