Rare Variation in LMNA Underlies Polycystic Ovary Syndrome Pathogenesis in 2 Independent Cohorts
Authors' 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.
Study context
- Population
- Women with polycystic ovary syndrome (PCOS) and healthy controls2 cohorts
- Comparison
- PCOS cases vs healthy controls and gnomAD non-Finnish European population controls
- PCOS (Discovery)n = 811
- Healthy controls (Discovery)n = 164reference
- PCOS (Replication)n = 718
- Healthy controls (Replication)n = 281reference
- Outcome
- Association of rare LMNA variation with PCOS
Methodological details2 independent cohorts, targeted sequencing (Discovery), whole-exome sequencing (Replication)
- 2 independent cohorts
- Targeted sequencing (Discovery)
- Whole-exome sequencing (Replication)
Main finding
As reported in the abstract
Rare LMNA missense variants in PCOS cases vs controls
| Group | Value | Missense variants | Variants | Unique variants |
|---|---|---|---|---|
| PCOS (Discovery) | 15/811 | 8 | ||
| Healthy controls (Discovery) | 1/172 | 1 | ||
| PCOS (Replication) | 15/718 | 11 | ||
| Healthy controls (Replication) | 1 |
Value
PCOS (Discovery)15/811
Healthy controls (Discovery)1/172
PCOS (Replication)15/718
Healthy controls (Replication)— not stated in the abstract
Missense variants
PCOS (Discovery)8
Healthy controls (Discovery)— not stated in the abstract
PCOS (Replication)— not stated in the abstract
Healthy controls (Replication)— not stated in the abstract
Variants
PCOS (Discovery)— not stated in the abstract
Healthy controls (Discovery)1
PCOS (Replication)— not stated in the abstract
Healthy controls (Replication)1
Unique variants
PCOS (Discovery)— not stated in the abstract
Healthy controls (Discovery)— not stated in the abstract
PCOS (Replication)11
Healthy controls (Replication)— not stated in the abstract
- Discovery cohort: association of LMNA variants with PCOS vs gnomAD non-Finnish European population controls
- χ2 = 17, P = 3.7 × 10-5, OR = 2.9
- Replication cohort: association with population controls
- χ2 = 30.5, P = 3.4 × 10-8, OR = 4.0
Observational data: associations, not effects.
Further findings
Phenotype of LMNA variant carriers
- In both cohorts, LMNA variants identify women with PCOS with high TG and extreme insulin resistance
Original publication
Rare Variation in LMNA Underlies Polycystic Ovary Syndrome Pathogenesis in 2 Independent Cohorts. J Clin Endocrinol Metab. Published 1 November 2024. doi:10.
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