{"doi":"10.1210/clinem/dgae761","title":"Rare Variation in <i>LMNA</i> Underlies Polycystic Ovary Syndrome Pathogenesis in 2 Independent Cohorts","abstract":"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.","journal":"The Journal of Clinical Endocrinology & Metabolism","year":2024,"id":456722,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1281582,"name":"C. Richard Parker","orcid":"0000-0001-6257-2272","position":1,"is_corresponding":false},{"id":515792,"name":"Lidija K. Gorsic","orcid":null,"position":2,"is_corresponding":false},{"id":21961,"name":"M. Geoffrey Hayes","orcid":"0000-0002-4617-3981","position":3,"is_corresponding":false},{"id":341544,"name":"Allen R. Kunselman","orcid":"0000-0001-8485-2953","position":4,"is_corresponding":false},{"id":235217,"name":"Richard S. Legro","orcid":"0000-0001-9927-7584","position":5,"is_corresponding":false},{"id":343992,"name":"Corrine K. Welt","orcid":"0000-0002-8219-5504","position":6,"is_corresponding":false},{"id":235218,"name":"Margrit Urbanek","orcid":"0000-0001-6994-7110","position":7,"is_corresponding":false},{"id":658796,"name":"Rosemary Bauer","orcid":"0000-0002-0350-1666","position":0,"is_corresponding":true}],"reference_count":119,"raw_metadata":null,"created_at":"2026-07-19T02:03:32.516678Z","pmid":"39484826","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}