Identifying susceptibility genes for primary ovarian insufficiency on the high-risk genetic background of a fragile X premutation

To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI). Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model. Participants were recruited from academic and clinical settings. 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. Clinical information and a DNA sample were collected for whole genome sequencing. 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. 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. 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. Identificación de genes de susceptibilidad para la insuficiencia ovárica prematura en un trasfondo genético de alto riesgo por premutación del X-frágil. Identificar genes modificadores que expliquen el riego de insuficiencia ovárica primaria asociada al X-frágil (FXPOI). Estudio de asociación de casos y controles basado en genes, seguido de un cribado funcional de genes altamente calificados, utilizando un modelo de Drosophila. Las participantes se reclutaron de entornos académicos y clínicos. Mujeres con una premutación (PM) que tuvieron un FXPOI a los 35 o menos años (n=63) y mujeres con una PM que tuvieron la menopausia a los 50 o más años, y de las que había información clínica y una muestra de ácido desoxirribonucleico para secuenciación del genoma completo. El cribado funcional se basó en líneas TRiP de Drosophila. Se recopiló la información clínica y una