1. Identifying susceptibility genes for primary ovarian insufficiency on the high-risk genetic background of a fragile X premutation
- Author
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Krista Charen, J. Christopher Rounds, Maureen A. Leehey, L. Rodriguez-Revenga, Lisa Shubeck, Heather S. Hipp, James N. Macpherson, Michael P. Epstein, Montserrat Milà, H. Richard Johnston, Anna Murray, Michael E. Zwick, Stephanie L. Sherman, Deborah A. Hall, Emily G. Allen, Jessica B. Spencer, Peng Jin, Elizabeth Berry-Kravis, Ying Liu, Dave J. Cutler, Cristina E. Trevino, Corrine K. Welt, and Stephen T. Warren
- Subjects
Adult ,0301 basic medicine ,Fragile X-associated disorders ,Fragile x ,Age at menopause ,Primary ovarian insufficiency ,Susceptibility gene ,Deoxyribonucleic acid sample ,Primary Ovarian Insufficiency ,Bioinformatics ,Risk Assessment ,Article ,Animals, Genetically Modified ,Fragile X Mental Retardation Protein ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Animals ,Humans ,Medicine ,Genetic Predisposition to Disease ,Gene ,FXPOI ,Whole genome sequencing ,030219 obstetrics & reproductive medicine ,SUMO1 ,business.industry ,Ovary ,Age Factors ,Obstetrics and Gynecology ,Middle Aged ,medicine.disease ,Menopause ,Drosophila melanogaster ,Fertility ,Phenotype ,030104 developmental biology ,Reproductive Medicine ,Case-Control Studies ,Mutation ,Female ,KRR1 ,business ,Genetic Background ,Genome-Wide Association Study - Abstract
Objective To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI). Design Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model. Setting Participants were recruited from academic and clinical settings. Patient(s) Women with a premutation (PM) who experienced FXPOI at the age of 35 years or younger (n = 63) and women with a PM who experienced menopause at the age of 50 years or older (n = 51) provided clinical information and a deoxyribonucleic acid sample for whole genome sequencing. The functional screen was on the basis of Drosophila TRiP lines. Intervention(s) Clinical information and a DNA sample were collected for whole genome sequencing. Main Outcome Measures A polygenic risk score derived from common variants associated with natural age at menopause was calculated and associated with the risk of FXPOI. Genes associated with the risk of FXPOI were identified on the basis of the P-value from gene-based association test and an altered level of fecundity when knocked down in the Drosophila PM model. Results The polygenic risk score on the basis of common variants associated with natural age at menopause explained approximately 8% of the variance in the risk of FXPOI. Further, SUMO1 and KRR1 were identified as possible modifying genes associated with the risk of FXPOI on the basis of an untargeted gene analysis of rare variants. Conclusions In addition to the large genetic effect of a PM on ovarian function, the additive effects of common variants associated with natural age at menopause and the effect of rare modifying variants appear to play a role in FXPOI risk.
- Published
- 2021