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Causal and Candidate Gene Variants in a Large Cohort of Women With Primary Ovarian Insufficiency

Year: 2021
Type: article
Study design: Observational Study
Abstract: CONTEXT: A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI). OBJECTIVE: We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI. DESIGN: The study was an observational study. SETTING: Subjects were recruited at academic institutions. PATIENTS: Subjects from Boston (n = 98), the National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), Italy (n = 43), and France (n = 32) were diagnosed with POI (amenorrhea with an elevated follicle-stimulating hormone level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). INTERVENTION: We performed whole exome sequencing (WES), and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model. MAIN OUTCOME: Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified. RESULTS: Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1, and BOD1L1). CONCLUSIONS: Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.
DOI: 10.1210/clinem/dgab775
Authors: B Gorsi, EJ Hernandez, B Moore, M Moriwaki, CY Chow, E Coelho, E Taylor, C Lu, A Walker, P Touraine, LM Nelson, AR Cooper, ER Mardis, A Rajkovic, M Yandell, CK Welt
Institutions: University of Utah, Sorbonne Université, Pitié-Salpêtrière Hospital, Saint Louis Art Museum, Nationwide Children's Hospital, The Ohio State University, University of California, San Francisco, University of California San Francisco Medical Center
Language: English
Subfield: Genetics
Open Access status: green
Awards: Translational Control in Oogenesis and Embryogenesis, G3905220926, Utah Center for Clinical and Translational Science, The Genetics of Primary Ovarian Insufficiency, Investigating the impact of genetic variation on the ER stress response, protein folding, and disease, Comorbid Disease in Women with Primary Ovarian Insufficiency
OpenAlex ID: W3208293348
FWCI: 2.763
Cites: 192
Cited by: 37
Related to: 10